Int J Colorect Dis (1998) 13: 256 259

Springer-Verlag 1998

O R I G I N A L A RT I C L E

J. G. Geoghegan E. Carton A. M. OShea

K. Astbury K. Sheahan D. P. ODonoghue
J. M. P. Hyland

Crohns colitis: the fate of the rectum

Accepted: 17 July 1998

Abstract Previous reports suggest that up to 70% of patients undergoing surgery for Crohns disease of the large
bowel do not have gastrointestinal continuity restored and
require a permanent ileostomy. In this study the experience
with patients requiring surgical treatment of large bowel
Crohns disease is reviewed with particular reference to the
management of the rectum. The records of 19 elective and
25 urgent colonic resections performed for large bowel
Crohns disease in 44 patients (16 males, 28 females; mean
age 41 years, range 1776) between 1983 and 1995 were
reviewed. Staged proctectomy was performed in 5 of 12
patients who had colectomy for acute colitis and in one patient who had had an elective colectomy. Permanent ileostomy was required in 72% of patients with acute Crohns
colitis and 84% of patients who had elective surgery for
large bowel Crohns. Over 70% of patients having surgical treatment of Crohns disease of the large bowel required
permanent ileostomy. No cases of cancer developed in patients with retained rectal stumps.

acute or fulminant colitis the rectum is usually left in situ

so that future reanastomosis remains an option, although
this cannot be achieved in 6070% of patients because of
continuing perianal or rectal inflammation [3]. Concerns
have been raised in these patients about an elevated cancer risk in the retained, defunctioned rectum, with some
reports suggesting that risk of malignant change is increased by 18- to 20-fold compared to the general population [5, 6]. This issue must also be taken into consideration in planning elective operations for Crohns proctocolitis. The relative merits of an aggressive approach to the
management of the rectum in patients with Crohns colitis
with early recourse to proctectomy compared with a more
conservative approach which offers some chance of restoring gastrointestinal continuity are still the subject of considerable controversy. In this report we describe the experience in this unit with the surgical management of Crohns
colitis with particular reference to the fate and management of the rectum.

Key words Crohn disease Colonic resections Cancer

Patients and methods
Introduction

More than 70% of patients with Crohns disease require

surgical intervention at some time in the course of their
disease [1, 2]. The majority of these operations are performed for small bowel disease, particularly in the terminal ileum; however, approximately 20% of Crohns patients require surgery for large bowel involvement. Previous reports have suggested that up to 5060% of these patients are unable to retain a functioning rectum in the long
term because of continuing proctitis or perianal suppuration [3, 4]. In patients undergoing urgent colectomy for
J. G. Geoghegan E. Carton A. M. OShea K. Astbury
K. Sheahan D. P. ODonoghue J. M. P. Hyland ()
Coloproctology Research Unit, Department of Surgery,
St Vincents Hospital, Elm Park, Dublin 4, Ireland

Between 1983 and 1995, 44 patients (16 males) with a mean age of
41 years (range 1776 years) underwent colonic resection for Crohns
disease of the colon or rectum. Patients undergoing right hemicolectomy for terminal ileal disease and patients who had segmental colectomy performed for short skip lesions were not included in the
study group. All patients were managed jointly with the medical gastroenterology service and received standard medical treatment comprising combinations of steroid with sulphasalazine or its analogues
according to disease site and activity. Nineteen operations were elective, and the remaining 25 were urgent procedures for acute or fulminant colitis, which was diagnosed according to standard criteria.

Results

Preoperative factors and operations performed

In the 25 patients with acute or fulminant colitis, the mean
duration of in-hospital treatment before operation was

257
Table 1 Indications for operation

Table 3 Indications for proctectomy

Failed medical management

Anorectal/colovaginal fistula
Perianal suppurative disease
Stricture/obstruction
Crohns mass

Acute

Elective

25
0
0
0
0

10
4
3
1
1

Table 2 Operative procedures performed in patients undergoing colonic resection for Crohns disease, including subsequent revision
procedures

Total colectomy and ileostomy

Total colectomy and IRA
Panproctocolectomy
Abdomino-perineal resection
Segmental colectomy
Total defunctioned
or requiring proctectomy

Acute

Elective

12a
8c
5
0
0
18 (72%)

5b
3
0
11
16 (84%)

5 secondary proctectomy
b
1 secondary proctectomy
c
1 defunctioning ileostomy

7 days (range 224). In five of these patients this was their

first presentation with inflammatory bowel disease. The
remaining patients had been first diagnosed with Crohns
disease an average of 54 months (range 4132) before the
acute presentation. The mean duration of symptoms prior
to elective surgical treatment was 67 months (range
1216). Table 1 shows the indications for operation. The
primary operations performed are shown in Table 2, divided according to whether the procedure was elective or
urgent.

Proctectomy at time
of primary operation

Perianal sepsis
Anorectal fistula
Proctitis

Acute

Elective

2
3

3
3
5

Delayed
proctectomy

3
1
2

Table 4 Preoperative systemic and local indicators of disease activity as predictors of the likelihood of rectal excision or diversion
in acute Crohns colitis
n
Rectum
7
in continuity
Rectum excised 18
or diverted

Albumin

ESR

Proctitis Perianal
disease

32 (2540)

37 (1259) 1

27 (2132)

38 (291) 15*

9*

*P<0.05, 2 test

ations have not had normal gastrointestinal continuity restored and currently have an ileostomy, making a total of
34 of the 44 patients (77%) who have needed an ileostomy. Twelve patients currently have retained, defunctioned
rectal stumps, with a mean follow-up of 30 months (range
562). No instances of rectal cancer developing in a retained rectal stump have been reported in this series. Prophylactic proctectomy because of concern about cancer
risk has not been performed in any patient (see Table 3).
Six patients who had total colectomy performed (four of
whom had been operated on for acute or fulminant colitis)
have required small bowel resection or stricturoplasty at a
later date.

Postoperative course and follow-up

There was one postoperative death (30-day mortality) in a
67-year-old man with pelvic sepsis due to extensive perianal and rectovesical fistulous disease. Other postoperative complications occurred in 20% of patients and included pelvic abscess (two patients), rectal stump blowout (two patients), and venous thromboembolism (three patients). Wound dehiscence occurred in two patients, and
one patient developed a colovaginal fistula. Mean followup for the entire group is 54 months (range 12132). Table 3 shows the indications for rectal excision whether performed at the initial operation or as a secondary procedure.
During this time 5 of the 12 patients (42%) who had undergone total colectomy and ileostomy for acute colitis required secondary proctectomy, all within 17 months for
persistent suppurative complications or bleeding. One patient who had a rectal stump leak after elective total colectomy eventually required proctectomy 4 years later for
continuing low-grade sepsis.
Thus 18 of the 25 patients who had urgent surgery for
acute colitis and 16 of 19 patients who had elective oper-

Factors predictive of subsequent proctectomy

or faecal diversion
In patients undergoing urgent colectomy for acute colitis,
a number of systemic markers of inflammatory activity as
well as indicators of local activity were examined to determine whether they could predict the likelihood of retaining the rectum in continuity. These results are shown
in Table 4. The presence of proctitis and perianal suppurative complications both predicted the likelihood of an ileostomy being required, whereas measures of systemic inflammatory actvity did not.

Discussion

The psychological and social sequelae associated with a

long-term stoma make avoidance of a permanent ileostomy
in patients who undergo colectomy for Crohns colitis an
important objective. However, in this series this goal could

258

not be attained in 77% of patients, which is in line with

rates of permanent diversion reported from other centres
[1, 3, 7]. The ultimate fate of the rectum was similar irrespective of whether the colectomy was performed for acute
(including fulminant) or chronic disease [8, 9].
While most previous reports agree that severe perianal
disease is a good predictor of the need for long-term faecal diversion, not all previous studies have agreed with our
finding that the presence of proctitis is also a sensitive indicator of patients who are likely to require long-term ileostomy [810]. This may be because we included patients
only with macroscopic evidence and previous studies have
included patients with microscopic disease. Although there
is some experimental evidence that faecal diversion may
ameliorate the inflammation of Crohns colitis, previous
clinical reports have shown that this occurs infrequently
[11, 12]. Indeed, in this series five out of 12 patients had
ongoing symptoms related to the diverted rectal stump
which were severe enough to mandate proctectomy.
For patients with rectal sparing or mild proctitis ileorectal anastomosis is the preferred option. Only one of ten
patients who had ileorectal anastomosis required later diversion, in contrast to previous studies in which the incidence of proctectomy following ileorectal anastomosis has
been reported as being as high as 50% [4, 9]. This disappointingly high rate of secondary surgery may reflect an
overly conservative approach to the primary operation, although proponents would argue that quality of life is generally satisfactory in these patients for 24 years before
they come to revisional surgery [4, 9, 10].
A further issue that must be addressed is the risk of cancer developing in the retained rectal stump. The risk of malignancy associated with Crohns colitis has been quoted
as being increased by as much as 18-fold compared to the
general population [5, 6]. Severe proctitis, associated perianal disease, or rectal stricture, as well as a long history
of inflammatory bowel disease have all been associated
with an increased risk of neoplastic transformation [5, 13].
Whether this risk persists in the defunctioned stump is not
clearly established. Indeed, there are few reports in the literature of cancer developing in the excluded rectal stump
of patients with Crohns disease, probably because most
high-risk patients undergo proctectomy for persistent
symptoms of bleeding or pain related to inflammatory
rather than malignant disease. No instances have been
noted of carcinoma developing in the 12 patients in this series with isolated rectal stumps after a mean follow-up of
30 months (range 548).
In patients undergoing elective colectomy for chronic
Crohns colitis, we offer proctectomy at the time of colectomy to those patients with severe rectal or perianal involvement, on the basis that the likelihood of retaining a
functioning rectum is very low [4, 8]. The question of how
best to manage the rectum in Crohns colitis is most
sharply brought into focus in the management of patients
with acute or fulminant colitis who require urgent colectomy. Primary anastomosis is generally not recommended
because of the increased risk of anastomotic failure [10].
This study and other previous reports have shown that up

to 80% of these patients will either require a staged proctectomy or be unable to proceed with colorectal reanastomosis, because of persistent proctitis or active perianal
disease [3, 8]. Identification of these patients at the time
of colectomy would allow proctectomy to be performed
at the initial operation.
Despite this, several factors argue against rectal excision for fulminant disease, particularly in the younger agegroup. Firstly, some patients will eventually prove suitable for ileorectal anastomosis. In addition, there may be
some uncertainty about the precise diagnosis, as differentiation from ulcerative colitis may be difficult in the acute
setting. A third consideration is the risk of sexual dysfunction following excision of the rectum. Although the incidence of erectile dysfunction and other related problems
should be minimized with careful technique, impotence,
retrograde ejaculation, and dyspareunia have all been reported after intersphincteric dissection, and this is an important factor that may influence the timing of proctectomy [12]. Many of these patients are toxic and nutritionally depleted, and it is reasonable to minimize the impact
of the procedure by avoiding, or at least deferring proctectomy. Finally, it is worth considering that an acutely ill
patient, particularly if the question of surgery arises during the first presentation with fulminant colitis (as in 16%
of our patients), may not be psychologically prepared for
a permanent stoma.
A realistic assessment of the long-term prospect of
avoiding a stoma is important in the preoperative counselling of these patients. Despite the probability of requiring
permanent faecal diversion we continue to recommend
staged proctectomy in most patients with acute or fulminant disease because there is always the possibility, albeit
small, of subsequently restoring gastrointestinal continuity. On the other hand, in patients with severe perinanal
disease or proctitis who come to elective surgery, we would
usually recommend primary excision of the rectum. In patients with persistent Crohns proctitis in a defunctioned
stump, staged proctectomy should be performed because
of concerns about the risk of cancer developing in the long
term, although in younger patients this secondary procedure can be delayed for several years if necessary.

References
1. Harper PH, Fazio VW, Lavery IC, Jagelman DG, Weakley FL,
Fariner RG, Easley KA (1987) The long-term outcome in
Crohns disease. Dis Colon Rectum 30:174179
2. Andrews HA, Lewis P, Allan RN (1989) Prognosis after surgery
for Crohns disease. Br J Surg 76:11841190
3. Mortensen NJ, Ritchie JK, Hawley PR, Todd IP, Lennard-Jones
JE (1984) Surgery for acute Crohns colitis: results and long term
follow-up. Br J Surg 71:783784
4. Chevallier JM, Ratelle R, Frileux P, Tiret E, Huguet C, Malafosse M, Loygue J, Parc R (1993) Total colectomy and ileorectal anastomosis in Crohns colitis. Functional results and recurrence factors (83 cases) Gastroenterol Clin Biol 17:723732
5. Hamilton SR (1985) Colorectal carcinoma in patients with
Crohns disease. Gastroenterology 89:398407

259
6. Gillen CD, Walmsley RS, Prior P, Andrews HA, Allan RN (1994)
Ulcerative colitis and Crohns disease: a comparison of colorectal cancer risk in extensive colitis. Gut 35:15901592
7. Harling H, Hegnhoj J, Rasmussen TN, Jamum S (1991) Fate of
the rectum after colectomy and ileostomy for Crohns colitis.
Dis Colon Rectum 34:931935
8. Guillem JG, Roberts PL, Murray JJ, Coller JA, Veidenheimer
MC, Schoetz DJ Jr (1992) Factors predictive of persistent or recurrent Crohns disease in excluded rectal segments. Dis Colon
Rectum 35:768772
9. Longo WE, Oakley JR, Lavery IC, Church JM, Fazio VW (1992)
Outcome of ileorectal anastomosis for Crohns colitis. Dis Colon Rectum 35:10661071

10. Cooper JC, Jones D, Williams NS (1986) Outcome of colectomy and ileorectal anastomosis in Crohns disease. Ann R Coll
Surg Engl 68:279282
11. Winslet MC, Allan A, Poxon V, Youngs D, Keighley MR (1994)
Faecal diversion for Crohns colitis: a model to study the role of
the faecal stream in the inflammatory process. Gut 35:236242
12. Bauer JJ, Gelernt IM, Salk BA, Kreel I (1986) Proctectomy for
inflammatory bowel disease. Am J Surg 151:157162
13. Nikias G, Eisner T, Katz S, Levin L, Eskries D, Urmacher C,
McKinley M (1995) Crohns disease and colorectal carcinoma:
rectal cancer complicating longstanding active perianal disease.
Am J Gastroenterol 90:216219

Int J Colorect Dis (1998) 13: 195

Springer-Verlag 1998

E D I TO R I A L

Editors address

On behalf of the new editorial board I wish to thank Professor Nicholls and his coeditors for their excellent work,
which provides the basis for the high scientific standard
and reputation of the International Journal of Colorectal
Disease today.
In recent years it has become evident that the complexity of medicine requires new ways for organizing research.
Communication and cooperation among researchers in different fields, involving both clinicians and basic scientists
of various institutions, even in different parts of the world,
is the key to progress and a future for medicine without
frontiers. Therefore it is our intention to make the International Journal of Colorectal Disease a new forum for
interdisciplinary work, to expand its spectrum to genetic,
immunological, and molecular science, and also to include
other organs involved with diseases of the colon and rectum.
To achieve these goals the new editorial board has decided on a number of changes:
1. Starting with the first issue in 1999, the Journal will appear with the subtitle Clinical and Molecular Gastroenterology and Surgery, thereby expressing our aim to include new research areas which we feel will be impor-

tant in the next millenium not only for the colon and rectum but for the entire gastrointestinal tract.
2. Each issue will have a major topic, with review articles,
original contributions, and invited commentaries (The
first issue will focus on inflammatory bowel disease).
3. The review process will be renewed to guarantee a rapid,
fair, competent, and supportive exchange of opinions,
thereby underlining the Journals policy to strengthen
the platform for interdisciplinary discussion and collaboration and to provide a forum especially for young researchers and new ideas and approaches in the field. (Details will be announced in the next issue.)
4. Other changes with the aim of actively involving both
readers and authors in the making of the new International
Journal of Colorectal Disease will be introduced stepwise.
The new concept is both a great challenge and a unique opportunity for all those who participate. Therefore we encourage you to submit the best of your work and be a part
of the new International Journal of Colorectal Disease:
Clinical and Molecular Gastroenterology and Surgery
H. J. Buhr
(Editor-in-chief)

Int J Colorect Dis (1998) 13: 196 207

Springer-Verlag 1998

REVIEW

T. Khbacher S. Schreiber N. Runkel

Pouchitis: pathophysiology and treatment

Accepted: 14 August 1998

Abstract Pouchitis is a potential complication after proctocolectomy and restorative ileoanal anastomosis. It is
more frequent in UC than in familial polyposis. Little is
known about the etiopathology of pouchitis. Risk factors
include the presence of extraintestinal manifestations, primary sclerosing cholangitis, cessation of smoking, and previous course of disease. A host of pathophysiological pathways have been identified as potential mechanisms of pouchitis, which include inflammatory mediators, adhesion
molecules, oxygen radical species, p-ANCA, and shortchain fatty acids. The microflora in the pouch may also be
an important factor in causing inflammation. The risk of
developing cancer in cases of pouchitis has not been established as clearly as in those of UC. Particular attention
should be paid to patients who have remaining anorectal
mucosa after pouch construction. Experience in the treatment of chronic relapsing and chronic refractory pouchitis
is limited. The continuation of conventional anti-inflammatory treatment is successful only in a small percentage
of patients. New biological response-modifying therapies
which target novel immunoregulatory molecules in IBD
will also have impact on the systemic and topical treatment
of pouchitis.
Key words Pouchitis Risk factors Biological responsemodifying therapies

Introduction

Ulcerative colitis (UC) is a chronic inflammatory disorder

of the intestine of unknown etiology [1]. It can be distinT. Khbacher () S. Schreiber
1st Medical Department, Christian Albrechts University,
Schittenhelmstrasse 12, D-24105 Kiel, Germany
N. Runkel
Department of Surgery,
University Hospital Benjamin Franklin, Free University,
Berlin, Germany

guished from Crohns disease in most but not all cases on

the basis of clinical manifestations, endoscopic appearance, histological characteristics, and differences in immuno-pathophysiology. Conservative therapeutic options
are often identical in the two diseases, and therefore the
definitive distinction between Crohns disease and UC is
often not vital for the patient. Thus, some studies report
conversion rates of up to 25%.
In contrast to Crohns disease, a definite surgical cure
exists for UC. Because UC is restricted to the large bowel,
the disease can be healed by procto-colectomy. The risk
of colonic adenocarcinoma, which is particularly increased
in patients with total colitis [2], can be reduced by colectomy. Moreover, overall morbidity after surgical treatment
appears to be much lower than with long-term medical
treatment of UC [3, 4]. However, procto-colectomy followed by restorative surgery can have devastating consequences in patients with Crohns disease or indeterminate
colitis [5] who have been wrongly diagnosed as having UC,
with severe fistulating or stenotic disease developing at the
pouch or ileostomy [610].
Procto-colectomy as a surgical treatment option for UC
may either lead to the construction of an ileostomy or be
followed by a restorative approach. Alternatively, one can
perform an ileoanal anastomosis, ileorectal anatomosis, or
ileoanal anastomosis, in which a pouch is constructed from
ileal loops to provide a reservoir for stools [1114]. These
three types of procedures offer a similar quality of life
[1520]; however, the ileoanal anastomosis tends to have
a higher postoperative complication rate and a higher frequency of incontinence. It remains unclear whether a modification of the straight ileoanal anstomosis by multiple
ileal myotomies offers an alternative to the pouch in UC
[21]. However, the rectal stump may lead to the development of rectal carcinoma [22, 23].
Most interestingly, procto-colectomy and ileostomy appear to provide a high level of treatment satisfaction in terms
of improved quality of life. No differences in quality of life
scores are seen between ileostomy patients and those regaining normal defecation by construction of a pelvic pouch
[2428]. Nevertheless, most younger patients decide to re-

197
Table 1 Types of pouch problems and frequency
Symptoms

Type

Frequency

Manifestation
(post-operatively)

Treatment

Cancer
surveillance
necessary

Fever, incontinence, pain

Pouch leakage

<10%

Immediately

Surgical revision

No

Urgency, stool frequency

Acute pouchitis
Chronic relapsing
Chronic refractory

<30%
<5%
<5%

Immediately
Any time
Any time

Metronidazole, anti-inflammatory
Metronidazole, anti-inflammatory
Metronidazole, azathioprine,
cyclosporine A, surgery

Unknown
Yes
Yes

ceive a pouch. Functional results from restorative procto-colectomy depend on the timing of the procedure, with patients
suffering from active disease having a higher risk of impaired
function than those in remission [29, 30]. Advanced age may
not be a risk factor for pouch failure [31, 32] if there was sufficient sphincter function before surgery [3337]. Importantly, the high intra-abdominal pressures in pregnancy do
not have a negative effect on pouch function [38, 39].
The development of inflammation in the pouch (pouchitis) is a troublesome and often disappointing complication. A substantial proportion of patients develop acute
pouchitis, but chronic inflammation is seen only in a minority of cases. It is unclear whether pouchitis represents
a reactivation of the immunological mechanisms that are
involved in the development of UC or an entirely new form
of inflammatory bowel disease (IBD). The anti-inflammatory treatment of chronic pouchitis is often difficult and
chronic inflammation may be associated with an increased
risk of developing pouch cancer in these patients. Although
disappointing, the failing pouch can always be converted
into an ileostomy.

Surgical proceedures, incidence,

and natural course of pouchitis

The construction of an ileal pouch-anal anstomosis after

procto-colectomy results in good long-term function and
high patient satisfaction [40] in over 90% of both adults
and children [41, 42]. However, some patients complain of
frequent stools and incontinence. The development of mucosal inflammation in the ileal pouch must be considered
[43] once technical reasons have been excluded for complaints (i.e., pouch leakage, gynecological complications
[44], pouch sepsis, and insufficient function of the anal
sphincter or pelvic floor [45]). It is important to distinguish
between symptomatic pouch inflammation, pouch sepsis,
and noninflammatory pouch failure. Large series [46] show
noninflamatory pouch failure to be a risk factor independent of pouchitis and pouch sepsis. Among 217 patients
receiving a stapled anastomosis without anal mucosectomy
14.7% developed symptomatic inflammation, 4.1% inflammation of the anal canal alone, and 10.6% pouchitis
in addition [42]. In other studies the development of pouchitis (acute and chronic) was seen in as many as 36% of

patients [47, 49, 50]. A series of 1232 patients with chronic

UC were compared to 76 patients with indeterminate
colitis [52]. Although the prevalence of pouchitis (33%)
was identical between the two groups, more patients with
indeterminate colitis developed a failure (19%) within
5 years after surgery than patients with UC (8%) [52].
When performed electively [29], the results of pullthrough procedures carried out months to years after permanent procto-colectomy are comparable to those of onestage reconstruction [51]. Of 311 patients undergoing restorative procto-colectomy with ileal J-pouch construction,
12.4% with UC and 1.3% with familial polyposis developed severe pouchitis, requiring pouch extirpation in 4.2%
and 1.3% of patients, respectively [53]. In another series,
Kock pouches were constructed in a similar patient population, with 11.1% developing severe pouchitis [54]. Other
studies report similar proportions of chronic pouchitis,
between 7% and 22% [5559]. However, for clinical management it is important to distinguish pouch leakage with
sepsis from patients with early pouchitis of one or only a
few episodes and from that in patients developing chronic
relapsing pouchitis [6063] (Table 1).
It is a subject of debate whether hand-sewn anastomoses
with complete mucosectomy of the anal mucosa perform
better than stapled anastomses in which the anal mucosa
and a short band of rectal mucosa are left. It has been argued
that preserving the anal transition zone results in greater
anal sensitivity and better control of defecation [64, 65].
Some series have found hand-sewn anastomoses to perform less well with regard to pouch leakage, pouch sepsis,
and the later development of pouchitis [66]. This problem
appears to be particularly frequent in patients with a short
distance between the dentate line and the anastomosis [66].
Double-stapled anastomoses which preserve the anal transition zone appeared to be functionally equivalent to handsewn anastomosis with mucosectomy, with no differences
observed in terms of pouchitis prevalence between the two
groups [67]. Residual rectal mucosa does not seem to affect clinical results or, in particular, the development of inflammation at follow-up [24]. A large series conducted
over 5 years found no differences in postoperative complications, quality of life, or frequency of pouchitis between
the two methods of constructing ileal pouch-anal anstomoses [58]. However, case reports have reported the occurrence of cancer in the anal canal which originated from
the transition zone [68]. It is therefore important to con-

198

Fig. 1 Pathophysiological factors that effect the development of

pouchitis. The invasion of inflammatory cells is affected by the expression of adhesion molecules on immune cells and on small-vessel endothelial cells. Upon penetration into the lamina propria PMN
and as macrophages are exposed to a host of nonspecific stimuli including bacterial products (LPS). Colonic metaplasia may reveal
neoantigens triggering specific inflammatory responses. An increased secretion of proinflammatory cytokines (including IL-8,
IL-1, and TNF) and lipid mediators contributes to the initiation and
perpetuation of intestinal inflammation. Binding of pANCA to their
perinuclear targets may have a stimulatory effect on granulocytes.
The decreased supply of nutrients to epithelial cells (e.g., shortchain fatty acids) from the lumen may be a factor promoting instability of the mechanical barrier against the stool contents

tinue endoscopic surveillance, particularly in patients who

undergo pouch construction without resection of the anal
transition zone.

Risk factors for the development of pouchitis

Epidemiological studies following patients from the indication for surgery to the postoperative phase have identified several independent risk factors for the development
of pouchitis:
Previous course of disease (high relapse rate, chronic refractory disease)
Presence of extraintestinal manifestations
Primary sclerosing cholangitis
Cessation of smoking
The presence of antibodies directed against neutrophil
granulocytes and which show a characteristic perinuclear

binding pattern (pANCA) was initially regarded as a

strong risk factor and has been advocated to play a primary role in the pathogenesis of pouchitis. However, recent studies have established that pANCA titers decrease
after colectomy, independently of the type of procedure
performed [69]. The presence of pANCA appears to be
secondary to the presence of chronic mucosal inflammation and independent of its cause (UC or pouchitis) [69,
70]. The study also indicates that pANCA may not be a
useful parameter for predicting the development of pouchitis [71]. However, high pANCA titers may identify patients with refractory pouchitis having particularly extensive disease and particularly frequent acute relapses [72].
The presence of primary sclerosing cholangitis also appeared to be a strong independent risk factor in a large series [73]. The development of pouchitis is correlated with
the presence of primary sclerosing cholangitis but not with
the severity of liver disease [73]. A second study comes
to a similar result and moreover indicates that liver transplantation does not alter the risk of developing pouchitis
[74]. Smokers have significantly fewer episodes of pouchitis than nonsmokers or former smokers [75]. This study
suggests a direct benefit from smoking on the clinical
course of pouchitis. The effects of preoperative smoking
and preoperative cessation of smoking must be evaluated
in further prospective studies. However, it appears that the
effect of smoking on pouchitis parallels that seen in UC
[7679]. In summary, there are strong independent risk
factors for the postoperative development of refractory
pouchitis which demonstrate that the development of
pouch inflammation is not a local but rather a systemic
immunological problem. They also indicate a common immunological disease process being involved in pouch mucosal inflammation, extraintestinal manifestations, and
sclerosing cholangitis.

199

Pathophysiology of pouchitis

A host of pathophysiological pathways have been identified as potential mechanisms of pouchitis. Some of these
are discussed below. However, little attention has been
given to the possibility of an ileum used for pouch construction having a regular appearance but nevertheless being abnormal with regard to its immunology and function
[80]. The possibility therefore exists that the quality of the
ileum used for pouch construction is an important factor
in the later development of pouchitis.

Adaptation and the potential for colonic metaplasia

The villus morphology alters as early as 5 days after ileal
pouch-anal anstomoses. A decrease in villous height is seen
in the ileal mucosa of both patients with familial multiple
adenomatous polyposis and patients with UC. However,
only in UC is this accompanied by an increased expression
of T cell activation and proliferation markers [81]. T cell
cytokines are known to have a profound effect on villous
morphology, as shown by MacDonald and coworkers [82,
83] in fetal gut organ cultures. In another series the histological analysis of clinically inflammation-free quadruple
loop ileal pouches in patients with UC or familial polyposis, respectively, showed focal inflammatory and architectural changes in 96% of patients [84]. Mucin histochemical analysis [85] confirms the structural impression of a
colonic epithelial phenotype. The histological changes appear to be more prominent in the distal pouch than in proximal pouch mucosa [86]. These changes in epithelial cell
morphology were initially identified as colonic metaplasia. However, they do not affect the pouch uniformly. Both
the adaptive and the inflammatory changes are focal in response to static fecal residue. However, other studies suggest that exposure to the fecal stream rather than fecal stasis appears to be the most important stimulus for the observed changes [87, 88]. Sucrase-isomaltase activity,
which is typical for the small bowel, could be detected in
all 25 pouch mucosa biopsies [88, 89].
These findings underscore the fact that although the histological picture resembles that of metaplasia, complete
transformation of the epithelium does not occur. Other
studies which prospectively followed the evolution of morphological changes prospectively find early alterations
(6 weeks) with neutrophilic/eosinophilic infiltration, mild
villus atrophy, paneth cell hyperplasia, and the development of a colonic mucin phenotype which appear to be
stable at 6 and 12 months (with the exception of the inflammatory infiltrate which increased in intensity) [90].
This study suggests that adaptation to a new luminal content induces morphological changes resembling the appearance of colonic mucosa, but that the potential for true
metaplasia is rather limited [90]. Moreover, similar
changes were seen although to a lesser extent in patients with familial polyposis undergoing reconstructive
pouch operations. Morphological changes in the pouch epi-

thelium, however, may be a prerequisite for the development of pouchitis [84]. Adaptive changes may be reflected
by an increased permeability which develops only days after pouch construction [91]. Although increased permeability may be a key finding for explaining the development of inflammation by the invasion of fecal bacteria, it
could be only secondary to adaptation of the ileal epithelium.
Inflammatory mediators and changes
Great interest has focused on the pathophysiological mechanisms which contribute to a disturbed immunoregulation
in chronic pouchitis and IBD. The goal is to identify primary mechanisms involved in disease etiopathology. Although many of the mechanisms described are of secondary nature, they may be still important targets for immunotherapeutic interventions. The further exploration of the
immuno-pathophysiological mechanisms will reveal important insights into the pathway from mucosal inflammation to intestinal lesions.
The inflammatory infiltrate
In both acute and relapsing chronic pouchitis the inflammatory cells invade the pelvic pouch mucosa, which leads
to dense histological infiltrates. 111In-labeled granulocytes have been used to study the influx of neutrophils into
the mucosa as well as their excretion with stools [92]. The
study documented neutrophil invasion in both chronic and
acute pouchitis. Histological scores of pouch inflammation were correlated well with the influx of 111In-labeled
neutrophils and with 111In content in 4-day stools [92]. The
assessment of fecal excretion of 1-antitrypsin leads to
similar results without the use of radioactivity [93]. The
histomorphology of the inflammatory infiltrate resembles
that seen in IBD [94]. Ratios between CD4 and CD8 cells
in the inflamed UC pouch mucosa are similar to those in
normal controls, with higher expression of interleukin (IL)
2 receptors and other activation markers than with pouch
mucosa from familial adenomatous polyposis patients [81,
89, 94, 139]. Increased concentrations of leukotriene B4
[95] and platelet-activating factors [96] have been found.
In particular, leukotriene B4 is a strong chemoattractant for
neutrophils and plays a major role in both Crohns disease
and UC [97].
Adhesion molecules
The homing of immune cells into inflammatory tissue sites
involves adhesion molecules expressed on both leukocytes
and endothelial cells [98101]. Adhesion molecules are
grouped into three families: the immunoglobulin superfamily (ICAM-1 on monocytes and endothelial cells,
VCAM on endothelial cells of small vessels), the integrin
family (including VLA-1 on lymphocytes and LFA-1 on

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leukocytes), and the selectin family (ELAM-1 on endothelial cells). An intial contact between selectin adhesion
molecules results in slowly rolling movements of leukocytes along the vessel wall and subsequently induces the
expression of integrins on the leukocyte surface which then
can bind to counterparts from the immunoglobulin superfamily. This interaction, which is also known as secondary
adhesion, is much stronger than that between selectins. It
stops the rolling movement and initiates leukocyte transmigration through the endothelial cell layer into the tissue
matrix.
The expression of nearly all adhesion molecules
(ICAM-1, ELAM-1, various integrins, and E-, P-, and Lselectins) is highly increased in active IBD. The expression of ICAM-1 on endothelial cells is dramatically increased, accompanied by an increase in CD11a on mononuclear phagocytes [102104]. Increased expression and
shedding of ICAM-1 and E-selectin have been described
in pouchitis [105].
Oxygen radical species
It appears likely that unspecific inflammatory mediators
such as oxygen radicals and nitric oxide play an important
role in both the pathophysiology of chronic pouch inflammation and tissue damage. Polymorphonuclear leukocyte
(PMN) function, has been examined in IBD by assessing
migration, chemotaxis, adherence, and phagocytosis.
Rhodes and coworkers [106, 107] as well as Wandall and
Binder [108] have demonstrated by using the skin window chamber technique that in vivo random migration of
PMNs was suppressed in UC and Crohns disease. These
studies show that there are intrinsic abnormalities of
PMN function in IBD, and that inhibitors of chemotactic
factor activity may be present in the sera of both Crohns
disease and UC patients. In vitro exposure to drugs frequently used for the treatment of IBD (prednisone, 5-aminosalicylic acid, sulfasalazine) inhibits both random migration and chemotaxis by normal peripheral blood leukocytes [106].
Interestingly, no functional difference are observed
between PMNs from normal controls and those from IBD
patients with regard to phagocytic capacity or chemotaxis
induced by zymosan-activated serum or casein [109]. It has
been established that PMN from patients with active IBD
are primed in vivo for activation [110112]. Earlier reports
of a decreased capacity to secrete superoxide anions in
vitro may be due to the effect of separation techniques
[113] or to the fact that circulating stimulatory substances
in the sera of IBD patients have already partially exhausted the capacity of isolated PMN for superoxide
anion secretion [114, 115]. Moreover, it has been demonstrated that elastase, which is a marker enzyme for activated PMN, is increased in IBD stools and intestinal
mucosa [116, 117].
Overproduction of NO by inducible NO synthase
(iNOS) may contribute to the pathophysiology of both UC
and pouchitis [118]. This has been suggested in animal

models (e.g., the 2,4,6-trinitrobenzenesulfonic acid sodium salt induced colitis model [118]) and in studies of
UC and pouchitis [119121]. It has been proposed that NO
is the main inductor of IL-8 and is associated with an increase in cyclo-oxygenase 2, tumor-necrosis factor (TNF)
and IL-1 expression. NO has also been shown to be a
neurotransmitter in the nonadrenergic-noncholinergic inhibitory nerves in the human gut and is therefore regarded
as an important contributor to the motility problems seen
in acute UC. Motility studies have shown NO to act more
strongly in the UC colon than in the normal colon [122].
Producers of NO are most likely macrophages and neutrophils within the colonic or pouch mucosa [123]. The exact role of NO as an immunoregulatory mediator is yet still
to be defined.
Proinflammatory cytokines
Proinflammatory cytokines (TNF-, IIL-1, IL-8, IL-12)
may play a pivotal role in initiating inflammatory reactions, while their endogenous inhibitors (e.g., IL-1 receptor antagonist, soluble TNF receptors) and contrainflammatory cytokines (e.g., IL-4, IL-10, IL-13) limit and downregulate inflammatory responses. Increased amounts of
proinflammatory cytokine mRNA and protein have been
convincingly described in the intestinal mucosa of patients
suffering from active IBD [97, 124134]. Neuromediators
including substance P [135, 136] may be able to modify
intestinal inflammatory reactions [137] by direct regulation of immune cells.
Mononuclear cells in the pouch mucosa show increased
secretion of most of the pro-inflammatory cytokines investigated (TNF-, IL-1, IL-6, and IL-8) [124134]. The recruitment and immunological activation of RFD9+ macrophage populations occurs, which can be detected in chronic
IBD but not in acute infectious colitis [89, 138]. The conclusion has been drawn from these data that pouchitis in
most cases reflects a reactivation of UC (caused by an adaptation-induced expression of certain colonic antigens
[139]). However, this hypotheses is not in fact supported
by the data because from all that we know the enhanced
secretion of proinflammatory cytokines in both IBD and
pouchitis reflects rather the acute inflammatory reaction
than a specific immunological alteration unique to the disease [140].
p-Anca
Saxon and coworkers [141] have described the presence of
anti-neutrophil cytoplasmic antibodies (ANCA) in IBD patients with colonic involvement. In this and other early
studies [142] most patients with UC were positive for
ANCA, and only a small number of Crohns disease patients with mainly colonic involvement had positive
ANCA titers [141]. Intriguingly, the ANCA observed in
IBD stained neutrophils with a nongranular, perinuclear
distribution (p-ANCA) and thus were distinctly different

201

from those observed in Wegners granulomatosis [143].

The target may be granulocyte lysosomal enzymes [141,
143, 144] or ubiquitinated histone 2A or poly-ADP ribose
polymerase, as recently suggested [145]. In large cohorts
it has been observed that p-ANCA are present in high titers in UC, sclerosing cholangitis, and autoimmune hepatitis [146]. In large studies it appears that the specificity of
the association of pANCA with UC and not Crohns disease is not as high as originally found. In larger cohorts
about two-thirds of UC patients are pANCA positive, compared to one-third of the Crohns disease population [144,
147]. The titer of pANCA may depend on disease activity
[148, 149]. pANCA production is seen from activated
mucosal B cells [150]. Procto-colectomy had led in some
studies to a reduction in pANCA titers [69, 151], whereas
others have found no effect of liver transplantation and
procto-colectomy on pANCA titers [152]. The contradictory findings may be explained by a different rate in the
development of pouchitis following restorative procto-colectomy. Some studies report an association between severe pouchitis and high titers of circulating pANCA [70,
153, 154]. Prospective evaluation of patients 2 or more
years after colectomy has failed to show a difference
between patients with UC and those with pouchitis [69,
151]. pANCA therefore seems to be a functional marker
dependent on disease activity and secondary to underlying
immunological events in the pathophysiology of chronic
pouchitis.
Short-chain fatty acids
The development of colitis can be observed when the
fecal stream is diverted from parts of the colon (e.g., by
forming a closed loop in animals). Diversion colitis shares
some morphological similarities with pouchitis [155].
Because a deficiency in short-chain fatty acids supplied
by fecal contents has been suggested in the pathogenesis
of diversion colitis [156] and has been found in IBD mucosa [157], the role of short-chain fatty acids has been investigated intensively in pouchitis. Some groups have
found decreased short-chain fatty acids in stools of patients
with active pouchitis [158, 159]. Is has been proposed that
low pouch concentrations of fermentable saccharides decrease the production of short-chain fatty acids by fecal
bacteria [159]. Increased glutamine metabolism is found
in pouchitis; however, no defect has been seen in butyrate
turnover [160]. Recent studies in a small but well-characterized group of patients with pouchitis could not confirm
a decreased fecal concentration of short-chain fatty acids
or bile acids [161]. It appears quite clear that changes in
stool composition with regard to nutrients supplied by the
feces cannot be the primary cause of pouchitis. Future prospective studies in larger cohorts of patients with normal
pouches, acute inflammation, and chronic relapsing disease are needed to evaluate the role of short-chain fatty acids and metabolic changes in the mucosa as a secondary
factor in tissue destruction.

Microbiology of pouchitis
The rectal mucosa is exposed to much higher concentrations of aggresive microbial organisms than the normal
ileal surface. After ileal pouch anal anstomosis the (ileal)
pouch mucosa is suddenly confronted with a host of
foreign microbial antigens. Fecal stasis in the pouch may
be an important cofactor facilitating bacterial invasion of
the epithelium. Fecal stasis may also be a cofactor in inducing the expression of colonic antigens by goblet and
columnar epithelial cells in the ileal pouch mucosa [84 88,
139]. A decreased ratio of anaerobes to aerobes associated
with a decrease in bifidobacteria and lactobacilli has been
found in stools of patients with pouchitis [162]. Intramural counts of facultative aerobe bacteria appear to be related to the severity of pouchitis [163]. High anaerobe
counts are associated with chronic pouchitis rather than
acute inflammation [164]. Onderdonk and coworkers [165]
carried out an elegant study using both culture and electron microscopy and demonstrated that pouch mucosa from
patients with inflammation contains higher counts of faculatively anaerobic bacteria, and that detection of anaerobes is more frequent in patients with pouchitis than in
noninflamed controls. Enteroadhesive strains of Escherichia coli have also been implicated in the etiopathology of
pouchitis in a small series [166]. Changes in the composition of fecal bacteria are still a subject of debate [161];
however, its appears clear that fecal micro-organisms may
play an important role in the amplification and chronic perpetuation of intestinal mucosal inflammation. An increased permeability of the pouch mucosa [91], a breakdown of tolerance to ones own flora [167], and as yet unknown causative infectious agents may contribute to bacterial invasion of the mucosal barrier and the stimulation
of an inflammatory mucosal response. It also appears that
changes in the intestinal microflora are restricted to the
pouch and do not ascend into the proximal ileum [168].
New insights into the role of bacteria are to be expected
from sophisticated animal models which are currently being developed [169] and from the use of molecular techniques for identifying and quantifying invasive bacteria
within the mucosa [170].

Risk for the development of cancer

in patients with pouchitis

It is well established that patients with chronic UC have an

increased risk of developing colonic cancer [171]. The risk
of colonic carcinoma increases with the duration of active
disease. After 1015 years of active disease the risk appears to increase exponentially. Restorative surgery with
construction of pouches has now been performed routinely
for a little more than a decade. Recent interest has therefore focused on whether chronic pouchitis is also a risk
factor for the development of pouch cancer. Long-term histological surveillance has shown three patterns of mucosal adaptation: a regular adaptive response with normal

202

mucosa or mild villous atrophy (with no or mild inflammation present, group A, 51% of cases), a transient atrophy response with temporary moderate to severe atrophy of villi
followed by a normalization of architecture (group B, 40%
of cases), and a constant atrophy with persistent subtotal or
total villous atrophy (group C, 9% of cases) [172]. Lowgrade dysplasia occurs in some patients of group C. Similar findings have been reported by Setti-Carraro and coworkers [173175], who also identified a subgroup of patients with a pouch mucosal histology characterized by severe chronic inflammatory changes. Although the risk of
developing cancer has not been established in chronic pouchitis as clearly as in chronically active UC, the morphological changes seen and the growing number of case reports describing pouch dysplasing and cancer [176, 177]
suggest that patients with chronic pouchitis might carry a
similar risk as those with chronic UC. In the case of pouchitis the area of inflammation is endoscopically well assessable. Appropriate surveillance strategies are currently
being developed to analyze the risk of pouch cancer and
find adequate clinical algorithms for screening and diagnostic procedures in patients with pouchitis. Particular attention should be paid to patients who have remaining anorectal mucosa after pouch construction [178].

Medical treatment strategies in pouchitis

Experience with the treatment of chronic relapsing or

chronic refractory pouchitis is limited. Most series include
only small numbers. However, it appears clear that the efficacy of presently available therapeutic options is not satisfactory. The continuation of conventional anti-inflammatory treatment is successful only in a small percentage of
patients (Fig. 2).
The bacterial flora, in particular anaerobes, may be affected by treatment with metronidazole. Systemic
(400 mg t.i.d.) or topical metronidazole (40 mg/day) often leads a reduction in symptoms accompanied by a reduction in stool anaerobes and a normalization of stool
fatty acid contents [179, 180]. It can be administered topically in a daily dose of 40 mg as a long-term treatment
[179]. Most interestingly, treatment of pouchitis with metronidazole also leads to reversion of some of the atrophic
morphological changes seen in the pouch mucosa [181].
A study of oral treatment with rifaximun, a nonresorbable
derivative of rifamycin, has shown improvement in 87%
of patients with pouchitis who had failed other antibiotic
therapy previously [182].
Cyclosporine A is an immunosuppressive agent that
strongly interferes with IL-2 controlled T cell activation.
Uncontrolled studies indicate a potential role for topical
treatment with cyclosporine A [183]. In UC a placebo-controlled study found no efficacy of topical cyclosporine A
[184]. A similar controlled study is urgently needed in pouchitis.
Allopurinol neutralizes potentially toxic oxygen radicals released by phagocytes in inflammatory lesions. In an

Fig. 2 Intensified treatment of pouchitis. Choice of treatment depends on the intensity of symptoms, pouch inflammation, and disease refractoriness. In some highly acute cases it may be necessary
to primarily use a systemically, anti-inflammatory treatment, whereas in most cases treatment can be intensified sequentially, as suggested here. Azathioprine is particularly useful in chronic pouchitis
which shows a high frequency of relapses. Experimental therapies,
which have been evaluated only in very small, open-label pilot trials,
include the use of various antibiotics, probiotic agents, allopurinol
(as an oxygen radical scavenger), and local anesthetics (e.g., lidocaine, ropivacaine)

uncontrolled, very small series allopurinol was used successfully in chronic pouchitis [185], although no controlled
trial has yet been carried out.
The rational for substituting nutrients are findings that
stool concentrations of short-chain fatty acids may be
decreased in pouchitis. A small, open-label series reported
a beneficial effect of butyrate or glutamine suppositories
in patients with chronic refractory pouchitis [186].
New medications presently being evaluated include
azathioprine and topical steroids. However, doubleblind, placebo-controlled studies have not yet been completed. Chronic, refractory pouchitis is clearly difficult
to treat. Future clinical studies will depend on the availability of activity indices, which must be validated in
prospective trials. Sandborn and coworkers [187] recently proposed an activity index for pouchitis which incorporates clinical and endoscopic criteria. Parameters
need to be defined for quantifying histopathological
changes in pouchitis. In addition, techniques for assessing pouch function and defecation must be further developed [188196].
The etiopathology and pathophysiology of pouchitis
are even less clear than those of IBD. The possibility exists that pouchitis is a third and distinctly different form
of iatrogenic IBD. The further exploration of mechanisms
involved in the development of inflammation in pouchitis
will greatly increase our knowledge of the inflammatory
cascade and may reveal new targets for a more effective
therapy.
New biological response modifying therapies which target novel immunoregulatory molecules in IBD [197, 198]
or the healing process [199] will also have impact on the
systemic and topical treatment of pouchitis. Improved
understanding of the interaction between bacterial flora

203

and mucosa associated immune system will allow the selective, targeted modification of the intestinal microbial
environment. Possible therapeutic approaches include the
topical and systemic use of antibiotics and the introduction of apathogenic bacteria after or before pouch construction.

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Int J Colorect Dis (1998) 13: 208 216

Springer-Verlag 1998

O R I G I N A L A RT I C L E

A. J. Porter D. A. Wattchow A. Hunter M. Costa

Abnormalities of nerve fibers in the circular muscle

of patients with slow transit constipation

Accepted: 14 January 1998

Abstract Abnormalities of the enteric nervous system are

thought to explain the pathophysiology of motility disorders. Our aim was to determine if particular classes of enteric neurons are affected in slow transit constipation
(STC). Specimens were taken from the terminal ileum and
ascending, transverse and descending colon of patients
undergoing subtotal colectomy for STC. Immunohistochemistry was performed using antisera to neuron-specific
enolase, tachykinin, leu-enkephalin, choline acetyltransferase, vasoactive intestinal peptide, nitric oxide synthase,
tyrosine hydroxylase and neuropeptide Y. The density of
nerve fibres labelled with these antibodies in each layer
was compared with age-matched controls. The density of
nerve fibres with tachykinin and enkephalin immunoreactivity was reduced in the colonic circular muscle of the 15
patients with STC, whereas innervation of all other layers
was normal. This reduction of tachykinin-immunoreactive
nerve fibres also occurred in nine of the 12 specimens of
terminal ileum examined. No difference was detected in
the density or distribution of nerve fibres using the other
antisera. Excitatory nerve fibres are present in the circular
muscle in STC but they are deficient in tachykinins and
enkephalin.
Key words Slow transit constipation
Immunohistochemistry Enteric nervous system

A. J. Porter D. A. Wattchow ()
Department of Surgery, Flinders Medical Centre,
GPO Box 2100, Adelaide 5001;
Tel.: 0061-8-8204-4140; Fax: 0061-8-8374-0832;
e-mail: pmnajp@pippin.cc.flinders.edu.au
A. Hunter
Department of Surgery, Royal Adelaide Hospital,
Adelaide, Australia
M. Costa
Department of Human Physiology and Centre for Neuroscience,
Flinders University of South Australia, Adelaide, Australia

Introduction

Patients frequently present to their physicians with symptoms of constipation and, in the absence of intestinal obstruction, are usually successfully treated by correcting a
fibre-deficient diet. In some cases, no cause is found and
the constipation does not respond to bulking agents, laxatives or prokinetic agents. In these patients, the constipation may be very severe, with the patients using their bowels every 23 weeks (most people daefecate between three
times a day and once every 3 days [1]) and having associated symptoms of distension and discomfort. Characteristically these patients are women whose constipation has
commenced in their teenage years, as first described by Arbuthnot Lane in 1908 [2]. It is likely that the disease he described is the same as the disorder now known as slow transit constipation (STC). In most cases, the colon and rectum are of normal calibre and, by convention, this condition excludes patients with megarectum or megacolon [3].
Patients with intractable constipation are classified into
those with slow, generalised passage of faecal content, as
determined by transit studies, and those in whom the transit is normal but there is a problem with evacuation of content from the rectum. When patients with severe chronic
constipation are investigated, about 10% have slowed transit alone and 5% have both slowed transit and pelvic floor
dysfunction [4]. In such patients, the available evidence
indicates that the pelvic floor dysfunction is not responsible for the colonic slow transit [5].
In patients with STC, symptoms are typically worsened
by increasing dietary fibre and they have usually had a considerable period of laxative use for alleviation of their
symptoms. If this is ineffective, subtotal colectomy with
ileorectal anastomosis may be indicated. This operation is
highly effective in relieving the constipation in these patients, although less effective in relieving problems of
bloating and pain [6].
The colon usually appears normal to routine histological evaluation of these subtotal colectomy specimens. Use
of the silver impregnation technique has revealed abnor-

209

malities in myenteric neurons [8] but these techniques do

not allow differentiation of the various functional classes
of myenteric neurons that are now known to exist, such as
motor neurons, interneurons or sensory neurons [9]. Several studies have reported abnormal innervation patterns
of the bowel wall in patients with STC, although the results have often been conflicting. This has especially been
true regarding the concentration of vasoactive intestinal
peptide (VIP) and density of VIP-immunoreactive (IR)
nerve fibres in the circular muscle, with decreases [10], increases [11] and no changes [12, 13] being reported. Several other abnormalities have been described in patients
with STC, such as an increase in calcitonin gene-related
peptide-IR nerve fibres in the myenteric plexus [12]. Some
of these studies examined only one region of colon, either
the sigmoid or descending colon or the rectum, which may
partially account for the disparity of results. In most studies, the control group was older than the STC group, as the
bowel was obtained from elderly patients with colon cancer. Given that significant changes occur in the enteric nervous system of humans and experimental animals with ageing [1416], it is essential that controls are age-matched.
The present study examines the innervation of the colonic wall of patients with well characterised STC using a
variety of neurochemical markers. The distribution and
density of innervation were compared with age- and sexmatched control specimens.

Patients and methods

Tissue collection
Fifteen women (median age 36 years; range 2366 years) underwent
subtotal colectomy and ileorectal anastomosis for the treatment of
STC. All had had constipation for many years unsuccessfully treated by increasing dietary fibre or fluids, or by the use of laxatives.
Laxative use was common but difficult to quantitate as multiple types
of laxatives had been used for varying lengths of time and the patients had poor recollection of exact laxative usage. In all of these
patients, the colon was of normal calibre as revealed by barium enema. Patients with megacolon or megarectum were excluded from
this study. Slow transit was defined by slow passage of radiopaque
or radionuclide markers, with retention of more than 20% of the
markers at 96 h being diagnostic of STC. For clinical purposes, these
two tests are equivalent [17].
Once the colon was removed, segments of approximately 22 cm
were cut from the terminal ileum (in 12 patients), ascending colon,
transverse colon and descending colon (in all patients). All specimens were cut from the inter-taenial portions of the colonic wall.
Control tissue was taken from six women (median age 35 years);
range 2644 years undergoing surgery for colonic cancer or polyps
or having colon removed as part of surgery for ovarian cancer or sarcoma. These six patients were age-matched to the STC group. There
were four specimens of terminal ileum, three of ascending colon, two
of transverse colon and three of descending colon. Histopathological examination of these specimens was performed to confirm that
there was no evidence of tumour invasion or inflammation in the
specimens. These patients had no symptoms of bowel obstruction
and none of the patients had systemic disorders affecting the enteric nervous system, motility disorders or inflammatory bowel disease.
All tissue was taken with prior informed consent. This study was approved by the Flinders Medical Centre Committee on Clinical Investigation.

Table 1 Antisera used for immunohistochemistry

Antigen

Antisera code

Host

Dilution

Reference

ChAT
leu-ENK
NOS
NPY
NSE
TK
TH
VIP

AB1582
198B
K205
RMJ263
A 589
RMSP4 I/II
LCN1
7913

Sheep
Rabbit
Sheep
Rabbit
Rabbit
Rabbit
Mouse
Rabbit

1:1000
1:400
1:1000
1:1600
1:500
1:2000
1:1000
1:3200

[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]

ChAT, choline acetyltransferase; leu-ENK, leu-enkephalin; NOS, nitric oxide synthase; NPY, neuropeptide Y; NSE, neuron-specific enolase; TK, tachykinin; TH, tyrosine hydroxylase; VIP, vasoactive intestinal peptide

Immunohistochemistry
Full thickness specimens of intestine were immersed in room temperature phosphate-buffered saline (if operation performed at Flinders Medical Centre) or in ice-cold phosphate-buffered saline (if operation performed at another hospital). After transfer to the laboratory, with a delay of about 2 h if transferred from another hospital,
the specimens were pinned to a Sylgard-lined petri dish with sufficient stretch to flatten the preparation. They were then immersed in
a solution of 2% paraformaldehyde with 15% picric acid, in a 0.1 M
phosphate buffer (pH 7.0) overnight at 4 C.
After fixation, the specimens were cleared by three 15 min washes in dimethyl sulphoxide and then placed in phosphate-buffered saline (pH 7.0) containing 30% sucrose. Frozen sections (12 m thick)
were cut both in the transverse and longitudinal axes, to provide
more accurate information about nerve fibre density, and collected
on chrome-alum coated glass slides before drying over P 2O5. After
incubating in phosphate-buffered saline containing 10% nonimmune serum for 30 min, the sections were incubated in the primary
antibodies (Table 1) overnight at room temperature. The choline
acetyltransferase (ChAT) antiserum (code AB1582; Chemicon,
Temecula, CA) was raised in a sheep using the method described by
Benecke et al. [18] and labels the same neurons in guinea-pig intestine as another well characterised ChAT antibody (code PO 3;
Yeboah, Hannover, Germany; kindly provided by Dr. M. Schemann
[26]). The sections were then washed in phosphate-buffered saline
and incubated for 1 h with secondary antisera. For rabbit antisera,
fluorescein-conjugated sheep anti-rabbit immunoglobulin (IgG)
(Wellcome Diagnostics, Beckenham, England; code 890520) was
used at 1:160; for sheep antisera, Cy5-conjugated donkey anti-sheep
IgG (Jackson, West Grove, PA; code 25324) was used at 1:20
and for the mouse antisera, fluorescein-conjugated donkey antimouse IgG (Jackson; code 34010) was used at 1:100. They were
again washed in phosphate-buffered saline and mounted in buffered
glycerol (pH 8.6)
Analysis
The specimens were viewed under a Leitz epifluorescence microscope (Leitz Inc., Rockleigh, New Jersey) or an AX70 epifluorescence microscope (Olympus Optical, Tokyo, Japan) fitted with appropriate filter blocks. The density of nerve fibres in each layer of
the intestinal wall was graded from 0 to 4+ by two independent observers (AJP and DAW); 0=no nerve fibres seen, 1+=sparse,
2+=moderate, 3+=high, 4+=very high (see examples in figures) [27].
In the rare occurrence that the two observers did not give the same
grade, the average of the two grades was taken. Data obtained from
each patient was grouped into ileum and colon (after averaging results from the different regions of colon, as there were no differences in innervation density between the regions of colon examined, except where specifically mentioned in the text). The density of nerve
fibres seen with each antibody was expressed as a mean and com-

210
Table 2 Mean density of nerve fibres containing each neurochemical marker in ileum and colon of control and slow transit constipation
(ST) patients
Ileum

NSE

TK

ENK

ChAT

VIP

NOS

NPY

C
4

ST
12

C
4

ST
12

C
4

ST
12

C
4

ST
6

C
4

ST
12

C
4

ST
7

C
4

ST
12

LM
MP
CM
SP
MU

3.0
4.0
4.0
3.3
4.0

2.6
4.0
4.0
3.3
4.0

2.3
4.0
4.0
2.0
3.7

1.6
4.0
1.5a
2.7
3.6

3.0
4.0
3.3
1.3
1.0

1.4
3.0
2.3
1.1
0.9

1.7
4.0
2.3
1.7
0.0

1.0
3.0
2.2
1.3
0.0

3.0
4.0
3.7
3.0
4.0

1.9
4.0
3.9
3.0
4.0

3.0
4.0
4.0
0.7
0.0

2.3
3.7
4.0
0.3
0.0

1.3
3.0
2.0
2.3
2.4

1.3
2.6
1.8
1.7
1.7

Colon
n

15

15

15

15

15

LM
MP
CM
SP
MU

1.7
4.0
4.0
3.6
4.0

1.2
4.0
3.9
3.4
3.9

0.6
3.9
3.5
2.7
3.9

0.5
3.8
1.2b
2.2
3.3

0.4
3.8
3.6
0.9
0.9

0.3
3.3
2.0c
1.3
0.9

0.5
3.0
2.5
1.5
0.0

0.4
2.9
2.3
1.3
0.0

1.1
4.0
3.9
3.0
4.0

0.6
3.9
3.8
3.0
4.0

1.3
4.0
4.0
0.6
0.0

1.1
4.0
4.0
0.4
0.0

0.4
2.8
2.0
1.4
1.9

0.3
2.2
1.5
1.4
1.7

ChAT, choline acetyltransferase; ENK, leu-enkephalin; NOS, nitric oxide synthase; NPY, neuropeptide Y; NSE, neuron-specific enolase;
TK, tachykinin; VIP, vasoactive intestinal peptide; LM, longitudinal muscle; MP, myenteric plexus; CM, circular muscle; SP, submucosal
plexus; MU, mucosa.
a
p=0.03, b p=0.003, c p=0.008
parisons of innervation density between STC patients and controls
were made using the Mann-Whitney U test corrected for ties, with a
probability of less than 0.05 considered to be significant. The numbers of patients having specimens labelled with each antibody is
shown in Table 2. The presence of nerve cell bodies in the myenteric and submucosal ganglia, mucosal endocrine cells and nerve fibres
surrounding blood vessels was noted with each antibody.

Results

Neuron-specific enolase
The same pattern of innervation with neuron-specific enolase (NSE)-IR nerve fibres was seen in the control group
and in the patients with STC. There were many nerve fibres in the circular muscle, the myenteric and submucosal
plexuses and the mucosa (Fig. 1). Many nerve cell bodies
were seen in both the myenteric and submucosal ganglia.
In the inter-taenial longitudinal muscle, the density of
nerve fibres varied from none (0) to high (3+) in both
groups of patients.

General
The mean density of immunoreactive nerve fibres in each
layer of gut is represented in Table 2 for terminal ileum
and large intestine for both the STC and the control group.
There was no apparent difference in innervation pattern
between the different areas of large intestine examined in
the control group, but there was some variation in density of tachykinin and enkephalin innervation between
different regions of large intestine in five of the patients
with STC. The density of innervation in each layer with
each antibody was very consistent, except for labelling
within the longitudinal muscle layer, which was variable.
Most specimens were from inter-taenial regions, where
only a very thin layer of longitudinal muscle was present.
It is not known if the innervation of this thin layer of longitudinal muscle is representative of the rest of the longitudinal layer, the bulk of which is contained in the taenia coli.
The specimens of bowel from patients with STC had
normal histology using standard haematoxylin and eosin
stains. They had no evidence of either muscle hypertrophy
or atrophy, the mucosa was not inflamed and melanosis
coli was present in only one patient.

Tachykinin
Patients with STC had a significantly decreased density of
tachykinin (TK)-IR nerve fibres in the circular muscle
layer compared to the control group in the terminal ileum
and large bowel (Fig. 2). TK-IR nerve cell bodies were seen
in the myenteric and submucosal ganglia in both groups,
as were many TK-IR nerve fibres in the myenteric plexus
and mucosa (Fig. 3).
In the control group, the density of TK-IR nerve fibres
in the circular muscle was similar in all regions examined.
However there was more variability in the STC group. Ten
patients had either sparse or no TK-IR fibres in the circular muscle (0/1+) in all regions examined. In four patients,
the decrease in density was more marked in the ascending
colon, and in one it was more marked in the descending
colon. Of the 12 specimens of terminal ileum examined,
three had normal TK-IR nerve fibre density in the circular
muscle (3+/4+) and nine had a significantly decreased density (0/1+).

211

Fig. 1 Transverse section through ascending colon of a patient with

STC labelled with neuron-specific enolase (NSE) immunoreactivity.
A very high density of nerve fibres (4+) was demonstrated in the circular muscle (closed arrowheads), longitudinal muscle (open arrowheads) and myenteric plexus (arrows). Calibration bar, 50 m
Fig. 2a, b Transverse sections through the descending colon of a
control patient (a) and a slow-transit constipation (STC) patient (b)
showing tachykinin-immunoreactive (TK-IR) nerve fibres. In the
control specimen, there were many TK-IR nerve fibres (4+) in the
circular muscle (closed arrowheads) but in the STC specimen, there
were none (0). There was a very high density of nerve fibres in the
myenteric plexus (arrow) of both patients. The longitudinal muscle
layer had scant innervation (1+) in the control patient (open arrowhead) and was absent in this specimen in the STC patient. Calibration bar, 50 m

Fig. 3 Abundant tachykinin-immunoreactive (TK-IR) nerve fibres

(4+) in the mucosa of ascending colon of a patient with slow-transit
constipation (STC) (closed arrowheads). Calibration bar, 50 m
Fig. 4a, b Ascending colon cut in transverse section in a control
specimen (a) and a slow-transit constipation (STC) specimen (b) labelled with leu-enkephalin antiserum. There were many enkephalin-immunoreactive (ENK-IR) nerve fibres (4+) in the circular muscle of the control specimen (closed arrowheads) but very few (1+)
in the STC specimen. The myenteric plexus of both specimens had
abundant ENK-IR nerve fibres (arrows), while the longitudinal muscle contained very few (1+) in the control specimen and none in the
STC specimen. Calibration bar, 50 m

212

Leu-enkephalin

Nitric oxide synthase

The number of Leu-enkephalin (ENK)-IR nerve fibres in

the circular muscle of the large intestine of patients with
STC was significantly less than the control group (Fig. 4).
In two patients, the decrease was more apparent in the ascending colon, and in one patient it was more marked in
the descending colon. These patients also had corresponding decreases in the density of TK-IR nerve fibres in the
circular muscle between different regions of large bowel.
There was no difference detected in the innervation of the
terminal ileum. The density of innervation in all other
layers of the bowel was the same in both groups of patients.

The pattern of nitric oxide synthase (NOS)immunoreactivity was similar in all patients. There were abundant NOS-IR
nerve fibres in both the myenteric plexus and throughout the
circular muscle layer (Fig. 7). Only a few NOS-IR nerve fibres were seen in the submucosa and these were mainly close
to the circular muscle, as has been described previously [28].

Choline acetyltransferase
There was no difference between the number of ChAT-IR
nerve fibres in any layer between the control group and
STC patients. Many ChAT-IR nerve fibres were seen in the
circular muscle in both groups (Fig. 5). The antibody to
ChAT labelled nerve cell bodies much more intensely than
nerve fibres and therefore evaluation of density of nerve
fibres with this antibody was less reliable. Small differences in the density of ChAT-IR nerve fibres between the
two groups of patients may not have been detected.
Vasoactive intestinal peptide
There was no significant difference in the density of VIPIR nerve fibres between control and STC patients in any
layer of the intestine. All layers of the intestine had abundant VIP-IR nerve fibres, except for the longitudinal muscle. VIP-IR nerve fibres appeared to be evenly distributed throughout the circular muscle in all specimens
(Fig. 6).

Fig. 5 Choline acetyltransferase (ChAT) immunoreactivity in a longitudinal section of transverse colon from a patient with slow-transit constipation (STC). There was a very high density (4+) of ChATimmunoreactive (IR) nerve fibres in the circular muscle (closed arrowheads) but none in the longitudinal muscle. Many ChAT-IR nerve
cell bodies were seen in the myenteric plexus (arrow). Calibration
bar, 50 m
Fig. 6 Vasoactive intestinal peptide (VIP) immunoreactivity in ascending colon of a slow-transit constipation (STC) patient. A very
high density (4+) of VIP-immunoreactive nerve fibres in the circular muscle (closed arrowheads) and a high density (3+) in the longitudinal muscle (open arrowheads) was seen. Many fibres (4+) were
also seen in the myenteric plexus (arrows). Calibration bar, 50 m
Fig. 7 Transverse section of terminal ileum from a slow-transit constipation (STC) patient labelled with nitric oxide synthase (NOS) immunoreactivity. A very large number (4+) of NOS-immunoreactive
nerve fibres were distributed evenly throughout the circular muscle
layer (closed arrowheads), while only scant innervation (1+) of the
longitudinal muscle was seen (open arrowheads). Neurons were seen
in the myenteric plexus (arrow). Calibration bar, 25 m

Neuropeptide Y
Neuropeptide Y (NPY)-IR nerve fibres surrounding blood
vessels and NPY-IR endocrine cells were abundant in both

213

groups of patients. The density of NPY fibres was the same

in the control group as in the patients with STC, with a
moderate number of nerve fibres in the circular muscle and
myenteric plexus and sparse innervation of the longitudinal muscle.
Tyrosine hydroxylase
The pattern of tyrosine hydroxylase (TH) immunoreactivity was the same in both groups. TH-IR nerve fibres were
abundant around myenteric ganglia and surrounding blood
vessels, especially in the submucosa. No nerve fibres were
seen in the muscle layers.

Discussion

General
There were no significant differences between controls and
STC patients using the NSE antiserum. The unchanged
density of nerve fibres labelled with NSE, which is a
marker of all enteric neurons, indicates that there is no general neuronal reduction in these patients in any layer or region of intestine.
Excitatory nerve fibres
In this study, a reduction of TK-containing nerve fibres was
demonstrated in the circular muscle of patients with STC.
While all STC patients had this abnormality in at least one
region of colon, several had regions of large bowel which
were relatively spared. The reduction of TK-IR circular
muscle nerve fibres was also present in the terminal ileum
of some patients. This indicates that the reduction of tachykinins in the circular muscle of these patients may be
part of a generalised disorder, with regions of the gastrointestinal tract showing variable degrees of this abnormality.
Indeed, this may explain why patients with STC often have
other motility disorders, such as reflux oesophagitis and
abnormalities of gastric and small bowel transit [7, 29, 30].
Long-term follow-up of these patients may indicate
whether the presence of abnormal innervation of the terminal ileum is a predictor of a poor long-term prognosis
following subtotal colectomy. Evidence in rats indicates
that substance P levels are not altered in the colon after
long-term treatment with laxatives, although VIP levels are
reduced [31], suggesting that the reduction of TK-IR fibres in our study is unlikely to be due to laxative treatment
in these patients.
Another study found that the concentration of substance
P and density of substance P-containing nerve fibres in the
circular muscle of patients with STC was not different to
that of control patients [13]. However, their control group
was significantly older than the STC group, so a direct comparison between the two groups is not possible, given the

reports of significant changes in the enteric nervous system

in humans and small animals with ageing [1416].
No difference was demonstrated in the density of TK
innervation in any of the other layers of intestine, suggesting that the decrease in tachykinins in these patients is specific to the circular muscle and is not a reduction of all TKcontaining nerve fibres. As the number of nerve fibres in
the myenteric plexus is so great, large reductions would
need to occur to be detected in frozen sections. The density of TK-IR nerve fibres in the submucosa and mucosa
from the terminal ileum to the descending colon was the
same in controls and STC patients, although another study
has shown that the concentration of substance P in the rectal mucosa and submucosa of patients with STC is reduced
[32]. There may have been a subtle decrease in the amount
of tachykinins in the mucosa and submucosa which our
methodology was unable to detect. The finding in our study
that there was no detectable change in the mucosa suggests
that performing mucosal biopsies and examining for the
markers we used on STC patients would not reveal any abnormality.
The tachykinin antisera used was raised against the Cterminal peptide of substance P and so did not differentiate
between the different members of the tachykinin family,
i.e. substance P, neurokinin A and neurokinin B. All three
peptides have been localised to the myenteric and submucosal plexuses, the circular and longitudinal muscle layers
and the mucosa of human bowel [33, 34]. As selective antisera or radioimmunoassay techniques were not used, we
were unable to determine if all three tachykinins are reduced in the circular muscle by the same extent or if there
is a selective decrease in STC.
The number of ENK-IR circular muscle nerve fibres in
the large bowel of patients with STC was also decreased
compared with the control group, although this decrease
was not significant in the terminal ileum. There was a correlation between the reduction of TK- and ENK-IR nerve
fibres at the different regions of large bowel in the patients
in whom the decrease occurred predominantly in one region. This close correlation between TK- and ENK-IR
nerve fibres is to be expected, given that the coexistence
of tachykinins and enkephalin in nerve fibres in circular
muscle of human colon is well recognised [35]. The density of ENK-IR nerve fibres in all other layers of the gut
was unchanged compared with the control group, indicating that the reduction in the circular muscle was not part
of a general decrease in all ENK-containing nerve fibres.
Much recent work, both in experimental animals and
humans, indicates that different functional classes of neurons can be identified by the combinations of neurochernicals within them, a concept known as chemical coding
[9]. These studies suggest that human colonic circular
muscle motor neurons contain NOSVIPNPY or ChAT
TKENK, and these two classes of neurons are likely to
represent inhibitory and excitatory motor neurons respectively [3540]. Our study found that ChAT-IR nerve fibres
were present in normal numbers in the circular muscle of
patients with STC, although a small reduction was possible
given the relatively faint labelling of nerve fibres with the

214

ChAT antibody. Thus it appears that while excitatory nerve

fibres are present in STC, they are deficient in tachykinins
and enkephalin.
Tachykinins have been shown to be involved in excitatory neurotransmission to human intestinal circular muscle, mainly via NK2 receptors [41, 42]. A reduction in the
release of tachykinins from nerve fibres to the circular
muscle would lead to a reduction of excitatory transmission to the circular muscle. This would affect the ascending excitatory reflex, as tachykinins have been shown to
be involved in this pathway in human intestine [43]. Interestingly, propagating contractions have been found to be
reduced in number and amplitude in patients with STC
[44, 45].
The role of opioid-containing nerve fibres in the circular muscle is less clear. In the circular muscle of the human colon, leu-ENK and met-ENK can act on prejunctional
-opioid receptors to produce inhibition of nonadrenergic,
noncholinergic inhibitory neuromuscular transmission
[461 and agonists also inhibit neuromuscular transmission [47]. Naloxone, the opioid antagonist, has been shown
to ameliorate constipation in patients with STC [48], although its site of action is unknown. Thus, the effect of reduced opioid containing nerve fibres in the circular muscle is unclear.
There is some evidence regarding functional abnormalities in patients with STC. There is a reduction in the release of acetylcholine from the taenia following electrical
field stimulation in patients with STC compared with controls [49], suggesting that fewer cholinergic nerves are
functional. In addition, the circular muscle of STC patients
was found to be hypersensitive to the application of carbachol [50]. These results support the theory that there is
a reduction of excitatory nerve fibres supplying the circular muscle in these patients. To date, no studies have examined neuromuscular transmission from excitatory or inhibitory motor neurons in STC.

targeted disruption of the gene, there is no obvious disruption to colonic function, although pyloric stenosis results
[53].
Extrinsic nerve fibres
The finding that nerve fibres with TH, which is a marker
of noradrenergic fibres, surrounding myenteric ganglia and
blood vessels were not different in STC patients suggests
that sympathetic innervation is preserved in these patients.
This is reinforced by the observation that NPY-IR nerve fibres around blood vessels, shown to be sympathetic nerve
fibres [51], are still present in STC patients.
Conclusion
The finding of a deficiency in tachykinins and enkephalin in excitatory nerve fibres in the circular muscle in
STC raises several questions. For example, it would be
important to address whether excitatory transmission is
impaired in these patients, especially whether tachykinergic excitation alone is abnormal or if cotransmitters such
as acetylcholine are also affected. It would also be interesting to investigate potential abnormalities of the projections and neurochemistry of circular muscle motor
neurons of patients with slow transit constipation using
retrograde tracing combined with immunohistochemistry. These further lines of investigation may provide crucial information regarding this poorly understood motility disorder.
Acknowledgements Anthony Porter is the recipient of a National
Health and Medical Research Council Medical Postgraduate Research Scholarship. We would like to thank Prof. P. OBrien, Mr. R.
Sarre, Mr. G. Otto and Mr. J. Sweeney for contributing patients to
this study and Janine Falconer-Edwards for expert technical assistance. This study was supported by a Flinders Medical Centre 2000
Research Foundation Grant.

Inhibitory nerve fibres

The distribution and density of NOS- and VIP-IR nerve fibres were the same in both groups. Nerve fibres which
contain NOS and/ or VIP are likely to be inhibitory nerve
fibres to the circular muscle [36, 52]. As we found no evidence of differences in control and STC patients in circular muscle fibres with these markers, it is likely that there
are no abnormalities of inhibitory innervation to the circular muscle in STC patients. Another study found an increased number of NOS-IR neurons and a decreased number of VIP-IR neurons in STC patients in both the submucosal and myenteric plexuses but incongruously reported
an increased number of VIP-IR nerve fibres in the circular muscle [11]. Some studies have shown a decreased concentration of VIP and density of VIP-IR nerve fibres in the
circular muscle [10], while other studies have reported normal concentrations of VIP [13] and density of VIP-IR fibres in the circular muscle [12, 13]. It appears that even in
the complete absence of neuronal NOS in mice, due to the

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Int J Colorect Dis (1998) 13: 217 222

Springer-Verlag 1998

O R I G I N A L A RT I C L E

M. Bouchoucha J.-M. Odinot G. Devroede

B. Landi P.-H. Cugnenc J.-P. Barbier

Simple clinical assessment of colonic response to food

Accepted: 20 May 1998

Abstract The colonic response to food (CRF) is an integrated function of the colon that has been poorly studied
in clinical practice. This study describes a new method to
measure it, based on the progress of radio-opaque markers, and shows the results in healthy subjects and in patients with irritable bowel syndrome (IBS). Thirty healthy
subjects and 43 patients suffering from IBS were studied.
Two studies of colonic transit time (CTT), at rest and
after eating a standard test meal, were performed. CRF was
quantified by calculating the variation in number of markers in each zone of interest of the large bowel using X-ray
films of the abdomen taken before and after eating. The results were as follows: (1) CRF is characterised by caudal
propulsion of the colonic contents in the two groups. In
controls, there is emptying of the cecum-ascending colon
region and filling of the distal large bowel. In IBS patients,
only emptying of the left transverse colon and the splenic
flexure is found. (2) IBS patients have a delayed CTT because of slowing in the right and left colon, and this is both
before and after a meal. The determination of the movements of markers after eating is a simple method that is
useful in clinical practice to evaluate CRF.
Key words Colonic transit time Irritable bowel
syndrome Methodology

M. Bouchoucha () J.-M. Odinot B. Landi

P.-H. Cugnenc J.-P. Barbier
Universit Paris V, Laboratoire de physiologie digestive et
dpartement de Gastroentrologie, Hpital Laennec,
42, rue de Svres, F-75007 Paris, France,
Fax: 0033-1-44-39-69-27, Tel.: 0033-1-44-39-69-22,
e-mail: michel.bouchoucha@lnc.ap-hop-paris.fr
G. Devroede
Dpartement de Chirurgie, Facult de Mdecine,
Universit de Sherbrooke,
Sherbrooke, Qubec, Canada

Introduction

Food is an important stimulus of colonic motility. The colonic response to food (CRF) is an integrated function of
the colon, characterized by an increase in magnitude and
frequency of colonic contraction [1]. The term gastrocolic
reflex, widely used, is not appropriate to describe the increased colonic activity that occurs after eating [2]. Neural or hormonal pathways have been implicated but no clear
mechanism of food action has been described [1, 2].
In humans, variations in colonic motility after a
meal have been studied by several techniques. Manometry [37], electromyography [810], scintigraphy [5, 6,
1113], and telemetry [13] have been used alone, or in combination with each other, to describe meal-induced changes
in motor activity. All these techniques are tedious, difficult to interpret, and not of practical use in the clinical evaluation of outpatients. These technical obstacles explain
why the postprandial rhythmic modulation of gastrointestinal motility, an important physiological phenomenon, is
not used to define the subtypes of functional bowel disorders [14].
IBS is a clinical disorder characterized by abdominal
pain and alterations in bowel habits, without recognized
organic disease [15]. Patients have altered colonic motility [16] and are often hypersensitive to various stimuli,
such as stress, sleep, food, or distention [16, 17]. Motor
abnormalities are recognized not only in the colon but
also in the entire digestive tract [18]. The nature of the
colonic motility response to eating is, nevertheless, controversial [9, 10]. There is a need for a simple clinical
test, applicable anywhere and at reasonable cost, to evaluate the effects of food or drugs on segmental transit in
the human colon in vivo. The scintigraphic technique [19]
is useful for measurement of large bowel transit, but not
for changes within segments of the large bowel. Conversely, other techniques may bring the radioactive material directly into the transverse colon [5], but they are
not simple to use clinically. Finally, colonic scintigraphy
is not performed everywhere, but patients can ingest ra-

218
Table 1 Clinical description of
patients at inclusion (n = 43)

Female/male
Age (years)
Duration of symptoms (years)

9.75, P < 0.001

41 17 (1968)
18 13 (260)

Abdominal pain

None

Severity (self-assessed)
Duration (years)

5
5

Bowel habit alteration

None

Decreased stool frequency (<1/3 days)

Hard stools
Straining
Loose stools
Fiber laxatives (>2/week)
Response to fiber supplement

0
1
1
36
37
42

Normal physical examination

43

Mild

Moderate

Severe

15
17

22
21

1
0

Occasionally

Frequently

Permanently

28
28
27
2
2
0

8
7
7
0
2
0

7
7
8
5
1
1

dio-opaque markers at home and have plain films of the

abdomen made practically everywhere. So far, no study
using radio-opaque pellets in a dynamic fashion has been
performed: previous reports were limited to evaluate transit time without measuring the impact of a physiological
stimulus.
The aims of the present study are thus: (1) to describe
a new method to measure CRF, based on movement of radio-opaque markers, the colonic transit response to eating;
(2) to compare results obtained with this technique in controls and IBS patients.

Patients and methods

Subjects
Studies were performed in 30 control subjects (19 females and 11
males, 1936 years old), recruited by a local announcement, and 43
patients (38 females and 5 males, 1968 years old). Informed consent was obtained from all subjects. All patients had been referred
consecutively to the laboratory of digestive physiology at the Laennec hospital with symptoms of IBS lasting for more than 2 years
(mean SD 18 13 years; range 260 years) as defined by the Rome
criteria (15). All clinical results at inclusion are shown in Table 1.
Lactase deficiency was excluded by history. Organic, infectious and
parasitic diseases were excluded by colonoscopic examination, barium enema, anorectal manometry, laboratory tests, stool examination and culture.

Fig. 1 The abdomen was divided in seven zones according to bony

landmarks and gaseous outlines: cecum and ascending colon, hepatic flexure, right transverse colon, left transverse colon, splenic flexure, descending colon, rectosigmoid segment

Experimental procedure
Data analysis
The protocol for the study was approved by the ethics committee
(comit consultatif mdical pour la protection des personnes dans la
recherche biomdicale, Ile de France-Paris Saint Antoine). The experimental design included one measure of colonic transit time in
every subject, with films taken at rest and after eating a standard test
meal.
Colonic transit was measured as described previously [21]. Briefly, 24 radio-opaque markers within a gelatin capsule (Rsch-France)
were ingested each day for 6 days at 9:00 a.m. A plain film of the
abdomen was taken on the seventh day, at 9:00 a.m., at rest. Thereafter a standard test meal (1000 Kcal, proteins: 32 g, lipids: 47 g,
glucides: 112 g) was ingested and a second plain film (postprandial
film) was taken at 11:00 a.m.

Markers were localized and counted in the different segments of large

bowel according to bony landmarks and gaseous outlines, as described previously [20]. The spinal column served to separate the
right from the left colon; the pelvic inlet was taken to separate the
rectosigmoid area from the left colon. The colon was also divided
into seven zones in order to better describe movement of the markers: three for the right colon, i.e., cecum and ascending colon, hepatic flexure and right transverse colon; three for the left colon, i.e., left
transverse colon, splenic flexure and descending colon; and the rectosigmoid segment (Fig. 1).
Segmental and total colorectal transit times (CTT) were calculated according to distribution of the markers in the different seg-

219
Table 2 Colonic transit
(hours, mean SEM)

Segment

Cecum + ascending colon

Hepatic flexure
Right transverse colon
Right colon
Left transverse colon
Splenic flexure
Descending colon
Left colon
Rectosigmoid area
Total colonic transit

At rest

After meal

Controls
(n = 30)

IBS
(n = 43)

P value

Controls
(n = 30)

IBS
(n = 43)

P value

14.0 1.4
1.7 0.5
4.0 1.2
19.7 1.8
3.3 0.9
2.6 0.8
8.4 1.3
14.3 2.4
12.4 2.2
46.4 4.5

18.5 2.1
1.9 0.5
6.3 1.1
26.7 2.8
7.2 1.5
3.7 0.7
18.2 2.4
29.1 3.0
18.5 2.7
74.3 6.3

NS
NS
NS
0.0362
0.0241
NS
0.0006
0.0002
NS
0.0006

12.0 1.5
1.9 0.6
3.9 1.1
17.8 1.9
3.5 0.9
1.7 0.6
8.1 1.6
13.3 2.3
15.3 2.3
46.4 4.5

16.4 1.9
2.4 1.0
7.3 1.3
26.1 2.9
5.4 1.0
2.2 0.6
19.4 2.4
27.0 2.8
21.2 3.1
74.3 6.3

NS
NS
NS
0.0204
NS
NS
0.0002
0.0005
NS
0.0006

ments of bowel. This was done using the equation CTT = T/N n
[20], where T is the time between two ingestion of markers, N is
the number of markers ingested at each intake, and n is the number
of markers in the zone of interest. According to the values used in
the present study, N = 24 radio-opaque markers and T = 24 h:
CTT = 24 n = n .
24

alyzed in this study, only six reports were different (4%).

In these cases, the films were reviewed for final analysis,
and the two physicians counted markers together.
Another difficulty was in determining the colonic sites
used for the analysis, especially when dolichomegacolon
was present. Using the position of the markers in the preand postprandial films to localize the colonic regions
solved this difficulty.

Intra-experimenter variation
To allow for possible observer variation , in the description of the
different bowel segments, two physicians read all plain films, independently and unaware of the status of the subjects.
Colonic transit response to food
The colonic transit response to food was quantified by determining
the variation in number of markers in each zone of interest between
the film taken after eating and that before eating. The response was
negative when a decrease in the number of markers was found (i.e.,
emptying of the zone), and positive when an increase was found (i.e.,
filling of the zone).

Repeatability
In the 16 subjects studied, no difference was found between
the two tests, either in measurement of CTT or in determination of the CRF to eating (P = NS for all variables).
Colonic transit time for the starved state

To validate the reliability of the technique, the study was performed

twice in 16 subjects independent of the present study.

Compared to healthy controls, IBS patients showed an increase of the total CTT (74.4 5.7 h vs 46.4 4.5 h; P =
0.0006) which was related to a delay in the right and left
part of the colon (Table 2). The main difference was found
in the transit time through the descending colon
(18.2 2.4 h vs 8.3 1.3 h; P = 0.0006).

Statistical analysis

Colonic transit time after eating

Reliability

The parameters to be analyzed were the differences between healthy

controls and IBS patients and the change in the number of markers
induced by the meal. Differences between the two groups were compared by the Student t test.

Similar results were found after eating (Fig. 2): in IBS patients, transit was prolonged in the right (P = 0.0204) and
left (P = 0.0005) colon. Transit in the rectosigmoid area
was not significantly different (Table 2). As found at rest,
the main difference was in the descending colon
(19.4 2.4 h vs 8.1 1.6 h; P = 0.0002).

Results

Preliminary studies

Colonic transit response to food

Intra-experimenter variation

The test meal induced caudal propulsion of colonic contents both in healthy controls and in IBS patients (Table 3).
In healthy controls, after eating, a significant outflow of
the right colon occurred (P = 0.0142), due to emptying of
the cecum-ascending colon zone (P = 0.0256) and filling

In some films, determination of the number of markers varied according to the experimenter, especially when patients
presented with a delay in CTT. Of the 146 films (273) an-

220
Fig. 2 In this healthy subject,
a meal induces a rapid movement of markers that are projected from the right part of the
transverse colon (left) to the
rectosigmoid area (right) after
eating

Table 3 Colonic transit response to food: variation in the

number of markers after food
intake

Segment

Cecum + ascending colon

Hepatic flexure
Right transverse colon
Right colon
Left transverse colon
Splenic flexure
Descending colon
Left colon
Rectosigmoid area

of the rectosigmoid zone (P = 0.0047) (Table 3). In contrast, in IBS patients, emptying of the right colon was not
significant; indeed, ceco-ascending emptying was more
significant than in controls (P = 0.0102). Filling of the
distal large bowel was not significant either. Significant
changes were found only in the left part of the colon and
consisted of net emptying of the left colon (P = 0.0102)
because of emptying of the left transverse colon (P =
0.0249) and the splenic flexure (P = 0.0024). These results
are summarized in Fig. 3.
Due to the great variation of the colonic response in the
left colon, no significant difference between IBS patients
and healthy subjects was found in the intensity of the CRF.

Discussion

Our major aim was to establish a simple technique to quantify CRF. In particular, we hoped to present and validate a
method that would be convenient in the clinical setting.
The use of radio-opaque markers permits the measurement

Controls (n = 30)

IBS patients (n = 43)

Variation
(mean SEM)

P value

Variation
(mean SEM)

P value

2.0 0.8
0.2 0.6
0.1 0.6
1.9 0.7
0.2 0.9
0.9 0.5
0.3 0.9
1.0 1.0
2.9 0.9

0.0256
NS
NS
0.0142
NS
NS
NS
NS
0.0047

2.1 0.8
0.5 0.9
1.0 0.7
0.6 0.9
1.8 1.0
1.5 0.5
1.2 1.1
2.1 1.6
2.7 1.8

0.0102
NS
NS
NS
0.0249
0.0024
NS
0.0102
NS

of CTT and the analysis of CRF as an expression of transit (i.e., propulsion of the bolus induced by the food intake). Moreover, with this technique useful physiological
information about IBS patients can be easily obtained.
Studies of colonic activity are divided into those analyzing movements of intraluminal contents and those
analyzing wall movements, i.e., contractile or myoelectric
activity. A combination of the two methods shows a correlation between these two patterns of colonic activity. It
is clear that the methodology developed for use in this study
is based on the flow pattern of colonic activity. Cannon,
who examined radiologically the movements of barium in
different species [21], was the first to perform studies of
flow movement. He showed that retrograde migrating
movements of contents were preponderant in the proximal
colon. Recent studies using isotopic methods showed
clearly that retrograde movements could occur in all colonic segments [22]. After eating, both anterograde and
retrograde movements increase, but the number of anterograde movements is greater [12]. One technique involves
ingestion of a long peroral tube and instillation at the
splenic flexure [5, 23, 24], a practice that, although useful,

221
Fig. 3 Representation of
movement of markers after ingestion of a test meal in controls and irritable bowel syndrome (IBS) patients. In the
two groups, there were emptying of the first part of the colon
and filling of the terminal intestine. However, in IBS patients
abnormal emptying of the left
transverse colon is associated
with filling of the right transverse colon (retrograde mass
movement) and filling of the
descending colon (anterograde
mass movement). In IBS patients food intake reduces the
number of markers in the left
colon and not in the right colon
as in controls and is unable to
fill the terminal intestine as in
controls

is difficult to apply in clinical practice. Noninvasive radioisotope techniques involve oral ingestion of 111In-DTPA
or [31]-iodine-cellulose or incorporation of 111In in nondigestible or coated capsules that disperse in the ileocecal
region [25, 26]. These techniques are inadequate to evaluate regional transit because they require a bolus injection
in a given site or mathematical correction [27]. Thus, scintigraphic investigations are not widely used in clinical
practice. The present radiological technique is simple, noninvasive, feasible in any clinic and does not significantly
increase the amount of radiation exposure.
Eating affects colonic motility. In young children, defecation is often observed during or just after eating. During this study, movement of markers were sometimes observed only in the oral direction (Fig. 2), and more frequently in both the oral and aboral directions, resulting in
a net movement of markers in the aboral direction. In many
subjects suffering from IBS, the test meal induced no motion: markers remained at the same place, independent of
the number of markers present in the colon. Nevertheless,
in the entire group, the importance of the migration was
weak, mainly in patients with delayed transit (there were
about two markers, which is the equivalent of 2 h of transit time).
The effect of a meal on intestinal motility, improperly
called the gastrocolic reflex, implies that all digestive
segments are involved. However, although an effective
stimulus occurs when food enters the duodenum [1], the
CRF is preceded by acephalic phase:food discussion, as
well as the sight and smell of food without taste act as important stimuli of the CRF [4]. In the interdigestive phase,
the motility of the stomach and the intestine is characterized by cyclic variations in activity, called the migrating
motor complex. After eating, irregular contractions appear
in the small intestine and are frequently propagated, with
high amplitude, but no clear relationships exist between
intestinal activity and transit through the gut [28]. The motor CRF is related to the amount of calorie intake [28] and

is characterized by an increase in migrating long spike

bursts during electromyographic recording [2931] and
an increase in giant migrating contractions during manometric recording [5].
Scintigraphic studies have shown that food intakes induces a propulsive activity, rarely found at rest, in the oralaboral direction in the entire colon [5, 12] and associated
in the splenic flexure with retrogrades movements that induce mixing of colonic contents [12]. Our findings are in
agreement with these results. In healthy subjects, the CRF
is associated with emptying of the ascending colon and filling of the terminal intestine. By contrast inn IBS patients,
there is emptying of the left transverse colon and a, not statistically significant, filling of the right transverse colon
and the descending colon (Fig. 3). In controls, there is a
rather smooth progression of colonic contents distally,
whereas in IBS patients there is a sort of bumpy progression because of the behavior of the left colon.
The method presented in this study demonstrates clearly
the abnormal response to food in IBS patients. After 2 h,
some IBS subjects showed no variation in the number of
markers in any zone, while in others important retrograde
or caudal movements were observed. By contrast, healthy
controls rarely had retrograde movements of markers. All
movements were localized in the transverse or descending
colon. This justifies, in retrospect, why the division used
in the present study, based on an earlier report [32], was
chosen. We also added a division of the transverse colon
in two zones, right and left.
This new test could be used to classify IBS patients according to the colonic response to eating: no change, oral
retropulsion, or aboral migration of pellets after eating.
Following the movements of markers has a major advantage over the more or less subjective modalities presently
in use, in that the methodis not based on symptomatology
but rather on objective physiological measurements.
It should also be noted thatthe speed of propagation of
bowel contents can be appreciated by the kinetics of the

222

marker movements (Fig. 2). As in this example, the speed

of the migration of bowel content was greater speed than
that of mass movements as determined by manometric
studies [1].
In conclusion, the determination of movements of markers after eating is a simple,clinically useful methodto evaluate CRF. This response is characterized in healthy controls by emptying of the cecum and ascending colon and
filling of the terminal intestine. In contrast in IBS patients,
these modifications are accompanied by significant variations in the left part of the transverse colon and the splenic
flexure
Acknowledgements The authors of this article received a grant
from Solvary Pharma for this study.

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(ed) Physiology of the gastrointestinal tract, 3rd edn. Raven,
New York, pp 9911024
2. Christensen J (1989) Colonic motility. In: Wood JD (ed)
Handbook of physiology: the gastrointestinal system, vol. 1,
part 2, 2nd edn. American Physiological Society, Bethesda,
pp 939973
3. Loening-Baucke V, Anuras S (1983) Effects of a meal on the
motility of the sigmoid colon and rectum in healthy adults. Am
J Gastroenterol 78: 393397
4. Rogers J, Raimundo AH, Misiewicz JJ (1993) Cephalic phase
of colonic pressure response to food. Gut 34: 537543
5. Bazzocchi G, Ellis J, Meyer JV, Reddy SN, Mena 1, Snape WJ
Jr (1991) Effect of eating on colonic motility and transit in patients with functional diarrhoea. Simultaneous scintigraphic and
manometric evaluations. Gastroenterology 101: 12981308
6. Kerlin P, Zinsmeister A, Phillips S (1983) Motor responses to
food of the ileum proximal colon, and distal colon of healthy humans. Gastroenterology 84: 762770
7. Willey J, Tatum D, Keinath R, Owyang C (1988) Participation
of gastric mechanoreceptors and intestinal chemoreceptors in
the gastrocolonic response. Gastroenterology 94: 11441149
8. Bassoti G, Morelli A, Whitehead WE (1992) Abnormal rectosigmoid myoelectric response to eating in patients with severe
idiopathic constipation (slow-transit type) Dis Colon Rectum
35: 753756
9. Dapoigny M, Trolese JF, Bommelaer G, Tornut R (1987)
Rponse colique au repas du colon droit, du colon gauche, du
recto-sigmoide, et de la charre recto-sigmoidienne au cours
des troubles fonctionnels digestifs. Gastroenterol Clin Biol
12: 361367
10. Sullivan MA, Cohen S, Snape WJ (1978). Colonic myoelectrical activity in irritable colon. Effect of eating and anticholinergic. N Eng J Med 298: 878883
11. Davies GJ, Crowder M, Reid B, Dickerson JWT (1986) Bowel
function measurements of individuals with different eating patterns. Gut 27: 164169
12. Picon L, Lmann M, Flouri B, Rambaud J-C, Rain J-D, Jian R
(1992) Right and left colonic transit after eating assed by a
dual isotopic technique in healthy humans. Gastroenterology;
103: 8085

13. Steed KP, Bohemen EK, Lamont GM, Evans DF, Wilson CG,
Spiller RC (1993) Proximal colonic response and gastrointestinal
transit after high and low fat meals. Dig Dis Sci: 38: 17931800
14. Drossman DA and the Working Team Committee Chairmen
(1994) The functional gastrointestinal disorders and their diagnosis: a coming of age. In: DA Drossman, JE Richter, NJ Talley, et al. (eds) The functional gastrointestinal disorders. Little,
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15. Thomson WG and the Working Team for Functional Bowel Disorders (1994) Functional bowel disorders. In DA Drossman, JE
Richter, NJ Talley, et al. (eds) The functional gastrointestinal
disorders. Little, Brown, pp 115152
16. McKee DP, Eamonn MD, Quigley MM (1993) Intestinal motility in irritable bowel syndrome: Is IBS a motility disorder? Dig
Dis Sci, 38: 17611782
17. Schuster MM (1993) Irritable bowel syndrome In: Sleisenger
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Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut 24: 405411
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20. Bouchoucha M, Devroede G, Ahran P, et al. (1992) What is the
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21. Cannon WB (1902) The movements of the intestines studied by
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Int J Colorect Dis (1998) 13: 223 227

Springer-Verlag 1998

O R I G I N A L A RT I C L E

M. Pescatori A. Interisano V. M. Stolfi M. Zoffoli

Delormes operation and sphincteroplasty for rectal prolapse

and fecal incontinence

Accepted: 20 January 1998

Abstract Clinical and manometric results of Delormes

operation and sphincteroplasty were assessed retrospectively in patients undergoing this procedure for fecal incontinence and rectal prolapse. A series of 33 patients (11
males, 22 females; aged 1883 years, mean 59) with external rectal prolapse were treated by Delormes operation
between 1989 and 1996. Mean follow-up was 39 months
(range 784). Sphincteroplasty was associated in 12 cases
with severe fecal incontinence due to striated muscle defects. Good results were achieved in 27 patients (79%);
prolapse recurrence was observed in 6 (21%), the mean recurrence time being 9 months (range 124 months). There
were no postoperative deaths. Minor complications occurred in 15 patients. Changes in preoperative and postoperative manometric patterns were as follows (meanSEM):
voluntary contraction from 596.9 to 667.1 mmHg
(P=0.05), resting tone from 335 to 324.3 mmHg, rectal
sensation from 595 to 615.2 ml of air (n.s.). A solitary
rectal ulcer syndrome was detected in five patients. The
histological pattern demonstrated pathological changes in
40% of cases. Fecal incontinence was resolved in 6 of 20
cases (30%) and chronic constipation in 4 of 9 (44%). Failure (n=3) was related primarily to postoperative sepsis. The
incontinence score showed a mean improvement of 35%
decreasing, from 4.50.39 to 2.90.44 after surgery
(P<0.01). In conclusion, Delormes procedure did not lead
to constipation and improved anal continence when associated with sphincteroplasty.
Key words Delormes operation Sphincteroplasty
Fecal incontinence

Introduction

Management of rectal prolapse is more difficult when it is

associated with constipation and fecal incontinence, and
M. Pescatori() A. Interisano V. M. Stolfi M. Zoffoli
Coloproctology Unit, Villa Flaminia, Via L. Bodio 58,
I-00191 Rome, Italy

many surgical procedures have been proposed to correct

these conditions [110]. Once the anatomical disorder is
corrected, any remaining problems with obstructed defecation or incontinence results in poor patient satisfaction.
Due to our presently incomplete understanding of the pathophysiology of the condition, there is no strong evidence
in favor of any particular surgical approach.
Mucosal stripping of the prolapsed rectum followed by
plication of the underlying muscular layer was first described by Delorme [1]. Several recent reports have shown
an increased interest in this operation particularly in elderly
patients at poor risk for major abdominal surgery and requiring a locoregional anesthesia [210]. Postanal and total pelvic floor repair have both been advocated to restore sphincter function, but the results are still controversial [11].
The purpose of this study was to investigate the clinical and functional results of Delormes operation alone and
in association with sphincteroplasty.

Patients and methods

Thirty-three patients (11 males, 22 females) with external rectal prolapse were treated by Delormes operation at the Coloproctology Unit
of Rome between January 1989 and May 1996. Their mean age was
59 years (range 1883 years), and the mean follow-up was 39 months
(range 784). Nine patients had severe constipation before surgery,
and 20 were incontinent. In 12 cases sphincteroplasty, either as postanal repair (n=6) or total pelvic floor repair (n=6), was also performed in the attempt to correct severe fecal incontinence. Sphincteroplasty was indicated when both the clinical examination and anorectal physiology tests (manometry, EMG, defecography, anal ultrasound) suggested a striated sphincter defect. All operations were carried out by the first author according to the technique reported elsewhere [911]. The extent of the prolapsing rectum never exceeded
8 cm on straining in the squatting position. lt was mainly mucous in
22 cases and full thickness in 11.
Informed consent was obtained from the patients, who were hospitalized the day before surgery for mechanical bowel preparation
and antibiotic prophylaxis with metronidazole and cephalosporine.
Specimens of the excised mucosa were sent to the pathology laboratory to assess any inflammatory or ischemic changes. Patients were
kept on a low-residue diet for 1 week postoperatively, and the first
evacuation was facilitated by either enemas or mild laxatives. Ano-

224
mm Hg
100
90
Preop values
Postop values

80
70
60
50
40
30
20
10
0
1

10

11

12

Fig. 1 Pre- and postoperative changes in resting tone at anal manometry in 25 patients undergoing Delormes operation for rectal
prolapse; 12 also had a sphincteroplasty ()

13

14

15

16

17

18

19

Results

Outcome of the Delorme procedure was satisfactory in

27 of the 33 patients (79%). Prolapse recurrence was observed in 6, with a mean recurrence time of 9 months
(range 124 months). There were no postoperative
deaths, but two patients died of nonrelated conditions, respectively, 1 and 3 years after the procedure. Minor postoperative complications occurred in 15 patients and resolved within a few days (minor dehiscence, negligible

21

22

23

24

25 pts.

Table 1 Manometric pattern before and after surgery

Voluntary contraction (mmHg)

Resting tone (mmHg)
Rectal sensation (ml air)
rectal manometry was performed before and, in almost all cases, at
least 2 months after surgery. Other tests were used prior to surgery
only in patients with severe fecal incontinence.
Fecal incontinence was graded according to a previously reported classification and score based upon both frequency and severity
of symptoms [12]. Incontinence was considered severe when it occurred weekly for liquid motions or worse (B2C3) according to our
grading. Anal manometry was performed, as reported by others [13],
using the slow station pull-through technique in which a microballoon mounted on a tiny probe is connected to a computerized Dyno
Polygraph via a pressure transducer. Follow-up was carried out in 29
patients by telephone interview and clinical examination with physiology tests.
Data are expressed as meansSEM. Differences in means were
compared using Students paired t test; P values less than 0.05 were
regarded as statistically significant.

20

Preop.

Postop.

597
375
595

667*
324
615

*P<0.05 vs preoperative

wound infection, urinary tract infection, pneumonia, hypertension). Differences in resting tone, voluntary contraction and rectal sensation at manometry are shown in
Figs. 13 and in Table 1. Of the 9 patients complaining
of constipation prior to surgery, 4 were cured postoperatively (44%); constipation did not develop in any of the
24 patients who had not been constipated preoperatively.
Of the 20 patients with fecal incontinence prior to surgery, 14 still had problems postoperatively: 8 improved,
5 remained unchanged, and in one the situation deteriorated, whereas 6 regained full continence (30%). Seven
of the improved and two of the cured patients also had a
sphincteroplasty. The remaining three who had had a
postanal repair, in our early experience, failed due to a
wide suture dehiscence following surgical wound sepsis.
Two of the continent patients became incontinent after
Delormes operation (Fig. 4).
The preoperative incontinence score improved from
4.50.4 to 2.90.4 after surgery (P<0.01). The histology
pattern of the excised rectal mucosa showed solitary rectal ulcer syndrome in 5 cases, inflammatory changes in
8, and was normal in 20.

225
mm Hg
180
170
160

Preop values

150

Postop values

140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
1

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25 pts.

Fig. 2 Pre- and postoperative changes in voluntary contraction at anal manometry in 25 patients undergoing to Delormes operation for
rectal prolapse; 12 also had a sphincteroplasty ()

mm Hg

120
Preop values

110

Postop values

100
90
80
70
60
50
40
30
20
10
0
1

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25 pts.

Fig. 3 Pre- and postoperative changes in rectal sensation at anal manometry in 25 patients undergoing Delormes operation for rectal
prolapse; 12 also had a sphincteroplasty ()

226

Fig. 4 Fecal continence before and after Delormes operation.

, patients who also had a sphincteroplasty; , patients unchanged;
A, B, C, incontinence for flatus, liquid, and solid stool; 1, 2, 3,
occasional, weekly, and daily incontinence

Discussion

Positive results following the association of two perineal

procedures (excision and plasty, plus either rectopexy or
Douglas sac resection) for rectal prolapse and sphincter
dysfunction have been reported by Prasad et al. [14] and
Lechaux et al. [5]. A transabdominal approach had previously been described by Graham et al. [15] who carried out
rectopexy associated with muscle plication. The reported
recurrence rate of rectal prolapse following Delormes operation varies between 7% and 22% (Table 2).

Chronic constipation and fecal incontinence still persist

to a certain extent in some patients following abdominal
correction of rectal prolapse [416]. Ripstein and Wells sacral rectopexy lead to obstructed defecation due to a number of factors, such as rectal stricture, increased rectosigmoid angle, and perirectal denervation [17, 18].
Preoperative fecal incontinence may be related to a reversible internal sphincter relaxation induced by the prolapse itself and/or to a concurrent weakness of the pelvic
floor [19]. Delormes procedure, advocated primarily in
high-risk patients in whom abdominal surgery is inadvisable, has also been performed in constipated patients in
good general condition with full-thickness rectal prolapse; the alternative is resection rectopexy requiring an
intra-abdominal suture and therefore increasing the risk
of postoperative morbidity [5]. Some 40% of the rectal
mucosa specimens showed an anomalous histological
pattern in the present series, thus confirming that inflammatory changes are likely to appear with prolapsed rectal mucosa [20]. In the case of rectal ulcer syndrome, the
advantage of this procedure over sacral rectopexy is the
possibility of achieving complete excision of the pathological tissue, for both diagnostic and therapeutic purposes.
The question arose whether a transanal approach would
be safer in terms of postoperative morbidity and less likely
to further impair bowel function. Most studies report no
post-operative mortality after Delormes operation, and an
extremely low constipation rate, ranging between 0% and
16% (Table 2) [210].
Plusa et al. [13], on the bases of manometric evaluation
before and after this procedure, reported an improvement
in rectal sensation. The latter is likely due to reduced compliance and may help those patients in whom the reduced
preoperative rectal sensation causes a delay in evacuation,
increasing fecal water reabsorption and making the expulsion of small hard stool more difficult. Nevertheless, postoperative improvement in the anal sensation was detected
in only 6 out of 25 patients in whom manometry was performed before and after surgery. This could be due to the
large number of patients with idiopathic incontinence in
our series; the underlying pudendal neuropathy may have

Table 2 Clinical and functional results of Delormes procedure for external rectal prolapse in the literature over the past 20 years
Author

Year

Mean
follow-up
(months)

Recurrence
(%)

Postop.
constipation

Improved
continence

Improved
manometry

Postop.
complications

Postop.
mortality

Christiansen and Kierkegaard [2]

Gundersen et al. [7]
Houry et al. [8]
Monson et al. [9]
Abulafi et al. [3]
Senapati et al. [10]
Oliver et al. [6]
Plusa et al. [13]
Present studyb

1981
1985
1986
1986
1990
1994
1994
1995
1997

12
18
18
27
22
32
40
19
33

36
42
18
35
29
21
47
28
39

17
6
17
7
5
21
22
17
21

NR
NR
6
NR
9
16
NR
0
15

50
NR
44
83
75
46
68
21
18

NP
NP
NP
NP
NP
NP
NP
YES
YES

0
17
NR
0
28
6
75
0a
45

0
0
0
0
0
0
2
0
0

Only articles dealing with more than ten patients are listed. NR, not reported; NP, not performed
a
Only severe complications reported
b
Sphincteroplasty associated in 12 cases

227

made the loss of sensation irreversible. Recordings of

electrical sensitivity and pudendal nerve terminal motor latency are necessary to better clarify this. Continence improved in 70% of our cases after surgery, with an increase
in voluntary contraction at anal manometry. Most patients
were incontinent prior to surgery, and their reduced rectal
capacity, due to the bulking prolapse, may have played a
negative role, since a well-distensible storage organ is important in preventing fecal incontinence in the presence of
weakened sphincters.
The perineum cleansed scrupulously following prolapsectomy and prior to sphincteroplasty to prevent postoperative sepsis leading to dehiscence of muscle suture, as observed in the early eases. Tailored antibiotic prophylaxis
and perineal disinfection after the endoanal procedure
therefore seems advisable.
In conclusion, we suggest Delormes procedure in patients suffering from rectal prolapse and also presenting
with constipation and who, due to either local (e.g., adhesions) or systemic (e.g., cardiopulmonary disease) problems, would not be able easily to tolerate transabdominal
resection rectopexy. Delormes operation is not only safe
and easy to perform, but the recurrence rate is reasonably
low. Furthermore, excision of a concomitant rectal ulcer is
possible, and when associated with a sphincteroplasty,
seems effective even in cases of severe fecal incontinence.
Since improved continence is reported in 5086% of patients undergoing Delormes operation alone [21], associated sphincteroplasty seems indicated when both clinical and physiology findings reveal a concomitant severe
pelvic floor dysfunction.
Acknowledgements The authors are grateful to Dr. C. Quondamcarlo for collecting the data, Dr. C. Zanna for carrying out the statistical analysis, and Mrs. M. S. Shields for help with the manuscript.

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operation: the first choice in complete rectal prolapse? Ann R
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10. Senapati A, Nicholls RJ, Thomson JPS, Phillips RKS (1994) Results of Delormes procedure for rectal prolapse. Dis Colon Rectum 37:456460
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12. Pescatori M, Anastasio G, Bottini C, Mentasti A (1992) New
grading and scoring for anal incontinence. Evaluation of 335 patients. Dis Colon Rectum 35:482487
13. Plusa SM, Charig A, Balaji V, Watts A, Thomson MR (1995)
Physiological changes after Delormes procedure for full-thickness rectal prolapse. Br J Surg 82:14751478
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Perineal proctectomy, posterior rectopexy and postanal levator
repair for the treatment of rectal prolapse. Dis Colon Rectum
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16. Madoff RD (1992) Rectal prolapse and intussusception. In: Beck
DE, Wexner SD (eds) Fundamentals of anorectal surgery.
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17. Broden G, Dolk A, Holmstrom B (1988) Evacuation difficulties
and other characteristics of rectal function associated with procidentia and the Ripstein operation. Dis Colon Rectum 31:
283286
18. Speakman CTM, Madden MV, Nicholls RJ, Kanun MA (1991)
Lateral ligament division during rectopexy causes constipation
but prevents recurrence: result of a prospective randomised
study. Br J Surg 78:14311433
19. Matheson DM, Keighley NRB (1981) Manometric evaluation
of rectal prolapse and faecal incontinence. Gut 22:126129
20. Nicholls RJ (1991) Internal intussusception the solitary rectal
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Int J Colorect Dis (1998) 13: 228 231

Springer-Verlag 1998

O R I G I N A L A RT I C L E

D. W. Oliver M. W. C. Booth V. F. M. Kernick

T. T. Irvin W. B. Campbell

Patient satisfaction and symptom relief after anal dilatation

Accepted: 14 September 1998

Abstract Anal dilatation is used as a simple method of

treatment and has been used for both anal fissure and haemorrhoids. This study examined longer-term results
among a cohort of 162 patients, 132 of whom responded
to a detailed questionnaire, an 82% response (66 patients
were male; age range 1775 years, median 42 years). Follow-up ranged from 16 months to 36 months (median
27 months) after anal dilatation (68 patients for fissure,
32 for haemorrhoids, and 32 for both). In the early months
after dilatation, 83% had symptomatic improvement and
76% remained improved. Five (7%) patients with fissure
and 11 with haemorrhoids (17%) required further hospital
treatment, while 10% and 17%, respectively, had received
further treatment from their general practitioners (GPs).
Seventy-one percent said they would have a further anal
dilation if symptoms recurred. There was no difference in
results obtained by surgeons of different seniority. Complications bleeding (29%) and difficulty controlling flatus (15%) or faeces (8%) resolved in all cases. The results of anal dilatation for fissure are generally satisfactory
in the longer term, with a trend toward better symptom relief in patients with fissure compared with those with haemorrhoids. We do not recommend anal dilatation as the
sole treatment of patients with haemorrhoids, but it may
be a useful adjunct to other treatments such as banding or
sclerotherapy. Morbidity was generally acceptable and the
majority of our patients would be prepared to have this procedure again if their symptoms were to return.
Key words Anal dilatation Anal fissure
Haemorrhoids

D. W. Oliver M. W. C. Booth T. T. Irvin W. B. Campbell ()

Departments of Surgery, Royal Devon and Exeter Hospital,
Barrack Road, Exeter, EX2 5DW, England
V. F. M. Kernick
Clinical Audit, Royal Devon and Exeter Hospital,
Barrack Road, Exeter, EX2 5DW, England

Introduction

Anal problems such as fissure and haemorrhoids are common, and there are a number of management strategies.
These include conservative measures such as topical local
anaesthesia [1, 2] or surgical treatment including anal dilatation [3], internal sphincterotomy [4, 5] and haemorrhoidectomy [6]. Relief of symptoms is the most important
outcome measure. Despite a number of studies assessing
the efficacy of anal dilatation for fissure or for haemorrhoids [69], few have looked at patient satisfaction as a
measure of success. The aim of this study was to assess
symptom relief and patient satisfaction both in the short
and longer term after anal dilatation.

Patients and methods

A surgical computer database was used to identify all patients who
had undergone manual dilatation of the anus between 1 July 1993
and 31 March 1995 for anal fissure, haemorrhoids, or both. Patients
undergoing anal dilatation for other reasons such as anal stenosis or
Crohns disease were excluded. There were 162 patients, of whom
eight were excluded due to death, mental infirmity, age under 16, unfamiliarity with spoken English or imprisonment.
Patients had been selected for anal dilatation following their initial out-patient appointment by a consultant or other senior clinician. Nearly all patients with anal fissure had a posterior fissure, except one with an anterior fissure who subsequently experienced recurrence. Patients treated for haemorrhoids had first- and second-degree haemorrhoids only.
Data collected from the case records included duration of preoperative symptoms, operative diagnosis, grade of surgeon, adjunctive
procedures, number of days in hospital, drugs on discharge and subsequent procedures. All patients were sent a questionnaire (Appendix).
Non-responders were contacted by telephone where possible. For
the remainder, GPs were contacted to obtain a current address, and
a further questionnaire was then sent, followed if necessary by a telephone call. Results were analysed by chi-squared testing.

229
Table 2 Change in symptoms recorded from the questionnaire in
the months following anal dilatation

Table 1 Presenting symptoms

Symptom
Pain and bleeding
Pain
Bleeding
Irritation

Number of patients
(132 total)

Percentage
of patients

72
48
11
1

55
36
8
1

Results

There were 162 patients who underwent anal dilatation

during this period; 116 completed questionnaires were
received and a further 16 patients were questioned by
telephone, giving a total of 132 replies (82% response),
from 66 men and 66 women (age range 1775 years,
mean 42 years). Of the 30 patients who did not reply,
8 were not sent a questionnaire, 22 had moved from the
area and could not be contacted by telephone or via their
GP. Sixty-eight (52%) patients had undergone the procedure for anal fissure, 32 (24%) for haemorrhoids and
32 (24%) for both.
Follow-up ranged from 16 months to 36 months (mean
27 months). Presenting symptoms are shown in Table 1.
Eight (6%) patients had undergone previous anal dilatation. Twenty-three (17%) patients had a history of out-patient treatment for haemorrhoids by injection, sclerotherapy or banding. Seventy (53%) patients had been symptomatic for over 12 months, while 24 (18%) had had symptoms for less than 6 months.
Thirty-five (55%) of the patients with haemorrhoids or
both haemorrhoids and fissure had adjunctive procedures:
haemorrhoidectomy in four, sclerotherapy/banding of haemorrhoids in 31. A further eight (6%) patients also underwent laying open of fistulae or removal of skin tags.
Twenty-six (20%) procedures were performed by a consultant, 46 (35%) by a registrar or staff grade and 60 (45%)
by a senior house officer. One hundred and twelve (85%)
patients were treated as day cases. On discharge, 60% were
prescribed analgesia and 31% laxatives.
One hundred and one patients (76%) were given a clinic
appointment between 3 weeks and 12 weeks after the operation; of these 84 attended (83%). Among those who attended the clinic, improvement was recorded in 70 (83%),
while 11 (13%) patients had reported that they were the
same or worse. Inadequate data were recorded for the remaining three (4%) patients.
Thirty-eight (29%) patients reported some bleeding immediately after the procedure and 20 (15%) had some difficulty controlling flatus. Forty-one percent of these symptoms resolved within 1 month, 60% within 2 months, 88%
within 6 months and 97% within 12 months. Ten (8%) patients had some degree of faecal incontinence (six men and
four women), but this resolved within 6 months in all cases,
and eight of these patients would have dilatation again if
their symptoms were to return. There were no significant
differences in the age or gender of the patients, or grade of

Change reported

Number of patients
(132 total)

Percentage
of patients

Much worse
A little worse
No change
A little better
No further symptoms
Cant remember

1
5
17
56
50
3

1
4
13
42
38
2

Table 3 Responses to How are your symptoms now? recorded

from the questionnaire
Response

Number of patients
(132 total)

Percentage
of patients

Much worse
A little worse
About the same
A little better
I have no symptoms
No response

2
5
21
37
63
4

1
4
16
28
48
3

Table 4 Indication for initial anal dilatation in the 28 (21%) patients

who would not have the dilatation repeated if their symptoms were
to return
Indication

Fraction of patients
with indication
who would not
repeat dilation

Percentage of patients
with indication
who would not
repeat dilation

Anal fissure
Haemorrhoids
Haemorrhoids
and fissure

15/68
8/32
5/32

22
25
16

operating surgeon between those who developed complications and those who did not.
Table 2 shows the alteration in symptoms over the
months following anal dilatation as reported in the questionnaire, and current symptoms are shown in Table 3. Of
the six patients who said they were worse following the
procedure, all had haemorrhoids (two combined with fissure). All had reported improvement at their out-patient
visit a few weeks after operation and had developed recurrence of their haemorrhoids since that time.
Ninety-four (71%) patients said they would have a further anal dilatation if their symptoms were to return, 28
(21%) would not and 10 (8% ) were undecided. Table 4
shows the surgical diagnosis of those patients who said
they would decline further dilatation if their symptoms returned: four (12%) of these had experienced relief of symptoms following dilatation.
Following anal dilatation, five (7%) patients with anal
fissure had required further in-patient treatment, one had
had an anterior fissure, four underwent lateral sphincterotomy, one anal dilatation. Seven (10%) had received topical treatment from their GP. Of the 64 patients with haemorrhoids or haemorrhoids and fissure, one underwent

230

haemorroidectomy and one further anal dilatation. Nine of

these patients (14%) had further out-patient treatment for
haemorrhoids, such as sclerotherapy or banding, and 11
(17%) had received treatment from their GP for example, topical creams and laxatives.
One hundred and three (78%) patients had been advised
to eat more fibre following their anal dilatation, and 86
(65%) patients had continued to follow this advice. Thirtynine (30%) patients had made no changes to their diet.
Seven (5%) did not answer. Eighty-five percent of patients
who had increased their dietary fibre reported that they
were now better, while 15% of these patients were the same
or worse.

take a high-fibre diet and if the dilatations had been more

controlled.
Anal dilatation is an acceptable form of treatment for
most patients, and 94 (71%) of our patients would be prepared to have the procedure repeated if it were required.
Failure of the technique to relieve symptoms is likely to be
due to poor case selection, and those with haemorrhoids
seem to fare less well than those with fissure. All six of
our patients who reported that their symptoms were worse
in the longer term were being treated for haemorrhoids.
This concurs with an earlier study with a failure rate of up
to 25% in patients with haemorrhoids [18]. Anal dilatation
is normally an effective treatment in over 90% of cases of
anal fissure [7, 8, 12] and has the advantage of being relatively simple to perform while confirming the diagnosis
under anaesthesia.

Discussion

Anal dilatation is easy to perform, avoids an incision and

is therefore often the treatment of choice for anal fissure,
particularly in the acute setting. However, views vary about
exactly what an adequate anal dilatation involves.
Descriptions of anal dilatation vary, ranging from two
to eight fingers, although the latter is no longer recommended [10]. Isbister et al. describe a gentle four-finger, 4-min technique with good success rates and no incontinence [11]. Placing a restricting ligature around the
operators fingers has been suggested [12]. Good results
have been reported using a Parks anal retractor and by
producing 40-mm recto-sigmoid pneumatic balloon dilatation (12.5 cm circumference) [8]. When patients were
dilated with a 30-mm balloon (9.5 cm circumference),
only 50% achieved healing, suggesting that a critical degree of dilatation is required for success. Measurement
of the four-finger circumferences of the opposed index
and middle fingers at the proximal interphalangeal joints
amongst our surgeons employed at the time of writing
ranged from 11 cm to 16 cm and all used a four-finger
technique.
The risk of post-operative incontinence is an important
consideration when performing anal dilatation [13], and
special care is required when dealing with elderly patients.
In our series, 15% had some difficulty controlling flatus
and 8% reported minor faecal incontinence. Most recovered within 1 month and all settled within 6 months. No
patients reported gross inconvenience from these temporary symptoms.
Our results are in keeping with earlier studies [11, 14,
15], and we did not detect a significant deterioration in results between the initial clinic follow-up visit and longerterm follow-up by the questionnaire except in the patients
with haemorrhoids, where improvement was short lived.
We therefore do not recommend anal dilatation as the sole
treatment for this group of patients. Failure to adopt an increased-fibre diet is associated with lower rates of healing
[16, 17]; this was confirmed in our study. This is an important component of management that may be overlooked
by surgical staff. We believe long-term results might have
been improved if more patients had been encouraged to

Appendix: Patient questionnaire

1. Following the procedure over the next few months,

what effect did the anal stretch have on your previous
symptoms? Were they:
Much worse than before
A little worse than before
About the same as before
A little better than before
I no longer have any symptoms
Cant remember
2. Immediately after the anal stretch did you suffer from
any problems in this area such as: bleeding, incontinence
of faeces (soiling yourself), difficulty controlling wind
(breaking wind uncontrollably), any other problems
3. If you had any problems how long in months did they
last
4. Compared to before the anal stretch how are your
symptoms now
Much worse
A little worse
About the same
A little better
I have no symptoms
5. If your symptoms improved soon after the anal stretch
and then again got worse, how long did the improvement last
1 week
More than 1 week but less than 1 month
More than 1 month but less than 3 months
Between 6 months and 1 year
My symptoms are still improved
6. Have you needed any further treatment for your symptoms
Yes, as hospital in-patient
Yes, as hospital out-patient
Yes, by my general practitioner
I have not needed any further treatment

231

7. If you needed further treatment what did you have done

and by whom
8. Do you use laxatives such as Fybogel, Senokot, or
similar preparations
Yes most days
Once or twice a week
Very occasionally
Never
9. Have you been advised to eat more fibre
Yes
No
10. If yes, by whom: hospital doctor, general practitioner,
nurse, other
11. Which of the following applies to the food you eat now
compared with your diet before your anal stretch:
Unchanged
I try to eat brown bread and plenty of fresh vegetables
I add extra bran or roughage to my diet
Other
12. If your symptoms returned, would you consider having an anal stretch again
Yes
No

References
1. Lund JN, Armitage NC, Scholefield JH (1996) Use of glyceryl
trinitrate ointment in the treatment of anal fissure. Br J Surg
83: 776777
2. Watson SJ, Kamm MA, Nicholls RJ, Phillips RKS (1996) Topical glyceryl trinitrate in the treatment of chronic anal fissure.
Br J Surg 83: 771775

3. Watts JMK, Bennet RC, Goligher JC (1964) Stretching of

the anal sphincters in the treatment of fissure-in-ano. BMJ
2: 342343
4. Pernikoff BJ, Eisenstat TE, Rubin RJ, Oliver GC, Salvati EP
(1994) Reappraisal of partial lateral internal sphincterotomy. Dis
Colon Rectum 37: 12911295
5. Oh C, Divino CM, Steinhagen RM (1995) Anal fissure 20 year
experience. Dis Colon Rectum 38: 378382
6. MacRae HM, McLeod RS (1995). Comparison of hemorrhoidal
treatment modalities. A meta-analysis. Dis Colon Rectum
38: 687694
7. Marby M Alexander-Williams J, Buchmann P, Arabi Y, Kappas
A, Minervini S, Gatehouse D, Keighley MR (1979) A randomised controlled trial to compare anal dilatation with lateral subcutaneous sphincterotomy for anal fissure. Dis Colon Rectum
22: 308311
8. Sohn N, Eisenberg MM, Weinstein MA, Lugo RN, Ader J (1992)
Precise anorectal sphincter dilatation its role in the therapy of
anal fissures. Dis Colon Rectum 35: 322327
9. Lund JN, Scholefield JH (1996) Aetiology and treatment of anal
fissure. Br J Surg 83: 13351344
10. MacDonald A, Smith AD, McNeill AD, Finlay IG (1992) Manual dilatation of the anus. Br J Surg 79: 13811382
11. Nielsen MD, Rasmussen O, Pederson JF, Christiansen J (1993)
Risk of sphincter damage and anal incontinence after anal dilatation for fissure-in-ano. Dis Colon Rectum 36: 677680
12. Isbister WH, Prasad J (1995) Fissure in ano. Aust N Z J Surg
65: 107108
13. Speakman CT, Burnett SJ, Kamm MA, Bartram CI (1991)
Sphincter injury after anal dilatation demonstrated by anal endosonography. Br J Surg 78: 14291430
14. Keighley MRB, Williams NS (1993) Surgery of the anus, rectum, and colon. Saunders, London
15. Lestar B, Penninckx F, Kerremans R (1987) Anal dilatation: how
I do it. Int J Colorectal Dis 2: 167168
16. Jensen SL (1987) Maintenance therapy with unprocessed bran
in the prevention of acute anal fissure recurrence. J R Soc Med
80: 296298
17. (1990) The management of anal fissure. Drug Ther Bull 28: 34
18. Hiltunen KM, Matikainen M (1992) Anal dilatation, lateral subcutaneous sphincterotomy and haemorrhoidectomy for the treatment of second and third degree haemorrhoids. Int Surg
77: 261263

Int J Colorect Dis (1998) 13: 232 234

Springer-Verlag 1998

O R I G I N A L A RT I C L E

N. Duraker . Bender K. Memisoglu A. Yalner

Intraoperative bowel irrigation improves anastomotic collagen metabolism

in the left-sided colonic obstruction but not covering colostomy

Accepted: 30 September 1998

Abstract This study investigated the effects of intraoperative colonic irrigation and proximal diverting end colostomy after segmental bowel resection in experimental
left-colonic obstruction on anastomotic healing. Simple
obstruction of descending colon was performed in male
Sprague-Dawley rats. After 24 h we performed segmental
colonic resection and anastomosis in the control group
(n =15); resection, anastomosis, and covering colostomy
in the colostomy group (n =14); resection and anastomosis after antegrade colonic lavage through cecum by using
isotonic saline solution in the irrigation group (n =13). In
rats that were killed 7 days later anastomotic dehiscence
and bursting pressure and tissue hydroxyproline concentration at the anastomosis were measured. No significant
differences were observed between groups in terms of
anastomotic dehiscence, bursting site, or pressure. The hydroxyproline concentration was significantly higher in the
irrigation group than the control group (P = 0.025) and the
colostomy group (P = 0.029), but no difference was noted
between the control group and the colostomy group. These
findings suggest that intraoperative antegrade colonic irrigation in the acute left-sided colonic obstruction positively
affects collagen metabolism at the anastomotic site; if the
anastomosis is performed without bowel cleansing, covering colostomy does not improve collagen metabolism.
Key words Irrigation Anastomosis Collagen metabolism

Introduction

Fecal loading is known to be detrimental to anastomotic

healing [13], and therefore segmental resection and primary anastomosis are generally avoided in patients with
left-sided colonic obstruction. Although good results conN. Duraker () . Bender K. Memisog lu
Third Department of Surgery, SSK Okmeydan Training Hospital,
Istanbul, Turkey
A. Yalner
From the Dzen Laboratories, Mecidiyeky, Istanbul, Turkey

cerning resection and primary anastomosis in some small

series have been reported [4, 5], many studies have noted
high anastomotic leakage and mortality rates [69]. The
anastomotic leakage rate may be high despite a proximal
diverting colostomy performed to protect the anastomosis
[10, 11]. In addition, closure of colostomy in the second
session is also associated with high morbidity and mortality rates [12, 13].
Dudley et al. [14] were the first to report primary anastomosis can be performed safely after intraoperative antegrade irrigation of the loaded colon, and clinically successful results have been reported using this procedure to treat
acute left-sided colonic obstruction [1518]. A few experimental studies have been carried out on the effect of intraoperative irrigation on colonic anastomotic healing.
The present experimental study investigated the effects
of proximal diverting end colostomy and intraoperative colonic irrigation after segmental bowel resection in the obstruction of the left colon on anastomotic healing.

Materials and methods

Surgical procedure
Male Sprague-Dawley rats (n = 42) weighing 220280 g were used.
They were allowed to feed ad libitum before and after the surgical
procedure. Operations were performed under ether anesthesia. At the
first laparotomy colonic obstruction was carried out through a 3-cm
lower midline incision with 2/0 silk ligature placed 3 cm above the
peritoneal reflexion without damaging the colonic vessels. Abdominal layers and skin were closed separately using running sutures
with 4/0 chromic catgut. At the second laparotomy performed 24 h
later it was observed that the colon proximal to the obstruction was
dilated, and that the distal part was empty in all of the animals. The
vessels of colonic segment that is 1 cm proximal and 0.5 cm distal
to the obstruction were ligated with 5/0 silk, and this segment was
prepared for resection. The ligature causing obstruction was left, and
the colon was transected 0.2 cm above this ligature. Any gas and solid feces present in the dilated colon were emptied by gentle milking
with the finger, being careful to avoid fecal soiling. End-to-end, onelayer colo-colostomies were then performed with nine interrupted
extramucosal inverting 6/0 polypropylene (Prolene, Ethicon, Scotland, UK) sutures.

233
Rats were grouped randomly. In the control group (n =15) anastomosis was performed after the colon segments 1 cm proximal and
0.5 cm distal to the obstruction were resected. In the colostomy group
(n = 14) the colon was transected proximal to the anastomosis at major flexure after colonic resection and anastomosis. The distal end of
the colon was ligated with 2/0 silk and left within the abdomen; the
proximal end was fixed to the abdominal layers and skin at the upper
part of the incision with four 6/0 polypropylene sutures. In the irrigation group (n=13) one end of the sterilized tube prepared by cutting
a 6- to 7-cm-long part of a no. 16 nasogastric tube was inserted into
the colon transected proximal to the obstruction; it was then fixed
by ligating with 5/0 silk around the colon. The other end of the tube
was taken out of the operation site to prevent soiling with the irrigation fluid. A 22-G intravenous cannula (Introcan, Braun Melsungen,
Germany) was inserted into cecum. Irrigation was performed through
this cannula by injecting a warm isotonic saline solution with a
20-ml syringe over 45 min. The fecal pellets were squashed if necessary in order to help in emptying the bowel. The irrigation was terminated when a clear effluent was obtained (with 3065 ml irrigation fluid). The colon segments proximal and distal to the obstruction were resected with the irrigation tube, and anastomosis was performed.
At the second laparotomy, after leaving 23 ml isotonic saline
solution in the abdominal cavity the abdomen was closed with 4/0
polyglactin 910 (Vicryl, Ethicon).
Bursting pressure
Seven days later the rats were killed by an overdose of ether. The adhesions at the anastomosis were cleared; anastomotic dehiscence was
recorded, if present. In cases in which anastomotic integrity was intact, a 4-cm colonic segment with the anastomosis at the center was
excised. Feces contained in this part was milked or irrigated with water. The distal end was ligated with 2/0 silk. A specially constructed
T-formed polyethylene tube was connected to the air intake pipe of
a sphygmomanometer (Spengler Vaquez Laubry, France), and its
longer arm was inserted into the colonic segment at the proximal end.
The tube was fixed with 2/0 silk with the aid of a metallic groove attached the tube. The colonic segment was put into a container filled
with tap water. At every 10 mmHg increase in the pressure as measured by sphygmomanometer we waited for 10 s. When the first air
bubble coming from the bowel segment was seen, the pressure was
recorded as the bursting pressure. All of the bursting pressures were
measured within 5 min following the death.
Hydroxyproline measurements
After bursting pressure was measured, a 1-cm-long colonic segment
centered on the anastomosis was removed. Tissue material within
isotonic saline solution was shipped to the laboratory within 2 h and
stored at 20 C until analyzed. Hydroxyproline concentration was
measured as micrograms per milligram tissue dry weight according
to the method of Switzer [19].
Statistical analysis
Anastomotic dehiscence rates and bursting sites were compared using the 2 test and Fishers exact test. Levels of significance for the
differences between groups concerning bursting pressure and hydroxyproline concentration were calculated by means of the Kruskal-Wallis test. For significant values (P < 0.05) the pairwise group
differences were calculated by using the Wilcoxon two-tailed test.

Results

Anastomotic dehiscence was seen in two rats in the control and in another two in the colostomy group but in none

Table 1 Bursting pressure and anastomotic segment hydroxyproline concentration in rats

Group

Bursting
pressure
(mmHg)

Hydroxyproline
concentration
(g/mg)

Control
Irrigation
Colostomy

13
13
12

134.6 63.9
158.1 34.5
129.6 55.3

43.9 17.6
103.2 69.8
48.2 35.5

in the irrigation group. There was no significant difference

between groups. Bursting pressure and hydroxyproline
levels were not measured in the rats with anastomotic dehiscence. The number of rats with bursting site outside the
anastomosis was eight (five proximal to suture line) in the
control group, six (three proximal to suture line) in the colostomy group, and eight (four proximal to suture line) in
the irrigation group; no significant difference was noted
between the groups.
As seen in Table 1, bursting pressure was slightly higher
in the irrigation group than in the control and colostomy
groups, but the differences were not statistically significant.
Hydroxyproline concentration in the irrigation group was
significantly higher than the control group (P = 0.025) and
the colostomy group (P = 0.029). No difference was noted
between control and colostomy groups. Table 1 presents the
mean (standard deviation) hydroxyproline levels.

Discussion

A large multicenter study [9] noted significantly higher

anastomotic leakage rate after segmental resection and primary anastomosis in patients with obstructed left colonic
tumor than in elective cases (18% versus 6%). The high
risk of anastomotic leakage in the colon loaded with feces
may be due to destruction of the anastomotic integrity by
fecal pellets and to disturbing effects of the localized infection at the anastomosis on the collagen synthesis [2, 16].
Irvin [20] suggested that the healing defect at the infected
colonic anastomosis are due to increased lysis of the newly
formed collagen or to the decrease in intracellular collagen synthesis. The fact that proximal diverting colostomy
to protect the anastomosis cannot prevent the leakage risk
effectively may be explained by the presence of feces
between the colostomy and the anastomosis [21].
Cleansing the colon by evacuating the feces with
intraoperative antegrade colonic irrigation eliminates these
threats to anastomotic healing. Mochizuki et al. [18] found
no significant difference in the incidence of anastomotic
dehiscence after primary resection and anastomosis in leftsided colorectal carcinoma between elective and obstructive cases in which intraoperative colonic irrigation was
carried out. Many clinical studies report low anastomotic
leakage rates (08.5%) after intraoperative bowel cleansing [1518].

234

In this experimental study, while anastomotic leakage

after colonic irrigation was not seen, the rate of anastomotic leakage was 13.3% in the group without bowel
cleansing and 14.3% in the group in which anastomosis
was protected with colostomy, but the differences between
groups were not statistically significant. While the bursting pressure also tended to be high again in the irrigation
group, no significant difference was seen between groups.
In one of the two similar experimental studies [22] the
bursting pressure on the sixth day in the group with anastomosis performed after colonic lavage with isotonic saline solution was found to be significantly higher than in
the group without colonic lavage. On the other hand, in the
other study [23] the bursting pressure measured in situ was
higher in the group without colonic lavage, and this result
was considered due to adhesion formed at the suture line
in the unprepared bowel. In our study, as in that of Aguilar-Nascimento et al. [22], the bursting sites were commonly outside the anastomosis. According to all of these
findings, it would not be wise to determine the clinical procedure on the basis of bursting pressure alone because
bursting pressure gives no information about the anastomotic strength itself.
A more reliable means for evaluating anastomotic healing is to investigate collagen metabolism, namely tissue
hydroxyproline concentration. In this study, anastomotic
segment tissue hydroxyproline concentration was found to
be significantly higher in the group with the colonic content removed than in the groups without bowel cleansing.
Hydroxyproline concentrations were similar in the two
groups in which anastomosis was performed without bowel
cleansing (without colostomy and with diverting end colostomy). It may be concluded from these findings that the
feces present in the anastomotic site disturbs collagen metabolism. Secondly, diverting end colostomy has no positive effect on anastomotic collagen metabolism; this may
be due to the presence of feces in the colonic segment
between the colostomy and the anastomosis.
In one of the two experimental studies mentioned above
[22] no difference in terms of tissue hydroxyproline levels
was seen between groups without and with colonic lavage
by using isotonic saline solution. In the other study [23]
tissue hydroxyproline level was found to be high in the
group with bowel cleansing, and it was thought that intraoperative colonic lavage favors collagen synthesis.
In conclusion, intraoperative antegrade colonic irrigation has a positive effect on collagen metabolism at the
anastomotic site in the acute left-sided colonic obstruction.
If the anastomosis is performed without removing the colonic content, covering colostomy does not improve collagen metabolism.
Acknowledgements This research was supported by grants from
the Institute for Experimental Medicine (DETAM), Istanbul University, Istanbul, Turkey (project no. 02-1995).

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morbidity and mortality after closure of loop and end colostomy.
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irrigation of the colon to permit primary anastomosis. Br J Surg
67: 8081
15. Koruth NM, Krukowski ZH, Youngson GG, Hendry WS, Logie
JRC, Jones PF, Munro A (1985) Intraoperative colonic irrigation in the management of left-sided large bowel emergencies.
Br J Surg 72: 708711
16. Murray JJ, Schoetz Jr DJ, Coller JA, Roberts PL, Veidenheimer
MC (1991) Intraoperative colonic lavage and primary anastomosis in nonelective colon resection. Dis Colon Rectum 34: 527
531
17. Tan SG, Nambiar R, Rauff A, Ngoi SS, Goh HS (1991) Primary
resection and anastomosis in obstructed descending colon due
to cancer. Arch Surg 126: 748751
18. Mochizuki H, Nakamura E, Hase K, Tamakuma S (1993) The
advantage of primary resection and anastomosis with intraoperative bowel irrigation for obstructing left-sided colorectal carcinoma. Jpn J Surg 23: 771776
19. Switzer BR (1991) Determination of hydroxyproline in tissue.
J Nutr Biochem 2: 229231
20. Irvin TT (1976) Collagen metabolism in infected colonic anastomoses. Surg Gynecol Obstet 143: 220224
21. Thomson WHF, Carter SSC (1986) On-table lavage to achieve
safe restorative rectal and emergency left colonic resection without covering colostomy. Br J Surg 73: 6163
22. Aguilar-Nascimento JE, Mathie RT, Man WK, Williamson RCN
(1995) Enhanced intra-anastomotic healing by operative lavage
with nutrient solutions in experimental left-sided colonic obstruction. Br J Surg 82: 461464
23. Foster ME, Johnson CD, Billings PJ, Davies PW, Leaper DJ
(1986) Intraoperative antegrade lavage and anastomotic healing
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Int J Colorect Dis (1998) 13: 235 240

Springer-Verlag 1998

O R I G I N A L A RT I C L E

M. A. Kuzu J. Kuzu C. Kksoy F. H. Akyol

D. Uzal I. T. Kale D. Orhan C. Terzi

Histological evaluation of colonic anastomotic healing

in the rat following preoperative 5-fluorouracil, fractionated irradiation,
and combined treatment
Accepted: 17 July 1998

Abstract There is a growing interest in neoadjuvant

chemo- and radiotherapy as a treatment modality for colorectal cancer which could affect mechanical and biochemical parameters of anastomotic healing. This study investigated the effect of such protocols on colonic anastomotic
healing by evaluating the histopathological parameters.
One hundred and sixty male Wistar rats were divided into
six groups: a control group (I, n=20), a saline group (II,
n=30) which received 1 ml NaC1 intraperitoneally, a shamirradiated group (III, n=20), a 5-fluorouracil (5-FU) group
(IV, n=30), which received 5-FU (20 mg/kg) intraperitoneally for 5 consecutive days, an irradiated group (V, n=40)
which received fractionated irradiation to the whole pelvis to a totaldose of 22 Gy, 5.5 Gy per fraction on 4 consecutive days, and a concomitant 5-FU + irradiation group
(VI, n=20) which received 5-FU as in group IV and irradiated as in group V. All groups underwent left colonic resection with primary anastomosis, and the last fraction of
irradiation and the last injection were given 4 and 3 days
before the operation, respectively. Within each group one
half of the animals were killed on the third postoperative
day and the other half on the seventh postoperative. day.
After the resection of the anastomotic segments, histopathological examination was evaluated. Apposition of the
37th World Congress of Surgery of the ISS/SIC,
2430 August 1997, Acapulco, Mexico
M. A. Kuzu () C. Kksoy
Department of Surgery, University of Ankara,
Faculty of Medicine, Ankara, Turkey,
Mertler sokak 52/1, Bes tepe,
06510 Ankara, Turkey
J. Kuzu D. Orhan
Department of Pathology, University of Ankara,
Faculty of Medicine, Ankara, Turkey
F. H. Akyol D. Uzal
Department of Radiation Oncology,
University of Hacettepe, Ankara, Turkey
I . T. Kale C. Terzi
Department of Surgery, Ankara Numune Hospital,
Ankara, Turkey

wound edges of the mucosa and the muscularis were not

affected by the therapy. The level of granulocytes was high,
inflammatory exudate and necrosis persisted, granulation
tissue formation was delayed, and the levels of macrophages and fibroblasts were low. We conclude that colonic
anastomotic healing can be affected by the administration
of preoperative chemotherapy, irradiation, and chemoirradiation.
Key words 5-fluorouracil Fractionated irradiation
Colorectal cancer

Introduction

Regrowth of residual cancer cells following surgical excision of rectum carcinoma is almost inevitably fatal. Various (neo)-adjuvant therapy protocols have been investigated in the effort to improve cure rates and reduce locoregional recurrences [17]. Radiotherapy either alone or in
combination with chemotherapy has yielded encouraging
results. However, it has been demonstrated that postoperative irradiation and antineoplastics have deleterious effects on intestinal anastomotic healing [811].
Despite improvements in diagnosis and therapy, wound
failure remains a major clinical problem. Intestinal wound
healing is a complex process involving various biological,
morphological, and immunological systems. Moreover,
multiple extrinsic and intrinsic factors affect this healing
in the gastrointestinal tract (GIT). Although the anastomosis is performed between healthy intestinal segments, it
may be prone to leak or be compromised by the (neo)-adjuvant therapy. This may further increase morbidity and
mortality.
Although mechanical and biochemical aspects of intestinal anastomotic healing have been reported following
antineoplastics and irradiation [815], only very few studies have investigated the histological aspects. Since (neo)adjuvant chemo- and radiotherapy for rectal carcinoma
could affect histological parameters of wound healing, this

236
Fig. 1 The protocols for the
six groups of animals in this
study

study assessed the early effects of such possible clinical

(neo)-adjuvant treatments on colonic anastomotic healing
in an experimental model similar to common clinical applications. We have recently completed investigating the
effects of these possible neo-adjuvant clinical protocols on
the healing of colonic anastomosis. In the present part of
the study, we consider mainly the early phase of histological aspects of wound healing.

Material and methods

A total of 160 male Wistar rats of median weight 240 g (range
205340 g) were used in the present study. All animals had free access to a standardized laboratory diet and water.

Technique of irradiation and concomitant therapy

There were six groups, (the first three of which were controls and
the second three treatment groups; Fig. 1):
Group I: control group (n=20)
Group II: saline group (n30), which received l ml intraperitoneal
NaC1
Group III: sham-irradiated group (n=20), which were handled similarly as the irradiation group but were not irradiated
Group IV: 5-fluorouracil (5-FU) group (n=30), which received 5FU (20 mg/kg) intraperitoneally for 5 consecutive days
Group V: irradiated group (n=40), which received fractionated irradiation to the whole pelvis at a total dose of 22 Gy, 5.5 Gy per
fraction through anterior and posterior fields, over 4 consecutive
days with 6-MV photon beams using a linear accelerator (SL-25;
Philips, Crawley Sussey, UK)
Group VI: concomitant 5-FU + irradiation group (n=20), which
received 5-FU as in group IV and irradiation as in group V

237
In accordance with common clinical practice, the total irradiation dose was fractionated as much as possible. As early anastomotic wound
healing was evaluated in the present study, the / ratio was 9 Gy and
the biologically equivalant dose (BED), which was calculated according to linear quadratic model, was 34 Gy [161. This dose was equivalent to a total dose of 2800 cGy, given at 200 cGy per fraction. Asymmetric collimator technique was used to eliminate the penumbra and
obtain a sharp beam edge at the superior border of the pelvic field,
which reduced the segment of the small bowel and other abdominal
organs to be irradiated. Irradiation fields were planned at the simulator (Phillips, Crawley Sussex, UK) using barium enema, and both the
simulations and the irradiation were carried out under general anesthesia (ketamine + Xylasine). To prevent septic complication due to
bacterial translocation and dehydration, all rats were given intramuscular injections of quinolone plus amplicililin and subcutaneous 10 ml
of 10% dextrose during the study period.
Operative procedure
All rats were operated on under general anesthesia 4 days after completion of irradiation or sham irradiation and 3 days after the last injection of 5-FU (Fig. 1). A 1-cm left colon resection 23 cm above
the peritoneal reflection was performed through a standardized midline incision. Bowel continuity was restored with an end-to-end anastomosis of 10 or 11 interrupted sutures (6/0 monofilament polypropylene, Serapen, Bayern, Germany). The abdominal muscle layer
and skin incision were closed separately with running sutures. Control animals also underwent the same operation. All procedures were
carried out by the same person. Within each group one half of the
animals were killed on the third postoperative day and the other half
on the seventh postoperative day.
Research procedures
After the resection of anastomotic segment, one half of the segment
was fixed in 10% formaldehyde and embedded in paraffin following
standard procedures. Serial longitudinal sections of 35 m paraffin
locks were stained with routine hemotoxylin-eosin, histological scoring was carried out according to de Roy van Zuidewijen et al. [17]
as follows: apposition of the wound edges of both the mucosa (a) and
the muscularis (b) were considered as good, moderate, or bad for
controlling the surgical technique. For examination of wound healing procedure, reepithelization of the mucosa (c), and the repair of
the muscularis propria (d) were investigated. The epithelization was
scored on a seven-point scale, while regeneration of muscularis propria was considered as positive or negative. Several other histopathological aspects such as necrosis (e), inflammatory exudate (f), granulation tissue (g), and the level of granulocytes (h), macrophages (i),
and fibroblasts (j) in this granulation tissue were all evaluated. The
histopathological parameters above were scored on a four-point scale
as: 0, negative; 1, low; 2, moderate; 3, high. Presence of suture material (k) was also considered and was assessed as positive or negative on the scoring scheme.
Microscopic slides were scored twice by the same observer in a
blind fashion. On the second observation the observer was unaware
of the score previously given. Not all the duplicate scores were equal.
We also defined combinations of bad or (almost) none on one
observation and good, much or (almost) complete on the other
as contradictory, and the result was scored unknown as it was in
the original scoring system. Each score was represented by a value.
A mean value was calculated when the results of the first and the
second observations were not contradictory.
Statistical methods
Differences between groups were evaluated using one-way analysis
of variance and the Student-Neuman-Keuls post-hoc test, where appropriate. Within-group differences on days 3 and 7 were by the
Mann-Whitney U test. Probabilities of less than 0.05 were considered as significant. Data are presented in Table 1 as mean+SEM.

Results

Eight contradictory scores were defined as unknown at the

end of the two histopathological examinations, one each
in groups I and II and two each in groups IV, V, and VI.
These results were not considered during statistical analysis.
There was no significant difference in the apposition of
wound edges of mucosa, muscularis, and the restitution of
the mucosal epithelial layer and repair of the muscularis
propria on either 3- or 7-day-old anastomoses between the
groups. Necrosis and inflammatory exudate showed a
slight decrease over time in the control and sham groups
(Table 1). However, necrosis and inflammatory exudate
persisted longer in the treatment groups (groups IV VI).
There was a significant difference between the treatment
groups and controls (IIII) in 7-day-old anastomoses
(P<0.01).
The level of granulation tissue was low in the treatment
groups. This reached statistical significance in the groups
which received irradiation (groups V, VI) in 3-day-old
anastomoses (Table 1). There was no significant difference
in the granulocyte level on day 3 between the groups, but
it was significantly higher in the treatment groups on day
7 (Table 1). No significant effect of treatments was found
on the macrophage level although, it was lower in the treatment groups (Table 1).
The level of fibroblasts was significantly lower in the
treatment groups both on day 3 and on day 7 than in the
control groups. Fibroblasts showed a significant increase
from day 3 to day 7 in all groups (Table 1).
All of the killed rats contained suture material.

Discussion

Neo-adjuvant therapy is used because of the high mortality rates from uncontrolled local recurrences due to rectal
carcinoma. As such therapies can adversely affect wound
healing, this study was conducted to assess the effects of
the preoperative fractionated irradiation, preoperative 5FU, and combined chemoirradiation, which may have a
role in clinical practice. We evaluated the histological aspects of wound healing in the present study.
Although the wound healing response can be divided
into three distinct but overlapping phases, of (a) hemostasis and inflammation, (b) proliferation, and (c) maturation
and remodeling, it varies within human body [18]. Intestinal anastomotic healing differs slightly because it is a controlled and immediate full-thickness injury, followed by
reconstitution of luminal integrity with artificial sutures.
During this period an organized and complex cascade of
cellular and biochemical events take place, and any disturbance in any phase of this healing process may result in
complications. Because of the large micro-organism content of the colonic lumen, this insufficient healing can be
characterized as anastomotic dehiscence. On the other

238
Table 1 Results
Day 3

Day 7

P within
group
differences

Necrosis
Control (I)
Saline (II)
Sham-irradiation (III)
5-Fluorouracil (IV)
Irradiation (V)
Concomitant (VI)

1.70.26
1.80.21
1.70.27
1.60.25
1.40.32
1.80.21

0.400.16
0.400.07
0.220.15
1.190.28*
1.050.23*
1.030.18*

<0.01
<0.01
<0.01
>0.05
>0.05
>0.05

Exudate
Control (I)
Saline (II)
Sham-irradiation (III)
5-Fluorouracil (IV)
Irradiation (V)
Concomitant (VI)

2.10.22
2.00.14
2.30.24
2.50.19
2.60.12
2.50.24

1.200.16
1.100.19
0.900.41
1.750.23
2.640.08*
2.020.18g*

<0.01
<0.01
<0.01
>0.05
>0.05
>0.05

Granulation tissue
Control (I)
Saline (II)
Sham-irradiation (III)
5-Fluorouracil (IV)
Irradiation (V)
Concomitant (VI)

2.200.26
2.140.14
2.100.24
1.730.15
0.900.15*
1.000.20*

2.700.13
2.600.13
2.500.15
2.400.06
2.160.17
2.260.18

>0.05
>0.05
>0.05
<0.05
<0.01
<0.01

Granulocytes
Control (I)
Saline (II)
Sham-irradiation (III)
5-Fluorouracil (IV)
Irradiation (V)
Concomitant (VI)

2.900.10
2.900.07
2.700.28
2.600.16
2.800.08
2.750.18

1.700.15
1.820.14
1.540.17
2.560.13*
2.840.09*
2.400.14*

<0.01
<0.01
<0.01
>0.05
>0.05
>0.05

Macrophages
Control (I)
Saline (II)
Sham-irradiation (III)
5-Fluorouracil (IV)
Irradiation (V)
Concomitant (VI)

2.090.13
2.210.11
2.100.17
2.010.18
1.570.09
1.650.12

2.400.16
2.530.13
2.330.17
2.100.13
1.870.14
1.750.20

>0.05
>0.05
>0.05
>0.05
>0.05
>0.05

Fibroblasts
Control (I)
Saline (II)
Sham-irradiation (III)
5-Fluorouracil (IV)
Irradiation (V)
Concomitant (VI)

1.430.25
1.790.11
1.560.18
0.870.13*
0.330.11*
0.520.09*

2.610.16
2.530.13
2.440.18
1.730.14*
1.150.18*
1.300.13*

<0.05
<0.05
<0.05
<0.01
<0.01
<0.01

Between group differences: *P<0.01, **P>0.05

hand, exuberant healing can take place, which results in

stricture formation.
The main finding of the present study is, as measured
by the histological scoring of the early colonic wound healing, that such possible neo-adjuvant treatment protocols
delay the wound healing process. The multilayered architecture of the intestinal wall affects its healing. Mucosal
eversion and inversion both delay this process. Apposition
of wound edges of mucosa and muscularis are highly dependent on the anastomotic technique. lf the layers of the
bowel wall are directly apposed, the anastomotic defect
can be sealed completely within 3 days [10]. In the present
study these parameters was not affected by the treatment

protocols. Investigating the normal histological development, Houdart et al. [20] reported that a 3-week period is
necessary for a normal colonic wound healing. As we
looked at the histological aspects during a 7-day period,
restitution of the mucosal epithelial layer and repair of the
muscularis propria did not seem to be affected by the preoperative treatments. as expected, similar to the results of
the previous study [17].
Although fibrinous exudate and necrosis were lower
from day 3 in the control and sham groups, the effects of
5-FU and especially irradiation can be severe, resulting in
persistent fibrinous exudate and necrosis in these groups.
Resection of the intestinal segment evokes an immediate
hemostatic vasoconstriction, followed by vasodilatation
and increased permeability. This process results in edema
and swelling of the tissue ends [19]. This may be further
compromised by irradiation, possibly due to adverse effects of irradiation on the microcirculation by damaging
the endothelial cells. Anastomotic sutures further enhance
this, and ischemic necrosis may develop as the suture strangulates the swelling tissue. The unique vascular supply of
the GIT which selectively downregulates its own perfusion
in pathological states may be responsible from these immediate changes [18]. Consistent with these findings,
Milson et al. [21] demonstrated an early decrease in seromuscular blood flow in colorectal anastomoses following
irradiation.
The greater omentum plays a crucial role in the healing
of intra-abdominal wounds, especially anastomotic repairs. It also adds to the formation of granulation tissue in
a positive way by wrapping around the suture line. In the
present study the amount of granulation tissue was largely
delayed on day 3 by irradiation. Neovascularization, a
component of granulation tissue formation, is also affected
by the treatment protocols, which result in delayed formation of granulation tissue. The previous study demonstrated
a positive correlation between granulocytes, macrophages,
and fibroblasts and the presence of granulation tissue [17].
These parameters were also affected by treatment in the
present study.
Granulocytes are the first to appear in wound healing.
Although both the white blood cell count and the tissue
myeloperoxidase activity were significantly low in our
treatment groups (unpublished data), we found a high level
of granulocytes in the early period of wound healing in all
groups. This also persisted longer in the treatment groups.
Investigating the collagenase activity in the GIT, Hawley
et al. [22] demonstrated that the amount of collagen in a
healing wound depends on lysis by collagenase, which is
found in granulocytes and synthesized by fibroblasts [23].
Previous studies have shown a possible correlation
between the appearance of granulocytes and the initial decrease in the amount of collagen in healing anastomoses
[24, 25]. Other studies also support this finding by showing that neutropenic animals heal normally, and that the decrease in postoperative anastomotic breaking strength in
rats is further prevented by neutropenia [26, 27].
Fibroblasts are normally found in the later phases of
normal wound healing. They are responsible for the pro-

239

duction of collagen and for establishing the structural extracellular matrix. However, the bulk of collagen within
the intestinal tract is contained within the submucosa since
intestinal smooth muscle cells in the lamina propria produce and maintain intestinal collagen. As a result, most of
the strength of the intestine is found in the submucosal
layer. Furthermore, it is responsible for anchoring the sutures that hold anastomosed bowel ends together [18]. The
fibroblast level was raised from day 3 onwards, but it was
significantly lower in the treatment groups. Previous studies have demonstrated that either pre- or postoperative
5-FU administration has little effect on the mechanical aspects of wound healing [2830]. Moreover, the clinical outcome regarding the anastomotic complication does not differ from that in the control group. 5-FU slows epithelial
mitotic activity and results in mucosal regression. Although minimal, it delays the histological aspects of colonic anastomotic healing.
Poor healing of intestinal anastomosis after irradiation
leading to anastomotic leak, sepsis, and death has been documented [31, 32]. The early effects of 20 Gy on the colonic
wall were evaluated by Weiber et al. [33], and histological
specimens demonstrated an acute inflammatory reaction
accompanied by atypia 3 days after irradiation. The same
group also showed that preoperative irradiation has no effect on the mechanical aspects of wound healing [12].
However, their experiment failed to simulate the fractionated sequence as practiced in a clinical setting. We recently
studied the effects of preoperative fractionated irradiation
[34] vs combination with 5-FU (unpublished) and found
that each of these delays the mechanical aspects of anastomotic wound healing in the rat left colon, but that nevertheless the clinical outcome in terms of anastomotic complications is not affected. In another study, doses greater
than 20 Gy caused acute crypt depletion followed by nonproductive attempts at regeneration and repopulation that
culminated in persistent epithelial denudation [35]. Assessing the intestinal anastomotic healing at varying times
after intraoperative irradiation, Dominguez et al. [36]
found that normal wound healing can be expected if a minimum of 2 weeks elapses between irradiation and intestinal anastomoses.
In conclusion, the results of this study show that, among
the histopathological parameters, necrosis and inflammatory exudate formation are more prominent in the treatment
groups. Delay in granulation tissue formation and fibroblast
proliferation were the most striking features affected by the
treatment groups, even though the study period was shorter
than the ideal healing period of anastomoses.

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Int J Colorect Dis (1998) 13: 241 246

Springer-Verlag 1998

O R I G I N A L A RT I C L E

S.-J. Lee Y.-S. Park

Serial evaluation of anorectal function

following low anterior resection of the rectum

Accepted: 14 September 1998

Abstract Purpose: This prospective study was performed to serially assess the changes in anorectal function
after low anterior resection of the rectum, and to elucidate
the mechanisms of functional impairment and the recovery process. Materials and methods: Thirty-two patients
undergoing low anterior resection for rectal cancer were
evaluated prospectively. Standardized interviews concerning anorectal function and physiologic studies consisting
of manometry and balloon proctometry were performed
preoperatively, then at 1, 3, and 6 months, and 1 year after the operation. Depending on the length of the residual
rectum, patients were divided into two groups: (1) shorter
than 4 cm (the short group, n = 18), and (2) longer than or
equal to 4 cm (the long group, n = 14). Results: Postoperatively, stool frequency increased and urgency to defecate
occurred, which continued until 36 months had passed
and was more remarkable in the short group. Overall incontinence score increased, which was more remarkable
in the short group. Anal resting pressure showed a moderate reduction after 3 months, whereas squeeze pressure did
not decrease significantly. Rectoanal inhibitory reflex was
postoperatively abolished in almost all patients in the short
group, which showed nearly no recovery for 1 year. In the
long group, it persisted postoperatively in half the cases,
and the reflex returned in a few cases within 1 year. Balloon proctometry revealed overall reduction in rectal capacity and compliance. Although the values tended to recover steadily, they did not reach the preoperative level for
1 year. Urgent volume and maximal tolerable volume remarkably declined, which continued for 1 year and for
6 months, respectively. Rectal compliance also decreased
considerably, which continued for 6 months. Most values
of rectal capacity tended to be smaller in the short group.

S.-J. Lee () Y.-S. Park

Department of Surgery, Chungbuk National University Hospital,
62 Gaeshin-Dong, Heungduk-Gu, Cheongju,
Chungbuk, Korea 361-711
Tel.: +82-431-269-6360, Fax: +82-431-266-6037
e-mail: sjlee@med.chungbuk.ac.kr

Conclusion: Impairment of continence after low anterior

resection seemed multifactorial, including diminished rectal capacity and compliance, impaired internal anal sphincter tone, and loss of rectoanal inhibitory reflex. Clinical
outcome was better and reduction in rectal capacity was
less in patients whose rectum remained more than 4 cm.
Most of the functional impairments clinically recovered by
6 months postoperation. In the process of clinical recovery of continence, restoration of rectal capacity and compliance and internal anal sphincter tone seemed to contribute a significant degree, while the rectoanal inhibitory reflex did not contribute as much.
Key words Anorectal function Low anterior resection

Introduction

Nowadays, the majority of patients who undergo potentially curative resection for rectal cancer have the anal
sphincter preserved. This change was made possible by improved surgical techniques, especially the advent of stapling devices allowing safe low anastomoses. Studies demonstrated that the recurrence of tumor was no more common and survival was as good after low anterior resection
as after abdominoperineal resection [1, 2]. Resection margins as short as 2 cm were sufficient for oncologic safety
[3, 4]. Rate of local recurrence and disease-free survival
depended on meticulous dissection of the mesorectum and
not on either preserving or removing the anal sphincters.
Although the quality of life after such sphincter-saving
procedure should be undoubtedly better than that after abdominoperineal resection with a permanent colostomy, it
does not depend on the preservation of the anatomy of the
anal sphincters but on the preservation of their function.
Therefore, sphincter-saving resection is justified only if
acceptable continence is achieved.
Twenty to twenty-five per cent of patients have been
reported to experience problems with anorectal function
after low anterior resection, complaining of increased

242

bowel movements, urgency of defecation, minor fecal

spillage, and difficulty in discriminating stool characters
[5, 6]. Such problems could be at their worst during the
early months after operation but may persist. However, reports on the underlying mechanisms and recovery process
widely vary.
The aim of this prospective study was to serially assess
the changes in anorectal function after low anterior resection of the rectum and to elucidate the mechanisms of functional impairment and its recovery process.

Patients and methods

Fifty-seven patients scheduled for anterior resection with low rectal
anastomosis due to rectal cancer were studied preoperatively. Two
patients who underwent abdominoperineal resection, 3 patients who
received coloanal anastomosis, 14 patients who had postoperative
radiotherapy, and 2 patients who suffered temporarily from anastomotic stricture were not further evaluated. Four patients were lost
during follow-up. Thus, 32 patients (14 males, 18 females, mean age
56.2 years ranging 2672 years) were recruited for the postoperative
evaluations 1, 3, and 6 months, and 1 year after the operation. Laboratory examinations at the first postoperative month were omitted
for fear of any adverse effect or patient discomfort.
The height of the anastomosis above the anal verge was determined by rigid sigmoidoscopy, and length of the anal sphincter highpressure zone was measured by anorectal manometry in the third
month following the surgery. Length of the residual rectum was calculated by subtracting the length of high-pressure zone from the
height of the anastomosis. The mean level of the anastomoses was
6.21.9 cm (range 3.09.5 cm) above the anal verge, and the mean
length of the residual rectum was 3.11.7 cm (range 0.26.9 cm).
Depending on the length of the residual rectum, patients were divided into two groups: (1) shorter than 4 cm (the short group, 18 patients), and (2) longer than or equal to 4 cm (the long group, 14 patients). We took into account that the level of rectal ampulla, acting
as an important reservoir preoperatively, will come up to about 4 cm
above the high-pressure zone postoperatively. Both groups were
comparable in age and tumor stage.
The pre- and postoperative examinations consisted of a standardized interview, anorectal manometry, and balloon proctometry.
Surgical technique
Low anterior resection for rectal cancer was performed by resecting
the sigmoid colon and rectum with high ligation of inferior mesenteric artery. For cancers located in the lower rectum, total mesorectal
excision [7], and lateral pelvic node dissection in T3 and T4 was performed. Autonomic nerves were preserved [8]. Straight colorectal reconstruction was performed with the handsewn Gambee method in
12 patients, single stapling in 9 patients, and double stapling in 11 patients. For stapling devices, Premium CEEA (outer diameter 31 mm,
Autosuture, USA) was used to restore intestinal continuity, and Proximate Access (length 55 mm, Ethicon, USA) to cross-staple.
Clinical assessment
The standardized interview consisted of questions concerning stool
frequency, ability to defer defecation more than 15 min, ability to
discriminate flatus from solid stool, and frequency of spillage of flatus/mucus, liquid, and solid stool. The anal incontinence score was
calculated according to the method described by Pescatorini et al.
[9]. Taking both degree and frequency of symptoms into account,
this scoring system ranges from 0 (full continence) to 6 (daily incontinence for solid stool).

Tests of anorectal function

The anorectal manometry was performed using a high-pressure, lowcompliance system (Arndorfer Medical Specialties Inc., Greenvale,
Wis.). We used an eight-channel water-perfused flexible catheter
with side-holes 5 mm and 45 C apart (external diameter 5.5 mm,
perfusion rate 0.5 ml/min) for pressure recording, and the procedure
was performed with a station pull-through technique. A computerized system (Polygram Lower GI, Synectics Medical, Stockholm,
Sweden) was used for data acquisition. The balloon reflex was elicited using a spiral catheter with eight spirally oriented perfusion ports
at 5-mm intervals and with an inflatable latex balloon fixed to its tip.
Serial inflation volumes of 15, 30, 45, and 60 ml of air were used to
elicit balloon reflex. Inhibitory reflex was considered present when
resting pressure decreased more than 20%.
The perception of rectal filling and the capacity of the neorectum
was measured by placement of a balloon with its lower edge 5 cm
above the anal verge and subsequent stepwise slow inflation with air
in 15-ml increments. The thresholds of the patients first perception
of rectal filling, urge to defecate, and maximal tolerable volume were
assessed. The pressures in the rectal balloon during stepwise inflations were measured with an air-filled transducer via a connected
catheter. Rectal compliance was determined as the slope of the volumepressure curve.
Statistical methods
Pre- and postoperative serial values were compared by the Wilcoxon matched-pairs signed-rank test or Fishers exact test. The MannWhitney U test for unpaired data or Fishers exact test was used for
comparison between the two groups. Significance was assumed with
P < 0.05.

Results

No significant difference between the two groups was

found in preoperative studies with respect to the clinical
features and anorectal physiologic studies (P > 0.05).
Clinical assessment
Postoperatively, stool frequency increased regardless of
the group (P < 0.05) (Table 1). In the short group, this increase continued until the sixth month. This elevation was
more remarkable in the short group (P < 0.05).
Urgency to defecate occurred regardless of the group,
and continued until the third month (P < 0.05). The difference between the two groups was statistically significant
(P < 0.05).
Ability to discriminate stool character was lost in 6 of
the total 32 patients (5 of the patients in the short group),
but did not reach a statistical significance (P > 0.05).
The overall incontinence score increased 1 month after
operation (P < 0.05), and continued until the third month in
the short group. This elevation was more remarkable in the
short group (P < 0.05).
Anorectal manometry
Postoperative maximal anal resting pressure showed a
moderate reduction regardless of the group, and was sig-

243
Table 1 Clinical assessment (mean SD). Group A: length of residual rectum <4 cm (n = 18). Group B: length of residual rectum
4 cm (n = 14). Urgency refers to the inability to defer defecation

more than 15 minutes. Discrimination refers to flatus from solid

stool. Pre-op. preoperatively; Post-op. postoperatively

Group

Pre-op.

1 month Post-op. 3 months Post-op. 6 months Post-op. 1 year Post-op.

Stool frequency (times/day)

Total
A
B

2.9 1.6
3.2 1.4
2.6 0.8

5.4 2.7 *
6.4 3.1 *,b
4.1 2.2 *,b

4.7 2.2 *
5.4 2.9 *,b
3.7 2.1 *,b

2.7 1.5
4.2 1.8 *,b
2.1 0.9 b

2.1 0.7
2.4 1.1
1.7 0.8

Urgency (number of patients/

total number of patients
examined)

Total
A
B

2/32
2/18
0/14

17/32 a
14/18 a,b
3/14 b

10/32 a
6/18 a,b
2/14 a,b

4/32
3/18
0/14

2/32
2/18
0/14

Discrimination (number of cases/

total number of patients
examined)

Total
A
B

31/32
17/18
14/14

25/32
12/18
13/14

28/32
14/18
14/14

30/32
16/18
14/14

30/32
16/18
14/14

Incontinence
Score

Total
A
B

1.2 0.3
1.8 0.7
0.4 0.1

2.7 1.3 *
3.6 1.9 *,c
1.6 1.1 *,c

2.2 0.8 *
3.2 1.7 *,c
1.2 0.7 c

1.5 1.1
2.7 1.8 c
0.6 0.4 c

0.7 0.2
1.1 0.4
0.8 0.6

* P<0.05: pre-op. vs post-op. (Wilcoxon matched-pairs signed-rank test)

a
P<0.05: pre-op. vs post-op. (Fishers exact test)
b
P<0.05: group A vs group B (Fishers exact test)
c
P<0.05: group A vs group B (Mann-Whitney U test for unpaired data)
Table 2 Anorectal manomertic findings (meanSD). Group A:
length of residual rectum <4 cm (n = 18). Group B: length of residual rectum 4 cm (n = 14). MRP, maximal resting pressure; MSP, maxGroup

imal squeeze pressure; HPZ, high pressure zone; RAIR, rectoanal inhibitory reflex; Pre-op. preoperatively; Post-op. postoperatively

Pre-op.

3 months Post-op.

MRP (mmHg)

Total
A
B

64 27.5
62 23.8
66 18.4

MSP (mmHg)

Total
A
B

129 38.5
132 24.2
125 31.7

Length of HPZ (cm)

Total
A
B

RAIR (number of positive cases/

total number of patients)

Total
A
B

46 12.3 *
40 16.2 *
58 11.3 *

6 months Post-op.

1 year Post-op.

52 15.7
48 17.9
58 13.4

60 20.7
57 17.5
63 22.1

104 32.7
103 29. 3
106 21.9

121 28.6
120 31.3
122 28.2

122 37.2
124 26.7
119 34.1

3.2 0.6
3.3 0.5
3.1 0.3

3.1 0.7
3.1 0.4
3.0 0.6

3.3 0.4
3.3 0.3
3.4 0.5

3.2 0.5
3.2 0.7
3.1 0.4

30/32
16/18
14/14

8/32 a
1/18 a,b
7/14 a,b

8/32 a
1/18 a,b
7/14 a,b

12/32 a
2/18 a,b
10/14 b

* P<0.05: Wilcoxon matched-pairs signed-rank test

a
P<0.05: pre-op. vs post-op. (Fishers exact test)
b
P<0.05: group A vs group B (Fishers exact test)

nificant only after 3 months (P < 0.05) (Table 2). No statistical difference was noted between the two groups. Maximal anal squeeze pressure decreased somewhat, but without statistical significance. Operation did not affect the
length of the high-pressure zone regardless of the group.
Rectoanal inhibitory reflex, preoperatively elicited in
30 of the total 32 patients, persisted in 8 cases 3 months
after the operation (P < 0.05). In the short group, it was elicited preoperatively in 16 of 18 patients, but persisted only
in 1 case 3 month postoperation (P < 0.05). It returned only in one other case within 1 year. In the long group, it was
elicited preoperatively in all patients, but persisted in seven of 14 patients 3 months postoperation. It returned in
three cases within 1 year.

Neorectal capacity and compliance (Table 3)

Postoperatively, balloon proctometry revealed overall reduction in rectal capacity and compliance. Although the
values tended to recover steadily, they did not reach the
preoperative level for 1 year.
First-perception volume was reduced regardless of the
group (P < 0.05), and continued for 6 months in the short
group. Urgent volume was remarkably reduced regardless
of the group (P < 0.05), and continued for 1 year. Maximal
tolerable volume also showed obvious reduction postoperatively (P < 0.05), and continued for 6 months. Although
most of the postoperative values of rectal capacity tended
to be smaller in the short group, the differences between
the two groups were statistically significant only with regard to the urgent volume at the third and sixth months,
and maximal tolerable volume at the sixth month (P < 0.05).

244
Table 3 Neorectal capacity and compliance (mean SD). A: length of residual rectum <4 cm (n = 18). B: length of residual rectum 4 cm
(n = 14). Pre-op. preoperatively; Post-op. postoperatively
Group

Pre-op.

3 months Post-op.

First perception (ml)

Total
A
B

35 13.2
32 8.2
38 12.6

Urgent volume (ml)

Total
A
B

Maximal tolerable volume (ml)

Rectal compliance (ml/mmHg)

6 months Post-op.

1 year Post-op.

17 9.1 *
15 4.7 *
20 7.2 *

18 7.2 *
15 4.8 *
22 9.2

21 8.2
17 7.2
24 6.5

205 40.3
196 57.2
217 46.8

72 21.6 *
58 34.5 *,a
89 27.3 *,a

83 38.2 *
71 20.1 *,a
98 21.9 *,a

Total
A
B

256 40.2
240 56.5
277 31.1

89 37.4 *
82 21.4 *
97 37.3 *

96 42.2 *
91 20.7 *,a
102 18.3 *,a

143 64.3
135 35.4
154 42.1

Total
A
B

8.0 2.4
7.7 3.0
8.3 2.2

3.7 1.7 *
3.3 1.4 *
4.2 1.2 *

4.3 1.4 *
4.2 1.1 *
4.4 2.4

5.1 1.0
4.9 1.1
5.4 1.9

104 24.3 *
97 25.7 *
112 32.4 *

* P < 0.05: preop. vs post-op. (Wilcoxon matched-pairs signed-rank test)

P < 0.05: group A vs group B (Mann-Whitney U test for unpaired data)

Table 4 Neorectal capacity and compliance according to the length of the residual rectum (mean SD). UV, urgent volume; MTV, maximal tolerable volume; RC, rectal compliance; Pre-op. preoperatively; Post-op. postoperatively
Postoperative period

Capacity and compliance

Length (cm)
2 (n = 14)

24 (n = 4)

46 (n = 9)

6 (n = 5)

3 months Post-op.

UV (ml)
MTV (ml)
RC (ml/mmHg)

55 21.2
81 30.7
3.3 1.6

63 14.7 *
89 35.9
3.4 1.1 *

83 18.5 *, a
96 31.2
4.1 0.6 *

98 25.3 *, a
104 28.3
4.3 1.0

6 months Post-op.

UV (ml)
MTV (ml)
RC (ml/mmHg)

69 25.8 *
90 24.5
4.2 1.2

78 37.7
94 19.1 *
4.3 1.8

97 28.5 *
101 24.7 *
4.3 1.9

99 26.4
104 27.2
4.6 1.6

1 year Post-op.

UV (ml)
MTV (ml)
RC (ml/mmHg)

95 37.2
133 39.4
4.8 1.3

105 28.5
142 28.3
5.1 1.8

109 31.7
150 23.1
5.3 1.2

117 34.6
161 42.4
5.6 1.2

*, a P < 0.05: Mann-Whitney U test for unpaired data

Rectal compliance also considerably decreased

(P < 0.05), and continued for 6 months in the short group.
No statistical difference was noted between the two groups.
The groups were subdivided for analysis (Table 4).
The difference in urgent volume was significant among the
2-cm to 4-cm, 4-cm to 6-cm, and 6-cm groups (P < 0.05)
at the third month, and between the 2-cm and 4-cm to
6-cm groups at the sixth month. The difference in maximal tolerable volume was significant at the sixth month
postoperatively between the 2-cm to 4-cm and 4-cm to
6-cm groups (P < 0.05). The difference in rectal compliance was also significant between the 2-cm to 4-cm and
4-cm to 6-cm groups (P < 0.05) at the third month.

Discussion

Although the rectum acts primarily as a reservoir and the

anal sphincter functions as an outlet obstruction, fine control of defecation results from close integration of rectal
and anal function. Factors considered important for maintaining anorectal continence are: (1) the anal canal high-

pressure zone (anal sphincter mechanism); (2) the anorectal angle and coordinated activity of the pelvic musculature; (3) anorectal sensory and reflex mechanisms; (4)
capacity, compliance, and tone of the rectum; (5) colon
transit; (6) anal canal motility; and (7) stool volume and
consistency [10]. Although no single component of this
complex arrangement appears to be all-important, functional reserve obviously decreases if reduction in rectal capacity or impairment of sphincter function is caused. Following low anterior resection, these complex functional
structures are excised and replaced or may be injured. The
continence mechanism is confronted with major changes
in its functional anatomy and may no longer withstand this
challenge.
The present study evaluated clinical outcome, manometric sphincter function, and neorectal capacity following low anterior resection of the rectum with different anastomotic levels. Data from clinical assessment obviously
showed impaired anorectal function following surgery. It
was more remarkable in the short group. This result is in
accordance with other reports [1114], but not that of Jehle
et al. [15]. Most clinical impairment of anorectal function
had recovered 6 months postoperation. Presence of the

245

tumor in the rectum itself may already have caused some

impairment in anorectal function, as shown by a slightly
elevated incontinence score before the surgery. When data
from healthy controls are used for comparison, the change
may be more dramatic.
Moderate decrease of anal resting pressure was observed following surgery regardless of the group. Up to
85% of resting pressure is produced by tonic contraction
of the internal anal sphincter. The sympathetic motor innervation arrives via the lumbar colonic and hypogastric
nerves. Since the lumbar colonic nerves are contained in
the vascular pedicle in the sigmoid and rectal mesentery,
transection of these nerves is inevitable, especially when
the inferior mesenteric artery is divided and the mesorectum included in the rectal excision [16]. It is also supplied
by myenteric nerves connected with the myenteric plexus
of the distal colon and rectum, and transection of the rectum could alter mesenteric innervation. During complete
dissection of the rectum down to the pelvic floor, with presacral mobilization of the rectum and division of the lateral
ligaments, the hypogastric nerves and pelvic plexuses will
be well preserved by the autonomic preserving procedure.
But the inferior rectal branches of the pelvic plexus innervating the internal sphincter could be partially sacrificed
[17]. In stapled cases, direct stretch injury to the internal
sphincter may have contributed in part to the fall in resting pressure [18]. Anal squeeze pressure, generated by contraction of the external anal sphincter and the puborectalis
muscle, did not show significant reduction following surgery. Since motor supply of the external anal sphincter is
by the somatic nerves, their innervation will not be injured
during the operation. Vassilakis et al. [19] reported postoperative impairment both in resting and squeeze pressures.
Rectoanal inhibitory reflex is mediated mainly by the
intramural nerve network and its activity can be modulated
by the sacral spinal cord. It remains intact following full
rectal mobilization or after presacral blockade, but abolished by circumferential rectal myotomy or transection of
the rectum, as occurs during anterior resection [20]. Some
report postoperative preservation of the reflex in all patients [21], others find the reflex in a portion of the cases
[2224], still others report absence of the reflex in most
patients, with a recovery several months postoperatively
in the majority of the patients [6, 21, 23, 24].
In this study, the reflex was postoperatively preserved
in 8 of a total 32 patients. With higher levels of anastomosis and a longer residual rectum, the reflex was frequently
preserved: 7 of 14 in the long group, compared with only
1 of 18 patients in the short group. There appear to be some
mechanisms whereby the reflex might be preserved after
low anterior resection. Inflation of the balloon just above
an anastomosis, while distending mainly the neorectum,
may have also stretched the anastomosis and rectal stump
just below it, thereby eliciting the reflex [23]. The existence of extrarectal pelvic pressure receptors contributing
to the reflex cannot be discounted. In the present study, the
reflex recovered only in four cases by 1 year after surgery;
this is compatible with the findings in other reports [23].

It is likely that regeneration of intrinsic intramural neurons

across the anastomosis is responsible for recovery of the
reflex, and recovery of the tonicity of the internal anal
sphincter [20, 22]. Discrepancies in the results on the reflex might reflect differences in technique or interpretation
of the results, as well as differences in the level and surgical technique of anastomosis. Although most of the impairment of anorectal function clinically recovered by the
sixth postoperative month, it was not accompanied by the
return of the reflex in the majority of the cases. The reflex
appears to be not absolutely necessary for full continence,
and continence may be maintained provided that sphincter tone and neorectal capacity are adequate [22].
Balloon proctometry showed remarkable reduction in
rectal capacity and compliance postoperatively. Capacity
and compliance tended to be more reduced in the short residual rectum group. The shorter the residual rectum was,
the smaller the values tended to be. This result is in accordance with another report [14]. Although they tended to
recover steadily, the values did not reach the preoperative
level until the first year.
Preoperative rectal capacity of the patient may be somewhat smaller than that of a healthy person due to space occupied by tumor, especially in the lower rectum. However,
we used the data provided by the patients themselves in order to observe the changes in sequence. It would be necessary to evaluate the change in tonicity of the neorectal
wall, and to record the motility of the neorectum and anal
canal with ambulatory manometry, to investigate the existence of pressure gradient and co-ordination between them.
In conclusion, impairment of continence after low anterior resection seemed multifactorial, including diminished rectal capacity and compliance, impaired internal
anal sphincter tone, and loss of rectoanal inhibitory reflex.
Clinical outcome was better and reduction in rectal capacity less in patients whose rectum remained longer than
4 cm. Most of the functional impairments recovered clinically 6 months postoperation. In the process of clinical recovery of continence, restoration of rectal capacity and
compliance and internal anal sphincter tone seemed to contribute to a significant degree, while the rectoanal inhibitory reflex did not contribute as much.

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Int J Colorect Dis (1998) 13: 247 250

Springer-Verlag 1998

O R I G I N A L A RT I C L E

M. Kruschewski N. Runkel H. J. Buhr

Radical resection in obstructing colorectal carcinomas

Accepted: 15 September 1998

Abstract Emergency resections of obstructing colorectal carcinomas usually involve only limited rather than
radical lymphadenectomy, which may contribute to the
poor long-term survival of these patients. Thirty patients
with ileus due to colorectal cancer have been included in
a prospective follow-up study since January 1995. Seventeen of these underwent potentially curative resections
with radical locoregional lymphadenectomy according to
current standards of elective oncological surgery; 2 had
radical right and 15 had radical left hemicolectomies.
Postoperative morbidity was 18%. An 89-year-old patient
died following postoperative bleeding from the colostomy site. During the same period, 13 patients with a metastasizing colorectal carcinoma underwent palliative
emergency surgery with a resection rate of only 38%. Morbidity and mortality were 69% and 46%, respectively.
These results suggest that emergency radical resections
can be safely performed in the majority of patients with
obstructing colorectal cancer without increasing the complication rate.
Key words Colonic obstruction Colorectal
carcinoma Emergency surgery Lymphadenectomy

Introduction

More than 10% of all patients with colorectal carcinomas

undergo emergency laparotomy due to acute obstruction
of the large bowel. The most important goal in this lifethreatening situation is treatment of the acute abdomen and
the ileus, while management of the underlying oncologic
disease is secondary [1]. According to the surgical princiM. Kruschewski () N. Runkel H. J. Buhr
Department of Surgery,
University Medical Center Benjamin Franklin,
Free University of Berlin,
Hindenburgdamm 30, D-12200 Berlin, Germany
Tel.: +49-3084452543, Fax: +49-3084452740

Table 1 5-year survival of patients with colorectal carcinoma after

elective or emergency surgery for ileus (without operative mortality) published in the literature since 1985
Author

Emergency
(%)

Elective
(%)

Total 5-year survival

Stower and Hardcastle 1985 [17]
Chapuis et al. 1985 [18]
Serpell et al. 1989 [19]
Kasperk et al. 1992 [20]

24
19
31
23

34
38
59
51

5-year survival after curative resection

Willet et al. 1985 [15]
Kyllnen 1987 [21]
Griffin et al. 1987 [22]
Serpell et al. 1989 [19]
Runkel et al. 1998 [2]

31
54
42
54
47

59
67
64
78

ple of minimal intervention in emergency cases, an ileus

is generally considered a relative contraindication for radical resection with locoregional lymphadenectomy. However, the poor long-term prognosis in patients with emergency resections calls for a critical view of this opinion
(Table 1).
Radical resections in emergency situations have rarely
been discussed in the literature thus far, and there are not
yet any prospective studies on this topic. We were able to
demonstrate that oncologic radical emergency resections
can be safely performed in selected patients and may have
a beneficial influence on their prognoses [2]. At the beginning of 1995, we started to perform radical surgery in all
patients with a potentially curatively resectable colorectal
carcinoma in the ileus and carried out a prospective assessment.
The aim of the study was to assess the morbidity and
mortality associated with this type of extended emergency intervention. The results are compared both with
those after palliative surgery obtained during the same
time period and with the literature. Due to the short follow-up, no data have been obtained regarding long-term
follow-up.

248
Table 2 Patient and tumor characteristics

Number of patients

Table 4 Postoperative complications and mortality (*)

Curative radical
surgery

Palliative
surgery

17

13

8
9

8
5

Gender
Male
Female
Median age (range)

65.3 (4289)

64.8 (5192)

Tumor localization
Right colon
Left colon

2
15

2
11

Union Internationale
Contre le Cancer stage
II
III
V

10
7

13

Table 3 a, b Surgical procedure and mortality (*)

a Curative radical surgery (UICC II, III)
Tumor site

Radical resection and

primary anastomosis

Radical discontinuity
resection

Right colon (n = 2)
Left colon (n = 15)

2
11

4/1 *

b Palliative surgery (UICC IV)

Tumor site

Right colon (n = 2)
Left colon (n = 11)

Resection
and primary
anastomosis

Hartmann
surgery

Bypass

Colostomy

2
1/1 *

8/5 *

Materials and methods

Complications

Curative
resection
(n = 17)

Palliative
resection
(n = 13)

Anastomotic insufficiency
Wound infection
Postoperative bleeding
Pneumonia
Multiorgan failure

1
1/1*
1

1
6/6*

Total

3 (18%)/1 (6%)

9 (69%)/6 (46%)

determined depending on the blood flow in the remaining intestine.

En-bloc colon resection was performed together with radical lymphadenectomy. There were two right-sited tumors, so that the ileocolic and right colic arteries were centrally ligated [5]. In both cases right hemicolectomy with ileocolonic anastomosis was primarily
established terminoterminally by interrupted suture.
In 15 patients, the tumors were situated in the left colon. Radicular ligation of the inferior mesenteric artery was done at the aorta
in all cases. In addition, the medial colic artery was centrally ligated in three carcinomas of the left colonic flexure. Primary anastomoses were established in 11 cases, seven of these after intraoperative orthograde intestinal lavage via a rinsing catheter introduced
into the cecum. The anastomoses were created terminoterminally in
a single row of interrupted sutures. Four patients with stenotic left
colonic tumor underwent primary radical resection without anastomosis: two had carcinomas at the rectosigmoid junction (distal resection level in the middle third of the rectum), and two were elderly
patients (86 years and 89 years old). This decision was made by the
surgeon on duty.
Palliative interventions
Thirteen patients proved to have distant metastases at surgery (UICC
IV) (Table 3). Two of these patients had right colonic tumors and
underwent primary resection (without locoregional lymphadenectomy) and anastomosis. Eight of the 11 distal tumors were treated with
deviating colostomies. One patient received a bypass (ileodescendostomy) and two underwent primary resection. Only one patient
with a tumor in the descending colon was treated by means of a primary anastomosis. Orthograde lavage was not carried out in this
group.

Patients
In our department between January 1995 and May 1998, 372 patients
with primary colorectal cancer were operated on, 30 (8%) of these
as an emergency within 24 h after admission due to a decompensated ileus of the large intestine. Patient and tumor characteristics are
listed in Table 2. The tumors were located aborally, extending as far
as the rectosigmoid junction. None of the patients evidenced
rectal tumors in the lower or middle third of the rectum. Curative
surgery was performed in all patients with no evidence of metastatic round foci in the chest X-ray or intraoperative detection of intraabdominal metastases [3]. Patients with metastases in the palliative
group.
Surgery
Curative interventions
The curative group [Union Internationale Contre le Cancer (UICC)
I-III] comprised 17 patients (Table 3). All underwent radical surgery
according to the guidelines of the German Surgical Society [4]. This
means that after identification of the tumor-bearing intestinal segment, radical ligature of the supplying trunk vessels was performed,
depending on the tumor site. In this way, the resection borders were

Results

Curative interventions
Of 17 patients, 14 had an uneventful postoperative course
(Tables 3, 4). The morbidity rate was 18% (3/17). There
were two surgical complications: an abdominal wall abscess and secondary bleeding from the colostomy site after discontinuity hemicolectomy in an 89-year-old patient
who refused a second intervention and died.
Palliative interventions
Morbidity (69%) and mortality (46%) were very high in
this group (Tables 3, 4). The most frequent and most serious complication was multiorgan failure as a consequence
of the irreversible ileus disease observed in one of four pri-

249

mary resections and five of eight deviating colostomies.

All patients who died had diffuse liver metastasis.

Discussion

Mastery of the life-threatening situation has top priority

when treating colorectal cancer patients with acute intestinal obstruction. For decades, a deviating colostomy was
initially created in all cases with distal obstruction, regardless of the underlying disease [6]. Following recovery,
resection was performed as a second step and colostoma
repositioning as a third step. This stepwise approach was
based on the surgical principle of minimal intervention in
emergency cases. It was assumed that this multistep therapeutic plan would be less stressful to emergency patients
and would allow better (and more radical) elective resections later. Another argument was that even surgeons with
little experience in colorectal surgery could at least reliably establish a stoma.
However, this concept was increasingly criticized in the
1970s. In many series, emergency resections (and the development of perioperative intensive care medicine) were
associated with a reduction of postoperative mortality to
10%, so that primary resection has now been generally accepted as the procedure of choice in malignant ileus [7, 8].
The idea that deviation alone is a safer and simpler procedure than resection has thus proved to be wrong in practice. Another important reason for primary resection is that
only a small number of patients undergo repeat resections
after primary deviation because the three-stage concept
was necessary in just half of the patients. Primary resection thus helps to improve long-term prognosis.
In the 1980s, the major concern was the time of anastomosing after primary resection. Whereas ileocolonic
anastomoses after right hemicolectomy were considered
safe even in emergency situations [911], colocolonic
anastomoses were judged to be highly insufficiency prone,
so that many preferred to carry out discontinuity resections
according to Hartmann. However, this procedure still requires an extensive second intervention with a correspondingly high morbidity of up to 33% [12]. Various methods
were developed to increase the safety of emergency anastomoses; colectomy with ileorectostomy and intraoperative orthograde intestinal lavage being the most commonly
used methods [13]. A recently published, randomized,
multicenter study from Scotland compared the two procedures and obtained a comparable mortality but a less favorable long-term morbidity after colectomy (61% vs
23%) [14]. Based on these results, we have preferred lavage over recent years and apply total or subtotal colectomy
only in multicentric carcinomas or proximal perforations
of the stenosed intestine. We observed no insufficiency in
our patient group after 11 primary hemicolectomies with
anastomoses. Although intraoperative lavage seems to reduce the risk of anastomotic insufficiency, the high mortality associated with insufficiency after emergency interventions is a real danger in individual cases. Assessing this

Table 5 Mortality associated with ileus in obstructing colorectal

carcinoma published in the literature since 1980
Author

Patients
(n)

Mortality
(%)

Raftery and Samson 1980 [23]

Kelley et al. 1981 [24]
Turunen 1983 [25]
Umpleby and Williamson 1984 [26]
Hermanek et al. 1985 [27]
Phillips et al. 1985 [9]
Kronborg 1986 [28]
Waldron and Donovan 1988 [29]
Buechter et al. 1988 [11]
Runkel et al. 1991 [30]
Kasperk et al. 1992 [20]
Sjdahl et al. 1992 [31]
Leitman et al. 1992 [32]
Runkel et al. 1998 [2]

101
156
91
103
173
713
55
238
99
57
134
115
80
55

22
18
15
31
25
23
15
33
23
21
30
17
6
4

danger is a difficult and responsible task for the surgeon

on call and explains why primary anastomoses were not
established in four of 17 patients of our study.
The long-term prognosis after potentially curative resections of a colorectal carcinoma is usually far less favorable in emergencies than in elective situations. In the literature, the difference in 5-year survival is 20% or greater
(Table 1). Even a stage-appropriate comparison yields
clearly less favorable results after emergency surgery [15].
Thus far, this has been explained by a different tumor biology; however, it should not be overlooked that the extent of emergency resectioning is usually more limited than
in elective situations, where the radical oncologic principles are usually followed.
Adopting oncologic principles in the emergency management of colorectal cancer is the last step in the development of ileus surgery. The more favorable results in
emergency surgery and the increasing standardization of
tumor surgery have played a decisive role here. The potential benefit of locoregional lymphadenectomy in elective
situations is generally accepted although it has not yet been
proven in randomized studies. It is thus justifiable to submit patients to radical surgery in emergency situations.
Since we were able to show, in the past, that this strategy
does not lead to an increased risk in selected patients [2],
we have radically managed all potentially curative resections, since 1995, even emergencies, according to current
standards. This extended intervention did not result in an
increased mortality compared with the data reported in the
literature (Table 5).
The most important result of this study is that it supports the new concept of radical emergency surgery. Expanding primary emergency resectioning by radical lymphadenectomy involves only minor additional stress to the
patient and is usually feasible in emergency situations. For
the experienced surgeon, applying oncologic principles in
left colon carcinomas with central ligation of the inferior
mesenteric artery and preaortic lymphadenectomy is only
a minor expansion of the intervention. The results of the
present study in a small group of 15 patients show that a

250

potential increase of postoperative morbidity due to expanding the intervention in emergencies is acceptable. The
only death in our study was an 89-year-old female patient
who refused relaparotomy due to bleeding after left discontinuity hemicolectomy [16]. Further severe complications or anastomotic insufficiencies were not observed in
our patient group.
Our study shows very clearly that, independent of the
surgical method applied, morbidity and mortality in emergency situations occur mainly in patients with advanced
cancer. Many patients die after the intervention, not of surgical complication but of progressive multiorgan failure as
a sign of irreversible ileus or very advanced tumor disease.
Patients with obstructing metastasizing colorectal carcinoma have a very poor prognosis, so that the emergency
situation should still exclusively determine the therapeutic strategy.
In summary, the preliminary results of our prospective
follow-up study confirm the importance of preoperative diagnostics, even in ileus. The surgical approach has to be
based on the extent of tumor spread, i.e., localized or disseminated. Progressive tumor diseases should only be
treated by minimal intervention, whereas curative interventions should involve oncologic surgery with radical
lymphadenectomy. Further studies have to show whether
radical emergency surgery improves the long-term prognoses of these patients.

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E, Colquhoun K (1985) A multivariate analysis of clinical and
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Obstructing carcinomas of the colon. Br J Surg 76: 965969
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(1987) Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 60: 23182324
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Carcinom als chirurgischer Notfall. Langenbecks Arch Chir
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30. Runkel NS, Schlag P, Schwarz V, Herfarth C (1991) Outcome
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31. Sjdahl R, Franzn T, Nystrm P-O (1992) Primary versus
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Int J Colorect Dis (1998) 13: 251 255

Springer-Verlag 1998

O R I G I N A L A RT I C L E

O. Schwandner T. H. K. Schiedeck H.-P. Bruch

Stoma creation for fecal diversion:

is the laparoscopic technique appropriate?

Accepted: 24 September 1998

Abstract This study assessed the results of laparoscopic

stoma creation for fecal diversion. All patients who underwent elective laparoscopic stoma creation as the sole
procedure were evaluated prospectively. Univariate analysis was performed to determine whether previous abdominal surgery, age, gender, body mass index, indication, or
surgeons experience has an effect on the outcome.
Between November 1992 and May 1998, 42 patients (17
males, 25 females) with a mean age of 62.1 years (range
1791) underwent laparoscopic stoma formation. Fecal diversion included loop ileostomy (n = 7), loop sigmoid colostomy (n = 32), and end-sigmoid colostomy (n = 3). Most
common indications were unresectable rectal cancer, rectal obstruction caused by advanced pelvic tumors and benign disorders such as perianal Crohns disease, and fecal
incontinence. Of the 42 procedures 41 were completed laparoscopically (97.6%). Complications occurred in four
patients (9.5%) requiring reoperation in two (4.8%). Mean
length of surgery was 74.4 min (range 30200). First
bowel movements resumed on the 3rd day (range 2nd7th)
after surgery and patients were discharged from hospital
after 13 days (range 647). Short-term results (>30 days
1 year) indicated that no further stoma-related complications occurred. Analyzing factors potentially predictive of
outcome, no statistically significant differences were documented in relation to previous abdominal surgery, age,
gender, body mass index, indication, or surgeons experience (P > 0.05). Laparoscopic stoma creation is appropriate to achieve fecal diversion because it is technically feasible and can be performed with low morbidity. In addition to the benefits of the minimally invasive technique for
the patients, laparoscopic stoma formation can be ideal for
the surgeon as basic and initial step to perform laparoscopic colorectal procedures.
Key words Laparoscopy Stoma Fecal diversion

O. Schwandner () T. H. K. Schiedeck H.-P. Bruch

Ratzeburger Allee 160, D-23538 Lbeck, Germany

Introduction

Stoma formation for intestinal diversion is a common procedure in colorectal surgery and is frequently required as
temporary or definite treatment option in fecal incontinence, severe perianal Crohns disease, and unresectable
rectal cancer [13]. As a nonresectional procedure without the need to create an anastomosis, the laparoscopic
technique is particularly appropriate for stoma creation.
The potential advantages of laparoscopic colorectal surgery have been clearly documented, including less postoperative pain, early return of bowel function with reduction
in postoperative ileus, quick recovery and better cosmesis
[48]. However, the laparoscopic approach is still in a
phase of critical appraisal [9]. The merits of laparoscopicassisted resections for the cure of colorectal malignancy
are still being debated, and the problem of port-site metastases must be resolved [1013].
The aim of this study was to assess the results of laparoscopic creation of intestinal stoma required solely for fecal diversion and particularly to outline short-term results. Specifically, an additional objective was to determine whether previous abdominal surgery, age, gender, body status, indication, and surgeons experience affect the outcome.

Patients and methods

All patients who underwent laparoscopic stoma creation for fecal diversion as the only abdominal procedure between November 1992
and May 1998 were evaluated prospectively. These included 42 patients (17 men, 25 women) with a mean age of 62.1 years (range
1791). Fecal diversion included loop ileostomy (n = 7), loop sigmoid colostomy (n = 32), and end-sigmoid colostomy (n = 3). Laparoscopic procedures were attempted in all patients who required
fecal diversion as an elective procedure during the study period; no
case of elective defunctioning stoma creation was scheduled as open
procedure. Of the 42 procedures 41 were completed laparoscopically (97.6%), and conversion to laparotomy was necessary in the other one (total conversion rate 2.4%) due to obesity (body mass index
29.8 kg/m2), which made laparoscopic colonic mobilization impossible. One third of the patients (n = 14) had had previous abdominal

252
Table 1 Procedures and
patients profiles (n = 42)
Age (years)
Male/female-ratio
Body mass index (kg/m2)
Previous abdominal surgery
Laparoscopically completed

Loop ileostomy
(n = 7)

Loop colostomy End colostomy

(n = 32)
(n = 3)

41.0 (1784)
0.2
20.3 (15.824.2)
1/7 (14.3%)
7/7 (100%)

66.8 (2791)
61.3 (4378)
62.1 (1791)
0.7
2.0
0.7
22.9 (14.029.8) 23.3 (21.227.0) 22.5 (14.029.8)
11/32 (34.4%)
2/3 (66.7%)
14/42 (33.3%)
31/32 (96.9%)
3/3 (100%)
41/42 (97.6%)

Table 2 Indications (n = 42)

Advanced rectal cancer

Unresectable cancer of small pelvis
Fecal incontinence
Crohns disease
Rectovaginal fistula
Colonic inertia
Radiation proctitis
Necrotizing pancreatitis

Total
(n = 42)

Table 3 Complications and management

n

Complications

Management

11
9
9
7
2
2
1
1

26.2
21.4
21.4
16.6
4.8
4.8
2.4
2.4

Intraoperative
Hemorrhage at trocar-site

Ligation of artery

Incision and drainage

(local anesthesia)
Laparoscopy: sigmoid resection +
stoma recreation
Laparotomy: segmental resection +
stoma closure

Postoperative
Parastomal abscess
Stoma retraction
Small bowel obstruction

surgery, most frequently appendectomy and hysterectomy. Mean

body mass index was 22.5 (range 14.029.8). Patients profiles and
procedures are outlined in Table 1. The most common indications
were unresectable rectal cancer and rectal obstruction caused by advanced pelvic carcinomas (ovarian cancer, cancer of cervix, prostate
cancer) followed by benign diseases such as fecal incontinence or
perianal Crohns disease. In three multimorbid patients, fecal incontinence was associated with advanced decubital ulcers which made
concomitant perianal dbridement and radical necrosectomy necessary. In one female fecal incontinence was caused by a third-degree
rectal prolapse. Indications are summarized in Table 2.
The intent to create a stoma as the only abdominal procedure was
made preoperatively. Previous abdominal surgery, radiotherapy, metastatic disease, or inflammatory bowel disease were not contraindications for laparoscopic stoma formation. However, exclusion criteria for this study were patients with a concomitant bowel resection,
or when the intent to resect was made preoperatively, but stoma creation was the only procedure performed. Further exclusions were stomas formed within an emergency procedure such as laparotomy for
acute large and small bowel obstruction or peritonitis.
The following parameters on laparoscopic stoma formation were
added to an anonymous database: patients age and gender, indication,
procedure, concomitant surgery, conversion to open surgery, intraoperative and postoperative morbidity, mortality, surgical reinterventions, duration of surgery, perioperative blood transfusion, length of
postoperative ileus, nutrition management, use of analgesics, and hospital stay. Furthermore, follow-up information included short-term results (>30 days1 year) focusing specifically on stoma-related morbidity, symptoms of adhesions and bowel obstruction, temporary and
definite diversion, recurrence of benign disease after stoma closure,
and death due to tumor progression and metastatic disease.
Preoperatively, patients underwent standard bowel preparation
(orthograde bowel lavage) if possible. Perioperative single-shot antibiotics (metronidazole, cefotaxime) were mandatory. The stoma site
was marked preoperatively by the stoma therapist in all cases.
All patients were placed in the supine modified lithotomy position. Three ports (10 or 12 mm) were routinely used, with the camera trocar placed infraumbilically, and the second port placed at the
selected port site. A third port placed in a contralateral position relative to the stoma site was used to mobilize the bowel and to divide adhesions. After diagnostic exploration a Babcock clamp was
placed via the stoma site port to grasp the selected intestinal loop. In
cases of loop ileostomy the most distal segment of ileum was used
without tension; in cases of loop colostomy (descending colon or sigmoidostomy) the sigmoid and descending colon regions were mobilized via the port contralateral to the stoma site by laparoscopic scissors and a tension-free segment was exteriorized through the stoma

1
1

site. For end-colostomy a stapler was used to divide the sigmoid colon. In all cases of laparoscopic technique the orientation of the bowel was verified by the camera, and fascial incision was routinely made
before exteriorization of bowel. Technical details of laparoscopic stoma creation have been described previously [14].
If any incision additional to those for the ports and the stoma creation had to be made, the procedure was described as converted.
To determine the effect of previous abdominal surgery, body status, age, gender, surgeons experience, and type of indication, statistical analysis was performed by the 2 test using Microsoft Excel 97
to determine P values for univariate analysis (P < 0.05 was taken as
statistically significant).

Results

Complications occurred in four patients: one hemorrhage

intraoperatively at the trocar-site made ligation of artery
necessary, and one parastomal abscess was drained postoperatively under local anesthesia, one stoma retraction
following rod dislocation was managed laparoscopically
by laparoscopic-assisted sigmoid resection and stoma recreation, and in one woman small bowel obstruction occurred 3 weeks after stoma formation, which made segmental resection by laparatomy necessary (Table 3). The
overall complication rate was 9.5% (n = 4); the overall reoperation rate was 4.8% (n = 2), including one laparotomy
and one laparoscopy. The overall laparotomy rate was 4.8%
(n = 2), including one converted case and one reoperation
caused by morbidity. There were two deaths within 30 days
after surgery which were not related to the procedure
(30-day mortality rate 4.8%): one man following loop ileostomy for necrotizing pancreatitis developed an acute respiratory distress syndrome with renal failure 3 weeks postoperatively and one woman who underwent loop sigmoid
colostomy for unresectable rectal cancer (Dukes stage D)
died 1 week after surgery due to tumor progression.

253
Table 4 Length of surgery and results of postoperative management
(n = 42)

Length of surgery (min.)

Postop. liquid diets (days)
Postop. solid diets (days)
Postop. first bowel movement (days)
Postop. use of analgesics (days)
Postop. hospital stay (days)

Mean

Range

74.4
1.3
3.0
2.8
3.3
13.0

30200
13
28
27
114
647

Table 5 Short-term results (>30 days1 year)

Late-onset morbidity
Stoma-related complications
Symptoms of adhesions or
bowel obstruction
Temporary diversion
Definite diversion
Recurrence of benign disease
after stoma closure
Death due to tumor progression
and metastatic disease a

Table 6 Factors affecting length of surgery, morbidity, and reoperation rate (univariate analysis by 2 test)
n

OP time Morbidity a
(min)

Reoperation rate a

Overall

42

74.4

9.5% (4)

4.8% (2)

Previous abdominal
surgery
Yes
No

14
28

82.9
70.2

14.3% (2)
7.1% (2)

7.1% (1)
3.6% (1)

Body mass index

24 kg/m2
< 24 kg/m2

11
31

77.7
73.2

0% (0)
12.9% (4)

0% (0)
6.5% (2)

Benign
disease
(n = 20)

Malignant
disease
(n = 20)

Age
65 years
< 65 years

21
21

76.9
70.3

14.3% (3)
4.8% (1)

4.8% (1)
4.8% (1)

Gender
Male
Female

17
25

72.4
75.8

5.9% (1)
12.0% (3)

0% (0)
8.0% (2)

Surgeons experience
Cases 121
Cases 242

21
21

82.6
66.2

14.3% (3)
4.8% (1)

4.8% (1)
4.8% (1)

Indication
Benign disease
Malignant disease

21
21

79.5
69.3

9.5% (2)
9.5% (2)

9.5% (2)
0% (0)

0
0
0

0
0
0

0
0
0

0
0
0

5
15
1

25
75
5

0
20

0
100

8*

53 *

Of 15 patients 8 (53%) died due to tumor progression or metastatic disease within 1 year of surgery; however, a total of 5 patients
could not be included in follow-up information

The mean length of surgery was 74.4 min (range

30200). Perioperative blood transfusion was necessary in
five patients (11.9%); however, all of these had tumor-induced anemia, and three of the five had their transfusion
preoperatively. Postoperatively the patients were advanced
to regular diet in relation to stoma function after a mean of
3 days (range 28); bowel movements resumed after a
mean of 2.8 days (range 27). Mean postoperative hospital stay was 13.0 days (range 647). Results of postoperative management are summarized in Table 4.
Short-term follow-up (>30 days1 year) revealed no
late-onset morbidity such as port hernias, stoma-related
complications, symptoms of adhesions, and small bowel
obstruction. In the group of fecal diversion for benign
disease (n = 20) 25% had temporary diversion and 75%
definite diversion. In one woman suffering from severe
Crohns disease, perianal Crohns fistula reccurred after
stoma closure and made second fecal diversion necessary.
In the group of patients who required palliative fecal diversion for unresectable malignancy (n = 20) 53% of those
who were available for follow-up died due to tumor progression or metastatic disease within 1 year after surgery,
but none of them had stoma-related complications or symptoms of bowel obstruction. Short-term results for the two
groups are presented in Table 5.
Analysis of factors potentially predictive of operation
time, morbidity, and reoperation rate showed no statistically significant differences in relation to previous abdom-

None of the differences were statistically significant

a
Absolute figures in brackets

inal surgery, body mass index, age, gender, indication for

surgery, or surgeons experience (P > 0.05). However, duration of surgery was decreased from 82.6 to 66.2 min
between the early and latter experience of laparoscopic
stoma creation (P > 0.05). Length of surgery was increased
to 82.9 min in patients with previous abdominal surgery
due to adhesiolysis in relation to 70.2 min in patients without history of previous surgery (P > 0.05). Results of univariate analysis are outlined in Table 6.

Discussion

Fecal diversion is a relatively common procedure in colorectal surgery. It has been demonstrated that loop ileostomy
is a safe surgical procedure for fecal diversion due to perianal Crohns disease or after ileoanal or coloanal anastomosis [3]. In patients with severe perianal disease, fecal
incontinence, or unresectable cancer the most distal suitable stoma, for example, sigmoid colostomy, is the preferred treatment option for diversion in our policy. Reviewing the literature, several authors have reported their results of laparoscopic stoma creation in recent years. Initial
case reports were focused mainly on the technical feasibility [1519], followed by a number involving small series
[2029]. The technique of laparoscopic stoma creation including loop ileostomy, loop colostomy, and end-colostomy was found to be a safe option.
Moreover, laparoscopic stoma creation is technically
less demanding than all other colorectal procedures performed by the laparoscope. In our experience, the three-

254
Table 7 Series of laparoscopic
stoma creation for fecal diversion

Reference

Year

Loop
ileostomy

Lange et al. [15]

Romero et al. [16]
Khoo et al. [17]
Hashizume et al. [18]
Jess et al. [19]
Lyerly et al. [20]
Roe et al. [21]
Weiss et al. [22]
Jager et al. [23]
Schmidt et al. [24]
Fuhrman et al. [25]
Ludwig et al. [26]
Oliveira et al. [27]
Hollyoak et al. [28]
Young et al. [29]
Current series

1991
1992
1993
1994
1994
1994
1994
1995
1995
1996
1994
1996
1997
1998
1998
1998

1
1
1
1
1
4
4
5
10
11
17
24
32
40
19
42

1
1
1
4a
4
9
2
16
25
ND
1
7

a
b

Loop
colostomy

End
colostomy

Controls

2
3

8
2
4

2
7b
6
3

18
32

No
No
No
No
No
No
No
No
No
No
No
No
No
Yes
Yes
No

Includes one split ileostomy

As part of abdominoperineal resection

port technique to create a stoma could be used in all but

three procedures in which adhesions due to previous abdominal surgery made a fourth trocar necessary. Additionally, colonic mobilization is laparoscopically feasible as
well and excellent visualization is provided. However, the
surgeon must respect general principles of ostomy surgery
to prevent the stoma-related morbidity which has been frequently described [3033].
Following the proposed advantages of minimally invasive surgery such as less pain and less disability, laparoscopic creation of intestinal stoma may be preferable to open
stoma formation. Previous reports of laparoscopic stoma
formation required solely for fecal diversion showed that
this approach may offer several advantages to the patients,
including less pain, quicker convalescence, earlier return
of bowel function, shorter hospital stay, and better cosmesis [1529]. However, only two series were comparative
studies which reported significant earlier return of bowel
function, shorter hospital stay, and lower analgesic requirements after laparoscopic stoma creation than open stoma
formation [28, 29]; both of these studies concluded that laparoscopic stoma creation is an alternative to open stoma
formation. Table 7 presents the series of laparoscopic
stoma creation required solely for fecal diversion.
The most common indications in our series were unresectable rectal cancer and rectal obstruction caused by advanced ovarian, bladder, or prostate cancer. These patients
had ceased enteral nutrition and required loop sigmoid colostomy to achieve fecal diversion and to enable oral intake
of regular diet. Short-term results in these patients show that
laparoscopic stoma creation is a safe option: no late-onset
morbidity, no stoma-related complications, and no symptoms
of bowel obstruction occurred within 1 year postoperatively.
Since defunctioning of the rectum means definite diversion,
and since it is associated with limited life expectancy due to
tumor progression and metastatic disease, it is crucial to use
the safest possible option particularly in these patients [34].
Complex anal fistulas, incontinence or stenosis with
concomitant proctitis are the main indications for fecal

diversion by loop ileostomy in patients suffering from perianal Crohns disease [14, 24, 35]. In our series seven patients with severe perianal Crohns fistulas underwent laparoscopic loop ileostomy. No conversion was necessary,
but one woman had a small bowel obstruction 3 weeks after surgery which made reoperation by laparotomy necessary. This complication was related to our early experience
in laparoscopic stoma creation due to an insufficient fascia incision at the trocar site. Currently an additional fascia incision at the stoma site is made to avoid both stoma
stenosis and small bowel obstruction. This phenomenon
has previously been described by others [24, 26]. Particularly patients with Crohns disease or with catabolic status
five of the seven patients who required loop ileostomy
for perianal Crohns disease had a body mass index below
20.0 kg/m2 in our series can benefit from the laparoscopic technique [2427].
In the current series, only one procedure had to be converted to laparotomy due to obesity, and complications occurred in only four patients; laparotomy was thus avoided
in 40 of 42 patients. However, the proposed advantages did
not result in an earlier discharge from hospital (mean hospital stay 13.0 days), as reported by other groups [24, 27,
28]. Three multimorbid patients had additional surgery in
the postoperative course due to decubital ulcers which prolonged hospitalization on 35, 38, and 47 days. Specifically
focusing on hospital discharge, all patients with Crohns disease (mean age 33.0 years) requiring loop ileostomy (n = 7)
were discharged after a mean of 7.3 days, while patients with
70 years of age or older (n = 19) were discharged from hospital after 11.2 days in the mean because they required intensive inpatient stoma care and home social care had to be
arranged before discharge. Additionally, return to oral intake in the first years of laparoscopic colorectal surgery did
not differ between the laparoscopic and open groups.
Previous abdominal surgery did not significantly affect
operation duration or morbidity (P>0.05). However, the duration of surgery was increased due to adhesiolysis in patients with previous abdominal surgery. Accordingly, the out-

255

come of laparoscopic of stoma formation did not differ in

terms of the age of the patient and advanced age did not result in increased morbidity (P >0.05). Comparing early and
later experiences, the learning curve resulted in a shortening
of operation time (P> 0.05). However, the results of univariate analysis are not generally conclusive as the collective is
still very small, and there are no controls. It is our policy that
every patient who requires elective stoma creation for fecal
diversion is considered suitable for the laparoscopic approach. Since the introduction of laparoscopic colorectal procedures in 1992, 90% of all stomas as sole procedures have
been laparoscopically performed in our department. Therefore the encouraging results of elective laparoscopic stoma
creation must be placed in the context that no selection of patients occurred.
In conclusion, laparoscopic stoma creation for fecal diversion as the sole abdominal procedure is a safe and technically feasible procedure and can be performed with low
morbidity. Patients with previous abdominal surgery, obesity, Crohns disease, or catabolic state can benefit from the
laparoscopic approach. As the current series was neither
comparative nor randomized, the conclusions are not definitive, but the laparoscopic technique is at least an alternative to open surgery. Nevertheless, our experience shows
laparoscopic stoma creation to be superior to open stoma
formation particularly appropriate for patients with adhesions due to previous abdominal surgery or inflammatory
bowel disease, which can make open stoma creation via a
limited incision very difficult or even impossible. Additionally, due to the advantage of being able simultaneously
to explore the entire abdominal cavity, stoma creation plays
an important role in laparoscopic colorectal surgery. Furthermore, one must not forget that laparoscopic stoma creation can be ideal for the surgeon as a basic and initial step
to perform laparoscopic colorectal procedures.
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2. Sprangers MAG, Taal BG, Aaronson NK, te Velde A (1995)
Quality of life in colorectal cancer: stoma vs. nonstoma patients.
Dis Colon Rectum 38: 361369
3. Wexner SD, Taranow DA, Johansen OB, Itzkowitz F, Daniel N,
Nogueras JJ, Jagelman DG (1993) Loop ileostomy is a safe option for fecal diversion. Dis Colon Rectum 36: 349354
4. Bruch HP, Schiedeck THK, Schwandner O (1998) Laparoscopic colorectal surgery: a five-year experience. Dig Surg (in press)
5. Fielding GA, Lumley J, Nathanson L, Hewitt P, Rhodes M, Stitz
R (1997) Laparoscopic colectomy. Surg Endosc 11: 745749
6. Koeckerling F, Schneider C, Reymond MA, Scheidbach H, Konradt J, Baerlehner E, Bruch HP, Kuthe A, Troidl H, Hohenberger
W (1998): Early results of a prospective multicenter study on 500
consecutive cases of laparoscopic colorectal surgery. Laparoscopic Colorectal Surgery Study Group. Surg Endosc 12: 3741
7. Schwenk W, Bhm B, Haase O, Junghans T, Mller JM (1998)
Laparoscopic versus conventional colorectal resection: a prospective randomised study of postoperative ileus and early postoperative feeding. Langenbecks Arch Surg 383: 4955
8. Wexner SD, Reissman P, Pfeifer J, Bernstein M, Geron N (1996)
Laparoscopic colorectal surgery. Analysis of 140 cases. Surg
Endosc 10: 133136

9. Ortiz H, Armendariz P, Yarnoz C (1996) Early postoperative

feeding after elective colorectal surgery is not a benefit unique
to laparoscopy-assisted procedures. Int J Colorect Dis 11:
246249
10. Bruch HP, Herold A, Schiedeck THK, Schwandner O (1997)
Chirurgie des Rektumkarzinoms. Zentralbl Chir 122:13341141
11. Seow-Choen F, Eu KW, Ho YH, Leong AF (1997) A preliminary comparison of a consecutive series of open versus laparoscopic abdomino-perineal resection for rectal adenocarcinoma.
Int J Colorect Dis 12: 8890
12. Wexner SD, Cohen SM (1995) Port site metastases after colorectal surgery for cure of malignancy. Br J Surg 82: 295298
13. Wexner SD, Latulippe JF (1997) Laparoscopic colorectal surgery and cancer. Swiss Surg 3: 266273
14. Schwandner O, Herold A, Schiedeck THK, Bruch HP (1997)
Laparoskopische Stomaanlage. Coloproctology 19: 228235
15. Lange V, Meyer G, Schardey HM, Schildberg FW (1991) Laparoscopic creation of a loop colostomy. J Laparoendosc Surg
1: 307312
16. Romero CA, James KM, Cooperstone LM (1992) Laparoscopic sigmoid colostomy for perianal Crohns disease. Surg Laparosc Endosc 2: 148151
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966968
18. Hashizume M, Harajuchi Y, Ikeda Y, Kajiyama K, Fujie T, Sugimachi K (1994) Laparoscopy-assisted colostomy. Surg Laparosc Endosc 4: 7072
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20. Lyerly HK, Mault JR (1994) Laparoscopic ileostomy and colostomy. Ann Surg 219: 317322
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4: 345347
22. Weiss UL, Jehle E, Becker HD, Buess GF, Starlinger M (1995)
Laparoscopic ileostomy. Br J Surg 82: 1648
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24. Schmidt WU, Mller FP, Hesterberg R, Rher HD (1996) Laparoskopische Ileostomie und Colostomie bei Morbus-Crohn-Patienten. Chirurg 67: 12611265
25. Fuhrman GM, Ota DM (1994) Laparoscopic intestinal stomas.
Dis Colon Rectum 37: 444449
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(1994) Loop ileostomy fixation: a simple technique to minimise
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(1997) Does preoperative stoma marking and education by the
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table analysis of stomal complications following colostomy. Dis
Colon Rectum 37: 916920
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Int J Colorect Dis (1998) 13: 260263

Springer-Verlag 1998

O R I G I N A L A RT I C L E

J. Hampe B. Hermann S. Bridger A. J. S. MacPherson

C. G. Mathew S. Schreiber

The interferon- gene as a positional and functional candidate gene

for inflammatory bowel disease

Accepted: 12 October 1998

Abstract Epidemiological and genome-wide linkage

analyses have provided firm evidence for a genetic component in the pathogenesis of inflammatory bowel disease.
The linkage regions on chromosomes 12 and 16 have been
replicated in several independent samples. These represent
the best positional evidence in the search for inflammatory
bowel disease susceptibility genes. While systematic association and physical mapping studies in these regions are
under way, the direct analysis of immunologically relevant
genes as positional and functional candidates may provide
a shortcut in this process. The interferon- gene resides in
the chromosome 12 linkage region near the marker
D12S83. Interferon- is an important proinflammatory cytokine in the interleukin-12 cascade and has been implicated in the pathogenesis of mucosal inflammation. We
tested this gene for evidence of linkage and association in
133 German multiplex families and 506 single patients
with their parents. An intragenic, highly informative CArepeat marker in intron 1 of the gene was typed using fluorescence-labeled polymerase chain reaction and analysis
on an automated sequencer. In the nonparametric linkage
analysis using GENEHUNTER, a nonsignificant maximum LOD score of 0.67 was obtained. The transmission
disequilibrium test for association was negative (P 0.22)
for Crohns disease, ulcerative colitis, and the combined
inflammatory bowel disease phenotype. In summary, the
findings make interferon- a very unlikely candidate for
the major susceptibility gene in the chromosome 12 linkage interval. Future efforts can concentrate on other transcripts in the region.
Key words Pro-inflammatory cytokines
Crohns disease Ulcerative colitis Susceptibility

J. Hampe B. Hermann S. Schreiber ()

First Medical Department, Christian-Albrechts University Kiel,
Schittenhelmstrasse 12, D-24105 Kiel, Germany
S. Bridger A. J. S. MacPherson C. G. Mathew
Division of Medical and Molecular Genetics,
Guys, Kings and St. Thomas School of Medicine, London, U.K.

Introduction

Inflammatory bowel disease (IBD) is characterized by a

dysregulated intestinal mucosal immune response [1, 2].
This process results in an imbalance of pro- and contrainflammatory cytokine production within the mucosa [3, 4].
While significant progress in the delineation of the pathophysiological process has been achieved [510], the etiological agent or molecular defect still remains to be identified.
Epidemiological studies have provided evidence for
genetic factors in the etiology of IBD. This includes a
higher concordance rate among monocygotic twins than in
dizygotic twins [11, 12] and a greater disease risk among
relatives of affected individuals. The estimate for the relative sibling risk (s) ranges from 10 to 50 in the various
studies [1315]. Genome-wide linkage analyses of large
cohorts of affected relative pairs have implicated susceptibility regions on chromosomes 1, 3, 4, 7, 12, and 16
[1618]. The susceptibility regions on chromosomes 12
and 16 have been replicated in a number of independent
populations [1921]. These well-established linkage regions are still very large in molecular terms and encompass between 30 and 40 cM; this corresponds to approximately 100150 transcripts in each of these regions. Each
of these could from a positional cloning point of view
represent the causative susceptibility gene. While approaches using systematic high-density disequilibrium
mapping are under way, the combination of immunological and positional evidence in the direct analysis of candidate genes could provide a shortcut in this process.
Interferon- (IFN- ) is an important TH-1 cytokine that
can be induced by interleukin-12. This pathway has been
implicated as an important mechanism in the induction and
maintenance of chronic inflammation in both animal models of IBD [22] and the human disease [2325]. Variations
in the IFN- gene or of regulatory elements in its promoter
would affect this immunoregulatory chain. The IFN- gene
is therefore a functional candidate gene for IBD. It has been
localized genetically to the linkage interval on chromo-

261
Fig. 1 Genomic structure of the
human IFN- gene [27]. Gray
boxes (on genomic sequence),
exons; above, respective numbers; scale, basepairs; black box
(in intron 1), localization of the
polymorphic CA repeat

some 12 near the marker D12S83 and is therefore also a

positional candidate for IBD susceptibility.
In this study we used a highly informative intragenic
polymorphism of the IFN- gene to evaluate its possible
etiological role. We used the transmission disequilibrium
test (TDT) to test for association with the disease [26].
This test provides a sensitive measure of linkage and association that is robust towards population inhomogeneities.

and 328 basepairs were designed from the database sequence (Genbank accession no. M37265; product length based on 12 CA repeats,
Table 2). The three products were genotyped simultaneously in a single lane using fluorescence-labeled primers. Absolute allele sizes
were standardized using two reference individuals in each gel. The
polymerase chain reaction (PCR) was performed in a buffer at
pH 9.2, 2.0 mM MgCl2 for pairs 1 and 3 and in a buffer at pH 8.3,
2.5 mM MgCl2 for pair 2. Product length was analyzed on an automated sequencer for all samples.
Linkage and association analysis

Materials and Methods

Patients and samples
Blood samples were obtained from German families with one or more
cases of IBD which was diagnosed as Crohns disease or ulcerative
colitis using standard diagnostic criteria [1]. The protocol was approved by the institutional ethics committees and the regional data
protection agencies. Written, informed consent was obtained from
all study participants. The panel included a total of 506 patients with
their unaffected parents (triplets) and 133 families with multiple
affected members (Table 1).

Since the genetic disease model of IBD is unknown, linkage analysis was carried out using both a nonparametric method, which does
not specify a genetic model, and parametric analysis, in which four
models as described by Naom et al. [28] were used. The FASTLINK
[29] and GENEHUNTER [30] programs were used for parametric
and nonparametric analysis, respectively. Linkage was investigated
by separate analysis of Crohns disease only, ulcerative colitis only,
and all IBD families. Finally, genotype data in both multiplex families and isolated cases were analyzed by the TDT [26], which determines whether a specific allele or haplotype is transmitted preferentially to affected offspring.

Results

Polymorphism genotyping
The IFN- gene [27] contains a polymorphic CA-repeat in intron 1
(Fig. 1). For an efficient simultaneous typing of multiple individuals per lane, three pairs of primers flanking the CA-repeat polymorphism in intron 1 of the gene yielding product lengths of 155, 202,
Table 1 Overview of the investigated cohort. (Affected sib pairs,
affected cousins the number of families with multiple affected members with IBD, Triplets sporadic cases of IBD recruited with their
unaffected parents to allow for robust testing for association with the
TDT [26])
Triplets

Affected
sib pairs

Affected
cousins

Ulcerative colitis
Crohns disease
Mixed ulcerative colitis,
Crohns disease

161
345

46
29
25

15
7
11

Total

506

100

33

Table 2 Primers sequences

used for the detection of the
CA repeat in intron 1 of the
IFN- gene. The product length
is based on 12 CA repeats as in
the Genbank sequence M37265

The single nucleotide polymorphism that is indicated in

the Genbank record at nucleotide position 4712 could not
be detected in 50 unrelated individuals with IBD. The CA
repeat in intron 1 was highly informative and was therefore typed in the total population. The heterozygosity of
this marker was 73%.
Linkage analysis of the CA-repeat polymorphism in the
IFN- gene in 133 German IBD families showed positive
nonparametric logarithm of odds (LOD) scores which were
not statistically significant (Table 3). The maximum parametric LOD score under the rare recessive model was 0.14.
Analysis under three of the parametric models resulted in
negative LOD scores, indicating that the chosen models
did not correctly reflect the true mode of inheritance. TDT
analysis of the IFN- alleles in these families and in 503
nonfamilial cases of IBD and their parents did not show
preferential transmission of any alleles either in the global

PCR

Primers

Product length (BP)

Pair 1:

5-TTC ATT ATT TGT TTA AAA CTT AGC TGT TAT
5-TGT GCC TTC CTG TAG GGT ATT ATT ATA CGA
5-GCT GTC ATA ATA ATA TTC AGA C
5-CCA CCC CAC TAT AAA ATA C
5-CGG AAC TTC GTT GCT CAC TGG GAT TTT GGA
5-ATG GTA CAG GTT TCT ATT ACA TCT ACT GTG

155

Pair 2:
Pair 3:

202
328

262
Table 3 Summary of the results of linkage and association analysis of the INF- gene polymorphism. The TDT analysis results are
reported as the most significant single allele test and as the global 2
significance test of the respective contingency tables
Ulcerative
colitis
TDT analysis
All (P values)
Single allele (1 df)
0.35
0.60
Global 2 (6 df)
Spontaneous IBD only (P values)
Single allele (1 df)
0.67
0.92
Global 2 (6 df)
Linkage analysis
Parametric (LOD scores)
Common dominant
Rare dominant
Common recessive
Rare recessive
Nonparametric
NPL
P value

1.21
3.48
2.86
0
0.08
0.27

Crohns
disease

All

0.35
0.45

0.22
0.26

0.92
0.78

0.72
0.92

0.72
3.26
1.52
0.18

7.35
13.3
8.98
0.14

0.67
0.42

sented, i.e., the direct investigation of polymorphisms in a

functional and positional candidate gene using a robust test
of association such as the TDT will be useful in the search
for the responsible molecular variants that confer susceptibility to IBD.
Acknowledgements The authors thank the physicians, IBD patients, and their families for participating in this study. We gratefully acknowledge the cooperation of the German Crohns and Colits
Foundation, Prof. Raedler, Hamburg; Prof. Kruis, Kln; Dr. Theuer,
Heilbronn; Dr. Meckler, Gedern; Prof. Lochs, Dr. Wedel, T. Herrmann, Berlin; Dr. Herchenbach, Recklinghausen; Prof. Scheurlen,
Wrzburg; Dr. Demharter, Augsburg; Dr. Simon, Munich; Dr. Purrmann, Moers; Dr. Jessen, Kiel; Dr. Zehnter, Dortmund; Dr. Lbke,
Dr. Weismller/Koblenz, Dr. Eiche, Denkendorf; Dr. Schnfelder,
Aachen; Prof. Fleig, Halle; Dr. Wewalka, Linz, Austria; Dr. Knofloch, Wels, Austria. This work was supported by the Deutsche Forschungsgemeinschaft (Schr 512/1-3 and SFB 415), a Training and
Mobility of Research (TMR) Network grant of the European Union
(ERB-4061-PL-97-0389), and an educational grant from Arzneimittelwerk Dresden to J. H. and from MFG.

0.46
0.11

or the allele-specific tests. Association tests in the Crohns

disease and ulcerative colitis phenotypes were also negative in all categories (Table 3).

Discussion

The moderate nonparametric linkage evidence observed in

this study for the IFN- gene polymorphism is consistent
with the reported linkage results from this population [31],
considering that only about one-fourth of the total sample
was characterized for linkage. The negative results in the
parametric linkage analysis underscore the complex nature
of the IBD phenotype as a result of the interaction of multiple genes and environmental factors.
More importantly, in this study there was no evidence
for association of the IFN- gene polymorphism to IBD or
the phenotypes of ulcerative colitis or Crohns disease. This
suggests that no sequence variant conferring susceptibility
to IBD is located in the vicinity of this polymorphism. Given
the small size of the IFN- gene of about 6 kb of genomic
sequence and the large number of individuals investigated,
this effectively rules out IFN- as the major susceptibility
gene on chromosome 12. However, we cannot definitively
exclude a minor effect of a mutation in the IFN- gene that
might contribute to the chromosome 12 linkage.
These data also have implications in terms of the immunological models for IBD. According to our results, the
involvement of INF- is most likely a secondary phenomenon due to other etiological agents or defects. INF- thus
has important effector functions in the induction and maintenance of inflammation but is itself not causative.
In summary, this study shows the INF- gene to be a
very unlikely candidate for the major chromosome 12 susceptibility gene. Future efforts can concentrate on other
transcripts in this susceptibility region. The approach pre-

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