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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1105_Библиотеки_им_академика_М_И_Перельмана
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Long-term Complications after
Surgical Treatment of Ulcerative Colitis
Gilberto Poggioli, Lorenzo Gentilini, Maurizio Coscia,
and Federica Ugolini
12.1 Introduction
Patients undergoing restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) could develop a wide range of longterm postoperative complications during their lifetime. These complications
could negatively inuence pouch function with a signicant impact on the functional outcomes and quality of life of patients with IPAA. The main complica-
tions include: perianal stulas (pouch-anal and pouch-vaginal stulas), acute
and chronic pouchitis, pre-pouch ileitis, cuftis, anastomotic stenosis, Crohn’s
disease (CD) of the pouch, irritable pouch syndrome and mega-pouch. All these
conditions are still a therapeutic challenge and require both medical and surgical treatment. Moreover, an unhealed complication could lead to pouch failure;
therefore, careful treatment is required.
All complications are treated below, with the exception of pouch stulas
which will be treated in chapter 13.
12
12.2 Pouchitis
Pouchitis is the most frequent long-term complication of IPAA represented by
non-specic inammation of the ileal reservoir, resulting in variable clinical
symptoms. Its occurrence is related to the duration of the follow-up and increases
over time ranging from 5% to 50%; it occurs in up to 50% of patients 10 years
after restorative proctocolectomy [1–3].
L. Gentilini (*)
General Surgery Unit, Department of Digestive Diseases, S. Orsola-Malpighi Hospital
Bologna, Italy
e-mail: lorenzo.gentilini@aosp.bo.it
G. Poggioli (Ed), Ulcerative Colitis,
Updates in Surgery
DOI: 10.1007/978-88-470-3977-3_12, © Springer-Verlag Italia 2019
173
174
G. Poggioli et al.
The incidence of this inammatory complication is higher in patients treated with
IPAA for UC than in patients with familial adenomatous polyposis; the reasons for
the higher frequency of pouchitis in UC patients are still unknown.
In patients with familial adenomatous polyposis the cumulative incidence of
pouchitis is much lower, ranging from 0% to 10%. Moreover, whether pouchitis
develops more commonly within the initial years after IPAA or whether the risk
increases continuously with follow-up remains undened.
The etiology and pathogenesis of pouchitis are not entirely clear, and long-
term management has been difcult. Risk factors, genetic associations, and
serological markers of pouchitis suggest that close interaction between the host
immune response and the pouch microbiota plays a relevant role in the etiology
of this idiopathic inammatory condition [4]. Fecal stasis and/or bacterial
overgrowth in association with an abnormal mucosal immune response to altered
commensal ora (dysbiosis) could lead to inammation of the pouch. Some
cases of pouchitis can be secondary to other conditions, such as infection from
intestinal pathogens (Clostridium difcile, candida or cytomegalovirus) chronic
use of nonsteroidal anti-inammatory drugs (NSAIDs), current autoimmune
disorders (celiac disease) or pouch ischemia.
The main risk factors for idiopathic pouchitis can be divided into genetic
factors, disease related factors, preoperative status and postoperative conditions.
The reported risk factors for pouchitis include genetic polymorphisms of the
IL-1 receptor antagonist, non-carrier status of TNF allele 2
and NOD2/CARD15,
extensive UC or colitis starting beyond the splenic exure, backwash ileitis,
preoperative corticosteroid or cyclosporine use, extraintestinal manifestations
(especially arthropathy), thrombocytosis, being a non-smoker and the regular use
of NSAIDs [5–8]. Similar to irritable bowel syndrome, visceral hypersensitivity
has been described in these patients.
Pouchitis is not a homogenous disease entity; it can be represented by a
wide spectrum of clinical presentations, endoscopic and histologic features,
and disease courses and prognoses. The symptoms related to pouchitis include
increased stool frequency, urgency, abdominal cramping, incontinence, nocturnal
seepage, tenesmus, pelvic discomfort and arthralgia [9]. Rectal bleeding,
fever and weight loss may also occur. The complications of pouchitis include
abscesses, stulas, stenosis of the pouch-anal anastomosis and adenocarcinoma
of the pouch. No correlations have been found between the severity of the
symptoms, and the degree of endoscopic or histologic inammation of the
pouch [10]. These symptoms are not all specic for pouchitis as they can also
be reported by patients with other inammatory or functional disorders of the
pouch, such as cuftis, CD of the pouch and irritable pouch syndrome. For this
reason, a combined assessment of symptoms, and the endoscopic and histologic
features should be carried out in order to diagnose pouchitis.
12 Long-term Complications after Surgical Treatment of Ulcerative Colitis
ba
Fig. 12.1 Pouchitis at endoscopy
175
The main endoscopic ndings compatible with pouchitis are diffuse
erythema, edema, granularity, friability, spontaneous or contact bleeding, loss
of vascular pattern, mucous exudates, hemorrhage, erosions and ulceration
(Fig. 12.1). Endoscopy is also helpful in excluding other complications of the
pouch, such as pre-pouch ileitis, cuftis or CD of the pouch. Biopsies should
be taken during a pouchoscopy to conrm the diagnosis and for surveillance for
dysplasia.
The histologic features of acute inammatory changes include ulceration,
neutrophil inltration and crypt abscess. Chronic histologic changes are villous
blunting, hyperplasia of the crypt cells and an increased number of mononuclear
cells in the lamina propria. The main aims of histological evaluation in clinical
practice are the detection of specic pathogens (such as cytomegalovirus,
candida and C. difcile), identication of ischemia and nding dysplasia.
For the purpose of research and clinical practice, various diagnostic criteria
have been used. The most commonly used score is the “pouchitis disease
activity index” (PDAI) developed at the Mayo Clinic, based on symptoms and
endoscopic assessment with histological evaluation (Table 12.1) [9].
The PDAI provides a useful guide to abnormal ndings and is the most
commonly used instrument. An overall PDAI score is simple to calculate
from three separate categories: clinical symptoms, endoscopic ndings and
histological changes. A total score of 7 or higher is dened as pouchitis.
In 2003, Shen et al. simplied the PDAI score in clinical practice with the
introduction of the modied PDAI (mPDAI). This score is based only on clinical symptoms and endoscopic ndings without data regarding the histologic
features [11].
176
Table 12.1 Pouchitis disease activity index (PDAI) score
Criteria Score
Clinical
Stool frequency
Usual postoperative stool frequency 0
1–2 stools/day > postoperative usual 1
3 or more stools/day > postoperative usual 2
Rectal bleeding
None or rare 0
Present daily 1
Fecal urgency or abdominal cramps
None 0
Occasional 1
Usual 2
Fever (temperature > 37.8° C)
Absent 0
Present 1
Endoscopic inammation
Edema 0 / 1
Granularity 0 / 1
Friability 0 / 1
Loss of vascular pattern 0 / 1
Mucous exudates 0 / 1
Ulceration 0 / 1
Acute histologic inammation
Polymorphic nuclear leukocyte inltration
Mild 1
Moderate crypt abscess 2
Severe crypt abscess 3
Ulceration per low-power eld (mean)
<25% 1
25–50% 2
>50% 3
Pouchitis is de
ned as a PDAI score ≥7.
G. Poggioli et al.
12 Long-term Complications after Surgical Treatment of Ulcerative Colitis
177
The standard PDAI remains an optimal method of diagnosing pouchitis;
however, the mPDAI offers similar sensitivity and specicity in diagnosing
patients with acute or acute-relapsing pouchitis. This approach simplies the
diagnostic criteria of pouchitis, reduces the cost of diagnosis and avoids delay
in determining the histology. In addition, the mPDAI offers better sensitivity
and specicity when compared with symptom assessment alone [11].
Pouchitis can be classied in different ways on the basis of symptoms and
endoscopic ndings. On the basis of disease activity, pouchitis can be divided
into remission (regular pouch function with normal frequency of evacuation) or
active pouchitis (increased number of bowel movements with endoscopic and
histologic features of inammations consistent with pouchitis) [10].
Active pouchitis can also be divided into mild to moderate (increased stool
frequency, urgency and occasional incontinence, usually treated without hospitalization) and severe (which frequently requires hospitalization due to the
high number of bowel movement accompanied by incontinence and dehydration) [11–13].
Depending on the symptom duration, it can also be divided into acute,
recurrent acute or chronic. Acute pouchitis is a single acute episode resolved
following short course of antibiotic treatment. Recurrent acute pouchitis is
characterized by recurrent acute episodes, lasting less than 2 weeks, followed
by normal pouch function. A symptom duration of more than 4 weeks is the
threshold for chronicity [11–13].
Pouchitis can also be classied according to its etiology into idiopathic versus secondary. On the basis of the frequency of clinical episodes, pouchitis can
also be divided into: infrequent (1–2 episodes/year), relapsing (more than 3
episodes/year), and continuous or chronic. Finally, pouchitis may also be classied based on the response to antibiotic therapy in antibiotic-responsive, antibiotic-dependent (patients who need continuous antibiotic treatment to maintain
remission), and antibiotic-refractory (patients not responding to antibiotics and
treated with a wide spread of drugs, from 5-ASA to anti-TNFα) [14].
Chronic antibiotic-refractory pouchitis is one of the leading causes of pouch
failure, resulting in permanent diversion or pouch excision [15]. In all cases
of chronic refractory pouchitis secondary causes of inammation should be
excluded.
The treatment of pouchitis is largely empirical and is based on different
categories of drugs. The rst-line therapy for acute pouchitis is represented
by antibiotics. The most effective agents are metronidazole and ciprooxacin.
Their use for at least two weeks often results in a rapid response [16].
Metronidazole and ciprooxacin have been compared in a small randomized
trial. Both antibiotics signicantly decreased the PDAI score. However, patients
treated with ciprooxacin have a signicantly greater benet as compared with
178
G. Poggioli et al.
metronidazole in terms of the total PDAI, symptom score, and endoscopic
score as well as having fewer adverse events [17]. Budesonide or mesalamine
administration with enemas or suppositories is also effective for inducing
remission.
Approximately 10–15% of patients with acute pouchitis develop chronic
pouchitis, which may be ‘treatment responsive’ or ‘treatment refractory’ to a
single antibiotic therapy. Patients with antibiotic-dependent pouchitis often
require long-term maintenance therapy to keep the disease in remission.
Maintenance agents include probiotics such as VSL#3 and a low dose of
antibiotics [18]. The efficacy of probiotics was proven in 2000 with a doubleblind study comparing probiotics and placebos for the maintenance of acute
relapsing pouchitis after remission which was induced by ciprofloxacin and
rifaximin. In this study, only 15% of the patients using probiotics reported
a relapse of pouchitis within the 9-month follow-up versus 100% of patients
treated with a placebo [19].
In a Cochrane systematic review, VSL#3 was more effective than a placebo
in maintaining remission of chronic pouchitis in patients who achieved
remission with antibiotics [20]. Proposed mechanisms of probiotics, such as
maintenance therapy for pouchitis, include: suppression of resident pathogenic
bacteria, stimulation of mucin glycoprotein by intestinal epithelial cells,
prevention of adhesion of pathogenic strains to epithelial cells, and induction
of host immune responses [21]. The efficacy of probiotics has also been proven
in the prevention of pouchitis within the first year after surgery. A randomized,
double-blind, placebo-controlled study showed a significantly lower incidence
of acute pouchitis in patients treated with VSL#3 when compared with patients
treated with a placebo; moreover, patients taking VSL#3 experienced a
significant improvement in their quality of life [22].
Patients with chronic, refractory pouchitis do not respond to conventional
therapy and often have ongoing symptoms. Combination antibiotic therapy or
oral budesonide may be effective [23–25]. The use of biologics in patients
with chronic, refractory pouchitis is still under debate. A recent systematic
review analyzed their clinical efficacy for the treatment of antibioticresistant pouchitis. The data available regarding Infliximab suggest clinical
effectiveness in treating antibiotic-refractory or fistulizing pouchitis. The data
for adalimumab are much more limited, and sufficient long-term outcomes are
lacking [26]. Recent studies have reported the effectiveness of vedolizumab
for the treatment of both antibiotic and anti-tumor necrosis alpha refractory
pouchitis; however, additional data are required regarding their large-scale use
in clinical practice [27, 28].
Surgical management of pouchitis refractory to medical treatment is limited
to a defunctioning stoma or pouch excision.
12 Long-term Complications after Surgical Treatment of Ulcerative Colitis
179
12.3 Pre-pouch Ileitis
An ileal inammation proximal to the pouch has been described in patients undergoing restorative proctocolectomy for UC, called pre-pouch ileitis. Pre-pouch ileitis
usually extends only a short distance beyond the pre-pouch ileal junction and is
limited to the distal ileal segment; a pan-small bowel inammation is uncommon.
The incidence of this condition ranges from 3% to 14% in the literature [29, 30].
The pathogenesis of pre-pouch ileitis is still unclear. Some authors have
suggested that its presence may indicate CD [31, 32]. For these authors, more
than 45% of patients who developed afferent limb ulcers or stenosis had a delayed
diagnosis of CD while no ulcers were reported in patients with conrmed UC at
follow-up. Conversely, other authors did not nd any association between pre-
pouch ileitis and CD. McLaughlin et al. described pre-pouch ileitis in 34 out of
742 patients treated with restorative proctocolectomies. None of the patients
with pre-pouch ileitis in this study had CD based on histopathological criteria
and none were diagnosed with CD during the subsequent follow-up of a median
period of more than 12 months [29].
Some studies have reported a close association between pouchitis and
pre-pouch ileitis. A study published in 2009 reported pre-pouch ileitis which
occurred only in patients with concurrent pouchitis, suggesting that these
conditions may have a similar cause [29]. Fecal stasis along with subsequent
bacterial overgrowth could be considered the major pathogenesis of both
conditions. According to this pathogenesis, both pouchitis and pre-pouch ileitis
have similar endoscopic, histological and immunological features.
Association with chronic pouchitis has not been conrmed by subsequent
studies. In a study by Bell et al. only half of their patients with pre-pouch ileitis
had concomitant pouchitis [33]. It has also been suggested that inammation
of the pouch or pre-pouch ileal loop could be related to distal structuring
[34]. A distal stenosis could lead to reux of the contents of the pouch which
could induce ileal inammation. In the study by Bell, this association was
not conrmed; only 20% of the patients with pre-pouch ileitis had signicant
stenosis of the ileal pouch-anal anastomosis [33].
Some authors have considered pre-pouch ileitis to be the consequence of
backwash ileitis. Backwash ileitis is a clinical condition occurring in some
patients with UC; it is represented by the extension of the inammatory process
to the terminal portion of the ileum due to reux of the large bowel contents into
the small bowel. Backwash ileitis has been reported in approximately 10% of
total colectomy specimens in patients with ulcerative pancolitis; treatment for
this condition is the same as for UC uncomplicated by blackwash ileitis. This
condition can be asymptomatic or associated with all symptoms of terminal
ileitis. The etiology of pre-pouch ileitis may be similar to that of blackwash
180
G. Poggioli et al.
ileitis. Thus, pre-pouch ileitis may be secondary to reux of the pouch fecal
contents into the pre-pouch ileum. Various studies have identied an association
between the presence of backwash ileitis before restorative proctocolectomy
and the onset of pre-pouch ileitis at follow-up of patients undergoing IPAA [35].
Contrarily, other studies did not nd any association between pre-pouch
ileitis and backwash ileitis [29, 36].
An association between pre-pouch ileitis and the chronic use of NSAIDs
has been suggested in the literature [37, 38]. The chronic use of NSAIDs could
induce injury to the pouch or the pre-pouch ileum, resulting in inammation,
ulcerations and strictures. Non-steroidal anti-inammatory drug-induced
mucosal inammation does not typically respond to pouchitis-targeted antibiotic
therapy and may resolve after the discontinuation of the drugs. However, the
long-term use of NSAIDs can cause persistent ulcers or strictures in the small
pouch, pouch inlet or outlet, or cuff even after drug withdrawal.
Finally, for some authors pouch design could also inuence the onset of prepouch ileitis. The pouch conguration may adversely inuence vascularization or
motility of the neo-terminal ileum conditions which could lead to inammation
of the terminal ileum above the pouch. A higher rate of pre-pouch ileitis has been
reported in patients with W pouches rather than in those with J- or S-pouches [33]
Many patients with pre-pouch ileitis can be asymptomatic; more than 20%
of patients have no symptoms at the time of diagnosis [29]. In these cases, it can
be diagnosed during endoscopies performed for routine follow-up.
Other patients have symptoms related to the ileal inammation; the main
symptoms include increased stool frequency, urgency and bleeding as reported
by more than 40% of patients. These disabling symptoms are similar to pouchitis;
a differential diagnosis should be considered. Patients with stenosis also report
abdominal cramps or obstructive symptoms, such as nausea and vomiting.
Subacute obstruction, abdominal atus or colic, evacuation difculties and weight
loss have been reported by 40%, 33%, 20% and 7% of patients, respectively [33].
More than 50% of patients have poor pouch function; an endoscopic examination of the neo-terminal ileum with biopsies is essential when investigating a
patient with non-specic symptoms, including poor function [29].
All patients with clinical suspicion of pre-pouch ileitis should be investigated.
A water soluble radiological examination should be performed. (Fig. 12.2)
Varying degrees and combinations of ulcerations, thickening of folds,
nodularities, irregularities and strictures are the main radiological ndings
described. The length of the abnormal bowel varied from 1 to 30 cm. The
diagnosis should be conrmed by endoscopic examination. The main endoscopic
features include discrete or segmental small and large ulcers, nodularity, exudate
and/or inammatory pseudopolyps in the afferent limb of the pouch (Fig. 12.3).
Inammation of the ileal segment above the pouch can be associated with
strictures of the ileum. All patients with symptomatic stenosis should be
evaluated with magnetic resonance or computed tomography enterography
.
12 Long-term Complications after Surgical Treatment of Ulcerative Colitis
Fig. 12.2 Pre-pouch ileitis with stenosis
at the inlet of the pouch
Fig. 12.3 Endoscopic nding of
pre-pouch ileitis
181
in order to dene the length of the intestinal stenosis and the presence of
extraintestinal complications, such as abscesses or stulas. These radiological
examinations are very important after the failure of medical therapy in patients
who should undergo surgical procedures (Fig. 12.4).
Patients with pre-pouch ileitis can be treated using different approaches.
Patients without symptoms should be followed with periodic endoscopies
without any specic medical treatment; spontaneous remissions have been
described. In symptomatic cases, medical treatment should be used. Patients
without stenosis should be treated with antibiotics, such as ciprooxacin alone
or in combination with metronidazole. The combination of these antibiotics used
for at least 4 weeks is effective; in selected patients, symptomatic remission
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G. Poggioli et al.
Fig. 12.4 Pre-pouch ileitis with stenosis at the inlet of
the pouch at CT enterography
ba
Fig. 12.5 Resection of the stenotic ileum above the pouch
associated with resolution of the pre-pouch ileitis or a reduction in the length of
distal ileum involved has been reported in more than 80% of cases [29].
In cases of persistent inammation after antibiotic therapy, patients should
be treated with 5-ASA or budesonide orally. In patients resistant to previous
medical approaches, the administration of iniximab can be attempted.
Iniximab has also been shown to be effective in the treatment of extensive pre-
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