Follow-Up of Restorative Proctocolectomy: Clinical Experience of a Specialised Pouch Clinic

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Introduction

Most patients with ulcerative colitis (UC) can be managed medically. However, about 20–30% will eventually require elective or emergency surgery.

Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) has become firmly established as the operation preferred by most surgeons and patients because of the advantages of complete removal of the diseased colorectal mucosa, preservation of continence with relatively normal defecation and avoidance of a permanent ileostomy [1–5]. This chapter describes our experience with the follow-up of UC patients undergoing IPAA, focuses on potential short-term and long-term complications and pres- ents our comprehensive, multidisciplinary approach.

Indications

Surgical treatment for UC patients is usually indicated due to one of three causes: (1) failure of medical therapy or dependence on therapy, mainly corticosteroids, with severe side effects; (2) prevention when dysplasia is diagnosed and treatment of colorectal cancer (CRC); and (3) a severe acute complication of UC, such as toxic megacolon or massive hemorrhage.

The appropriate timing of elective surgery is deter- mined by collaborative assessment of the gastroenterologist and the surgeon and should be tailored to each patient according to the specific clinical setup.

Ulcerative Colitis Refractory to Medical Therapy

Patients with chronically active UC and those with frequently recurrent disease, despite appropriate medical therapy, are candidates for elective surgery [6, 7]. These patients usually suffer from frequent bloody diarrhoea and abdominal cramps. They may also suffer from anaemia, mild-to-moderate chronic malnutrition and hypoproteinaemia. In addition to signs and symptoms, patients experience chronic

disability and diminished physical, emotional and social quality of life [8]. In the pediatric population, growth impairment is an important indication for IPAA, often leading to significant growth accelera- tion [9]. Infrequently, surgery is also indicated for intractable and debilitating extraintestinal manifestations (EIM) of UC, such as peripheral arthritis, pyoderma gangrenosum, ocular, haematological and vascular manifestations [10]. Despite their well- known side effects, corticosteroids are still widely used for the treatment of UC. In contrast to their beneficial effect in remission induction of an acute flair [11], their use as maintenance is not effective and is associated with severe side effects, some of which are irreversible [12, 13]. Thus, prolonged treatment with systemic corticosteroids should be avoided [14]. Although it is widely agreed that steroid-dependent disease is a clear indication for surgery, there is no strict definition of steroid dependency or an agreed-upon time limit for this therapy. Thus, collaboration and mutual discussions between gastroenterologist, surgeon and patient are essential to determine the appropriate timing for surgery in these cases.

Cytotoxic agents, such as 6-mercaptopurine and azathioprine, are widely used as steroid-sparing agents to control chronic symptoms and maintain remission [15, 16]. Although severe side effects of these drugs are less frequent, they are not risk free;

thus, side effects that preclude their use [17] or lack of response to immunosuppressive therapy may also be indications for surgery in UC patients [18].

Prevention and Treatment of Colorectal Cancer

Long-standing UC is a predisposing factor for development of CRC, as it is clear that cancer is more common in these patients compared to the age-matched general population [19, 20]. The actual prevalence varies in different series [21, 22], and the cumulative probability of developing CRC is 18% after 30 years of disease [23]. In addition to disease duration, dis-

Follow-Up of Restorative Proctocolectomy:

Clinical Experience of a Specialised Pouch Clinic

Hagit Tulchinsky, Iris Dotan, Zamir Halpern, Micha Rabau

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ease extent also correlates with an increased risk of cancer, with the risk being most significant in patients with pancolitis [24]. Another two independ- ent risk factors for CRC in UC patients are family history of CRC [25, 26] and primary sclerosing cholangitis (PSC) [27]. Common practice is to start an(PSC) annual or biannual surveillance colonoscopy, as cancer risk increases over that of the background population. This would usually mean 8–12 years after disease onset for patients with pancolitis or upon diagnosis of concomitant PSC. Confirmed precancerous lesions, such as high-grade dysplasia or dysplasia- associated lesion or mass (DALM) would be an indication for proctocolectomy [28, 29]. In most inflammatory bowel disease (IBD) referral centres, confirmed low-grade dysplasia would also be an indication for surgery [30] although strict follow-up is an optional alternative suggested by others [31].

Diagnosis of already existing colorectal carcinoma is an obvious indication for surgery, and if curable intent is possible, surgery should include removal of the entire colon and rectum, as the presence of one proven cancer puts the patient in a significant risk of having a synchronous or developing a metachronous carcinoma [32]. In patients with good operative risk and adequate anal sphincter mechanism, IPAA is the most suitable procedure for cancer prophylaxis as well as preservation of reasonable quality of life.

Short- and Long-Term Complications of IPAA

While restoring the natural route of defecation, usually with improved quality of life and good long-term functional outcomes [33–35], IPAA may also be associated with various complications that, depending on duration of follow-up and diagnostic criteria, may occur in 10–60% of patients [36]. Complications may appear early or late and may be surgical or medical.

Of note, clear distinction between purely medical or surgical complications seems to be artificial. Several complications are a combination of the two and thus require the surgeon’s, as well as the gastroenterologist’s, insight. Pouch dysfunction is the most frequent end result of a range of complications.

Amongst the various complications reported that lead to pouch dysfunction are mechanical causes, functional disorders, pelvic sepsis and pouch inflammation. Systemic complications include new onset or persistent EIM as well as haematological, nutritional and electrolyte disturbances. The most dreaded con- dition, despite its rarity, is pouch and rectal-stump dysplasia or cancer [37]. However, the most common and frustrating long-term consequence is pouch inflammation [38]. A careful case selection is essential for a good outcome. Poor functional result or

pouch failure are usually the end result of major unmanageable complications [39].

The Concept of a Comprehensive Pouch Clinic

At present, colorectal surgeons usually conduct the follow-up of patients after IPAA although this dis- tinct patient population often requires medical as well as surgical follow-up, as shall be discussed in the following sections. With a primary goal of improving quality of patient care, we have established a multidisciplinary pouch clinic comprised of a colorectal surgeon and an IBD-oriented gastroenterologist.

Patients are interviewed, examined and treated by both surgeon and gastroenterologist simultaneously at their outpatient clinic visit. Laboratory blood tests, pouch endoscopy and biopsies are done routinely 1 year post-IPAA or at the beginning of follow-up at the clinic and yearly thereafter or upon demand. Our experience, based on the follow-up of 125 UC patients after IPAA in such an approach, is integrat- ed in the following sections.

Complications of IPAA that May End in Pouch Dysfunction

“Normal” or acceptable pouch function is hard to define since it varies from one person to another and from day to day in the same individual. Most patients with pouch dysfunction have an increased stool frequency, which is often associated with small amounts of stools. Incontinence may be the predominant symptom or may occur in association with frequency and urgency. The causes of pouch dysfunction can be divided into four categories: septic complications, mechanical or surgical complications, functional disorders and inflammation, mainly pouchitis and, to a lesser, extent cuffitis. Diagnosis is based on accurate history and physical examination combined with one or more auxiliary assessments, such as evaluation under anaesthesia, pouch endoscopy, anorectal physiology tests and various imaging techniques. The major conditions that may result in pouch dysfunction are described below.

Pelvic Sepsis

Pelvic abscess is usually the result of a leak or dis- ruption of the ileoanal anastomosis, leak from the pouch suture line, or an infected haematoma. The prevalence of postoperative pelvic sepsis varies between 5% and 25% [40–42], this wide range being partially attributable to the lack of a standard defini-

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tion. Symptoms and signs include fever, anal pain, tenesmus, purulent discharge, bleeding from the anus and leukocytosis. Diagnosis may be established by examination under anaesthesia alone or in combination with imaging studies such as contrast pouchography, computerised tomography (CT) and magnetic resonance imaging (MRI). Pelvic sepsis may be clinically evident in the immediate postoperative period, after ileostomy closure or after a long follow-up period. Late sepsis may be expressed as pouch dysfunction with frequency, urgency, incontinence or pouch-related fistula without systemic signs of sepsis. The treatment is modified according to the severity of sepsis. Some patients can be managed successfully with antibiotic treatment while others will need operative or CT-guided percutaneous drainage.

It is clear that severe pelvic sepsis with extensive anastomotic breakdown results in a high failure rate despite salvage attempts [43].

Pouch Fistulae

Fistula originating from the ileoanal anastomosis or the pouch itself is a serious complication. The incidence varies between 5% and 17% and depends on the accuracy and duration of follow-up [44, 45]. It often requires further surgery and may alter ultimate functional outcome and lead to pouch excision. Fis- tulae may occur to the perineum, vagina, bladder or abdominal wall skin. Aetiologic factors include anastomotic dehiscence, pelvic sepsis, surgical experience, localised ischaemia, entrapment of the posteri- or vaginal wall in the stapling device and Crohn’s disease. Pelvic sepsis is probably the major predisposing factor. Patients may be asymptomatic, some may have only minor symptoms whereas others may have disabling symptoms. Symptoms consist of purulent discharge and flatus or stool passing through the vagina, perineum or abdominal wall. Diagnosis is based on history and physical examination and may be confirmed by examination under anaesthesia.

Other diagnostic modalities may be used to assess the tract, including endoanal ultrasound, pouchography, fistulography, CT and MRI. Initial management includes local procedures to drain the sepsis, and Crohn’s disease must be excluded [46]. Most pouch–perineal fistulae originate from the ileoanal anastomosis. When superficial, these fistulae can be managed by fistulotomy. If the fistula is transsphinc- teric, it can be managed by staged fistulotomy using a seton or by a pouch advancement procedure. At our clinic, nine patients (7.6%) had a perineal fistula at a mean follow-up of 57 months. All were treated by staged fistulotomy. In none of these patients was the diagnosis changed to Crohn’s disease.

Pouch-vaginal fistula (PVF) occurs in 6.3% (range 3–16%) of women who undergo IPAA [47]. Symptoms are discharge of flatus and faeces through the vagina.

PVF are classified in relation to the ileoanal anastomosis (above, below or at the anastomosis), and management is challenging. Diversion may be considered in order to alleviate symptoms and control sepsis.

Several surgical procedures have been described for the repair of PVF with variable success rates [48, 49].

Local procedures, such as transvaginal repair or endoanal ileal advancement flap, are appropriate for low fistulae whereas combined abdominoperineal procedures should be considered for high fistulae.

Overall, more than 50% of patients maintain a func- tioning pouch without fistula recurrence, and about 20% require pouch excision [50]. Among the pouch clinic patients, four developed a PVF: two occurred early after a one-stage IPAA and were successfully treated by loop ileostomy. The other two patients had very mild symptoms and refused surgery.

Ileoanal Anastomotic Stricture

Stenosis of the ileoanal anastomosis is the most common perineal complication after IPAA. The precise definition is unclear and contributes to the wide range of incidence reported in the literature. Narrow- ing, which requires at least one dilatation under anaesthesia, has been reported in 4–40% of cases [51, 52]. The main causative factors are pelvic sepsis with subsequent fibrosis and tension on the anastomosis leading to ischaemia. Patients most frequently present with symptoms of straining, increased number of bowel movements per day, watery stool, urgency of defecation, a feeling of incomplete evacuation and abdominal or anal pain. Rectal examination and contrast pouchography if needed confirm the diagnosis.

Anastomotic strictures can be noted before or after ileostomy closure. Most strictures, especially those found during an outpatient clinic visit before ileostomy closure, are annular and web like due to lateral adhesions across the anastomosis and can be treated successfully with a simple digital anal dilatation.

Severe strictures usually require repeat dilatations. If a stricture persists in spite of repeated dilatations, surgery is required. Despite all salvage attempts, up to 15% of patients with severe anastomotic stricture will eventually come to pouch excision and permanent ileostomy [53].

Pouchitis

Pouchitis, defined as nonspecific inflammation of the ileal pouch, is the most common long-term compli-

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cation of IPAA in UC patients [54]. Aetiology is poor- ly understood, and several mechanisms have been suggested, such as genetic susceptibility, immune alterations, faecal stasis resulting in bacterial over- growth, lack of mucosal nutrients, ischaemia and missed diagnosis of Crohn’s disease, none of which have been proved. Pouchitis may be a form of IBD that recurs in the pouch or a novel third form of IBD.

It tends to occur in equal frequency irrespective of the pouch configuration. A number of factors have been studied as potential predictors for the development of pouchitis. A positive association was found between the presence of EIM and PSC and the risk of developing pouchitis [55, 56]. Smoking appears to protect from developing pouchitis [57]. Data regard- ing other predictive factors are more controversial and include previous course of extensive colonic disease, backwash ileitis and serum perinuclear anti- neutrophil cytoplasmic antibody (pANCA) staining pattern [58]. The true incidence of pouchitis in patients operated for UC is difficult to determine as it depends on diagnostic criteria used to define the syndrome, accuracy and intensity of evaluation as well as length and method of follow-up. Reported incidence varies between 5% and 59% [59–61]. Diagnosis should be based on clinical, endoscopic and histologic criteria [62]. To address this issue, a pouchitis disease activity index (PDAI) was developed taking into account clinical symptoms, endoscopic findings and histological changes, with pouchitis defined as a score greater than or equal to 7 points [63]. The use of clinical symptoms alone leads to overdiagnosis of pouchitis and unnecessary antibiotic use [62]. Pou- chitis may appear late in the postoperative course, and its incidence increases with increased length of follow-up [64].

Clinically, patients present with a marked increase of stool frequency, usually watery but occasionally bloody, urgency and incontinence. Abdominal pain and pelvic discomfort, fever, fatigue, anorexia and malaise are often present. Pouchitis is a heteroge- neous disease and can be classified depending on the activity (remission, mild to moderate or severe) and pattern (acute, acute relapsing and chronic persistent). It is usually well controlled with medical therapy and a variety of agents have been used. For the majority of patients, 10–14 days of antibiotic treatment will rapidly control symptoms [65]. Metronida- zole is probably the most commonly used first-line agent and has been shown to be effective for active chronic pouchitis in a meta-analysis [66]. However, long-term use of metronidazole may be hazardous and cause peripheral neuropathy. Ciprofloxacin has been widely used as an alternative or in combination with metronidazole [67].

Relapse is common. About 60% of patients who

experience one episode of acute pouchitis will develop recurrent attacks [68]. In patients with chronic pouchitis who respond to antibiotic treatment and are in remission, the use of probiotics seems to be effective in the prevention of further episodes.

Gionchetti et al. [69] in a double blind, placebo-controlled trial found that oral administration of a mix- ture of probiotic bacterial strains (VSL3) was effective in secondary prevention of pouchitis. In total, about 4.5–21.5% of UC patients develop chronic pouchitis, which is defined as symptoms that persistent for more than 3 months or chronic antibiotic treatment [59, 70]. Chronic pouchitis may eventually lead to persistent use of anti-inflammatory agents, corticosteroids or immunosuppressive therapy [71]. A recent study found that patients who had suffered from chronic pouchitis had poorer functional results and general health perception when compared with patients with no or acute pouchitis [72]. About 1% of the patients develop chronic persistent pouchitis refractory to any medical treatment. In these patients, pouch excision is thus the only alternative since no other surgical approach has proved to alleviate symptoms and prevent recurrent pouchitis [60].

In our group of patients, the cumulative risk of developing at least one episode of pouchitis (that is, PDAI艌7) was 50%. Of the patients who developed pouchitis, 28% had a single acute episode that responded to antibiotics, 45% had recurrent acute attacks and 27% had chronic pouchitis that required long-term maintenance antibiotic therapy. Patients with pouchitis were followed for a statistically significantly longer period of time compared with patients without pouchitis. This finding supports the observa- tion that the incidence of pouchitis tends to increase with time. Thus, we recommend that patients be followed up on a regular basis after the operation.

Cuffitis

A stapled ileoanal anastomosis without mucosecto- my is done routinely at the level of the anorectal junction; hence, a 1- to 2-cm strip of rectal columnar cuff is retained. Some degree of persistent inflammation of the rectal cuff is common. This may be severe enough to cause local symptoms of bleeding, burning and urgency in up to 15% of patients [73]. There may be disordered evacuation with frequency. Diagnosis, as with pouchitis, is based on clinical symptoms, endoscopy and histology taken from the rectal-cuff mucosa. In some patients, cuffitis coexists with pouchitis. Treatment consists of topical corticosteroids or 5-aminosalicylate. A few patients may need further systemic treatment or a salvage surgery [74]. In

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our group of patients, three (3%) were diagnosed with cuffitis. All were treated with corticosteroids or 5-aminosalicylate enemas with good response; no one needed a salvage operation.

Irritable Pouch Syndrome (IPS)

IPS is a functional disorder diagnosed in symptomatic patients who suffer mainly from increased bowel frequency, urgency and abdominal pain without endoscopic or histologic evidence of rectal cuff or pouch inflammation [75]. Clinical features overlap with those of pouchitis and resemble those of irritable bowel syndrome. The aetiology is unclear, and is probably multifactorial in nature. Brain–gut factors may play a role in the pathophysiology of IPS. It is currently a diagnosis of exclusion. A recent study by Shen et al. [76] reported that patients with IPS have significantly poorer quality-of-life scores than patients with normal pouches. Treatment is empiric and symptom oriented. Some authors had reported that dietary modifications, antidiarrhoeal medica- tions (e.g. loperamide) or tricyclic antidepressants might be effective in treating these patients [75]. In our series, the incidence of IPS where patients had symptoms but pouch endoscopy and biopsies did not demonstrate a significant pathology (thus PDAI was

<7) was 5.1%.

Small-Bowel Obstruction

Small-bowel obstruction is a common complication after major abdominal surgery. After IPAA, it may occur before ileostomy closure; however, it is more common after closure. The cumulative probability of developing small-bowel obstruction increases with longer duration of follow-up. The risk varies between 14% and 27% at 5 years after ileostomy closure whereas at 10 years, it increases to 31% [77]. While most patients may be treated conservatively, up to 17% of patients after IPAA require laparotomy with adhesiolysis or small-bowel resection due to this complication [78].

Nonsurgical Complications of IPAA

In contrast to IPAA complications that may result in pouch dysfunction or small-bowel obstruction, there are various complications that usually do not end in pouch dysfunction or excision. However, they may produce various signs and symptoms that interfere with the patients’ health and quality of life and may require investigation, follow-up and treatment by

both surgeon and gastroenterologist. Some of these conditions are related to the defunctionalised stage, i.e. the ileostomy, which are not discussed herein.

Amongst the complications that may occur in the long-term follow-up of these patients, some merit specific attention.

Vitamin Deficiency

Patients after IPAA may develop vitamin B12 deficiency that often requires the exogenous addition of this vitamin; the mechanism is unknown [79]. A possible explanation for this complication is change in bacterial flora in the neoterminal ileum and pouch.

Iron-Deficiency Anaemia

Chronic pouchitis was reported as a risk factor for the development of iron-deficiency anaemia [79, 80].

Iron deficiency occurred in 10.4% of patients after IPAA. Massive, overt bleeding is a rare complication of patients after IPAA. Iron-deficiency anaemia was found in 22% of our patients. They were treated with oral or intravenous iron supplements. There was no correlation between pouch inflammation and iron- deficiency anemia. In the follow up of pouch patients, including those with a good pouch function, we recommend on periodic laboratory evaluation that should include a complete blood count, elec- trolytes and renal function tests, liver function tests and vitamin B12 and folic acid determinations.

New Onset or Persistent Extraintestinal Manifestations (EIM)

Cutaneous, peripheral articular, ocular, haematologic and vascular EIM are linked to exacerbation of UC, so by excision of the entire diseased colorectal mucosa, EIM amelioration is anticipated. Nevertheless, these manifestations may persist or be aggravated in some patients whereas others may even develop EIM for the first time after surgery, with or without pouchitis [81–83]. It was shown that 31% of colitic patients post-IPAA had joint symptoms. In two thirds, joint involvement was polyarticular and the symptoms were intermittent. Forty percent reported that their symptoms interfered with daily life. No relationship was found between pouchitis and the presence of joint symptoms [81]. Goudet et al. [82] assessed the clinical evolution of pre-IPAA EIM after surgery in a retrospective study. As expected, ocular manifestations and PSC were unaffected. Arthralgia, erythema nodosum and thromboembolic events benefited the most from IPAA and tended to improve or disappear.

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Dysplasia

Dysplasia in the ileoanal pouch or the rectal cuff is a very rare complication after IPAA [84, 85]. Reported potential risk factors are cancer or dysplasia in the colectomy specimen, chronic pouchitis, and the time after IPAA [86]. The risk of developing dysplasia or cancer after IPAA had promoted us to perform annual surveillance by pouch endoscopy with random mucosal sampling from the pouch and the rectal cuff.

Of note, in our pouch clinic, out of 105 patients screened of which 17% had diagnosed dysplasia or cancer in the colectomy specimen, none had cancer or dysplasia in the pouch or rectal cuff after a mean follow-up of 57 months (range 1–258) post IPAA.

Perspective

IBD patients after IPAA may well present with both medical and surgical complications. A comprehensive pouch clinic is a novel approach in their management. It seems to be more efficient and beneficial to patients as well as provide an ideal milieu for surgical and gastroenterological teamwork. We believe that it should be applied to all major centres treating pouch patients.

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