Document 61173

REVIEW
ETIOLOGY AND PATHOPHYSIOLOGY OF
IRRITABLE BOWEL SYNDROME AND CHRONIC CONSTIPATION
—
Michael Camilleri, MD, PhD*
ABSTRACT
Functional gastrointestinal (GI) disorders are collections of symptoms attributable to the GI tract in
the absence of mucosal, structural, or biochemical
disease. Two of the most common disorders, chronic constipation and irritable bowel syndrome (IBS),
have common etiopathogenetic features—notably
psychosocial disturbances, dysmotility, and heightened sensitivity. In some patients with IBS, there is an
association with a postinfective state. In constipation,
transit disorders and abnormal evacuation represent disturbances of function that are amenable to
therapy. This review is an update of the mechanisms
and pathophysiology of these disorders. IBS and
constipation are defined, and control of gut motility
and sensation and their disturbances in these disorders are reviewed along with the mechanisms and
pathophysiology of IBS and constipation.
F
(Adv Stud Med. 2005;5(10B):S955-S964)
unctional gastrointestinal (GI) disorders
are defined as collections of functional
symptoms that are not attributable to
structural, mucosal, or biochemical diseases of the GI tract.1 Symptoms include
indigestion, abdominal pain, bloating, distension, and
symptoms of disordered defecation. The most common functional bowel disorders are functional dyspepsia, irritable bowel syndrome (IBS), and chronic
*Atherton and Winifred W. Bean Professor, Professor of
Medicine and Physiology, Mayo Clinic College of
Medicine; Consultant in Gastroenterology, Mayo Clinic,
Rochester, Minnesota.
Address correspondence to: Michael Camilleri, MD, PhD,
Mayo Clinic, Charlton 8-110, 200 First St SW, Rochester,
MN 55905. E-mail: [email protected]
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constipation.2,3 These are biopsychosocial disorders in
which psychosocial factors, prior gastroenteritis,
abnormal motility, gas retention, and heightened sensation interact to induce symptoms.
IBS is the most common functional bowel disorder
and is characterized by chronic or recurrent symptoms
that are thought to arise in the small bowel or colon.
Symptoms have been embodied in the Manning4 or
Rome II1,2 criteria and include lower abdominal pain
related to bowel movements, changing bowel habit
(eg, diarrhea, constipation, or alternating between the
two), abdominal bloating, a sense of incomplete rectal
evacuation, and passage of mucus.
Constipation is variably defined, but usually refers to
persistent difficult, infrequent, or seemingly incomplete
defecation.5 Diagnosis often is arbitrary and may depend
on the patient’s perception of what is abnormal. The
prevalence of constipation depends on the definition and
the population studied. Individual patients’ symptoms
must be analyzed in detail to ascertain what is meant by
“constipation” or “difficulty” with defecation (Figure 1).
Patients also may perceive incorrectly that they are constipated. When formally evaluated via daily diary during
a 4-week period, only 20 out of 44 patients who perceived they were constipated had reduced stool frequency
(ie, <3 bowel movements per week).6 The perception of
hard stools or excessive straining is more difficult to assess
objectively, though instruments such as the Bristol Stool
Form Scale7 may be helpful. The need for enemas or digital disimpaction is a clinically useful marker to corroborate the patient’s perceptions of difficult defecation.
PATHOPHYSIOLOGY AND MECHANISMS IN
IRRITABLE BOWEL SYNDROME
In addition to classical concepts of the pathophysiology of IBS,8 this section addresses current understanding9
of the role of inflammation in IBS and the potential of
novel mechanisms, serotonin, genetics, and intraluminal
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factors. Intrinsic and extrinsic neural influences modulate
the motor and sensory functions of the gut (Figure 2).
CLASSICAL PATHOPHYSIOLOGY
The pivotal mechanisms involved in the pathophysiology of IBS are altered psychosocial function,
motility, and hypersensitivity. Psychosocial aspects8 are
important determinants of the emotional response to
visceral stimulation, and they influence the time to
presentation as well as the severity of disease—and
provide the rationale for treatment with antidepressants and other behavioral approaches.
Important motor dysfunctions10 include prominent
symptoms and colonic contractions after feeding in diarrhea-predominant IBS (D-IBS),11,12 and poor colonic
response in constipation-predominant IBS (C-IBS) or
functional constipation associated with slow transit.13
Disturbances of transit profiles reflect the predominant
bowel dysfunction,14-16 and gas transit also is demonstrable experimentally and is related to bloating sensation.17,18
An associated evacuation disorder (eg, puborectalis
spasm) may result in an overlap with symptoms of CIBS.19,20 Epidemiologic studies document overlap with
upper functional disease, specifically dyspepsia or upper
abdominal pain, which occurred in 80% of IBS patients
in one study.21
Overlap of IBS with celiac disease may merely
reflect the concurrence of 2 relatively common disorders in the same person and the limited repertoire of
symptoms of diverse gut disorders. Screening for celiac disease is important in susceptible populations;
however, population-based studies in a community
with a predominant northern European extraction
suggest that serologic screening does not identify significant numbers of patients with celiac disease among
individuals with IBS and dyspepsia.22
Visceral hypersensitivity and hyperalgesia are well
documented in IBS,23-28 and the rectal sensory threshold for pain of 32 mm Hg has relatively high sensitivity and specificity for identifying hypersensitivity. The
increased activation of the limbic or emotional motor
system in IBS patients during rectal distension has
been confirmed in several studies.29,30
Figure 1. Mechanisms Involved in Continence and
Defecation in Humans*
At Rest
A
B
During Straining
Pubis
Puborectalis
Coccyx
Anorectal
External anal
angle
sphincter
Internal anal
sphincter
Anorectal
angle
Descent of the pelvic floor
The figure shows a sagittal section through the pelvis and emphasizes the role of the
pubo-rectalis and pelvic floor muscles in facilitating continence by contraction and
allowing defecation by the straightening of the anorectal angle. Conversely, pelvic
floor dyssynergia may result in obstruction to defecation with a sense of incomplete
evacuation, constipation, and secondary abdominal discomfort.
*Reprinted with permission from Lembo A, Camilleri M. Chronic constipation. N Engl
J Med. 2003;349:1360-1368.20 Copyright © 2003. Massachusetts Medical Society. All
rights reserved.
Figure 2. Extrinsic and Intrinsic Control of Gut Motility
IN TR INS IC
E XTR IN SIC
Parasym pathetic
Vagal
IC C s
Enteric brain
10 8 neurons
Sympathetic
Thoracolumbar
smooth muscle cell
with receptors for transmitters
modulates peristaltic reflex
inter
inter
IPAN: sensory
motor
motor
V IP /
AC h
S u b P /S u b K
N OS
Ascending contraction Descending relaxation
d is t e n ti o n b y b o l u s
DOES INFLAMMATION PLAY A KEY ROLE IN
IRRITABLE BOWEL SYNDROME?
Several lines of evidence address this question.
First, epidemiologic studies suggest an association
between inflammation as a result of earlier infection and
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The enteric nervous system controls stereotypic motor functions such as the migrating motor complex and the peristaltic reflex; intrinsic control is modulated by the
extrinsic parasympathetic and sympathetic nerves, which respectively stimulate and
inhibit nonsphincteric muscle.
ICC = interstitial cells of Cajal; IPAN = intrinsic primary afferent neuron.
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the persistence of IBS symptoms.8 The interdependence
of prior infection and psychologic status also has been
consistently documented,8 and may raise questions as to
the role of persistent inflammation as an independent
risk factor. Alternatively, the data are interpreted as evidence of the importance of psychoneuroimmune interactions; it is unclear whether inflammation is a common
final pathway to nonspecific psychologic influence on
gut function and the prior infection potentially unrelated, other than as an initiator of the cascade of events.
However, a summary of the epidemiology data also
shows that the prevalence of postinfectious IBS (PI-IBS)
is no higher than IBS in the general population.
In addition, several studies have documented
increased numbers of CD3, CD25, or mast cells in
ileal, colonic, or rectal biopsy specimens,31-38 but the
differences in lymphocyte counts between controls
and IBS are small, with predominant overlap in the
counts between the 2 conditions. A few outliers seem
to be exceptions, and it is unclear whether these higher immune cell counts have functional significance (eg,
influence sensitivity or permeability).
Differences in ileal mast cell numbers34-38 between
IBS and controls appear to be more substantial and consistent, and there is now evidence of functional correlates
in the significant association between mast cells in close
proximity to nerves and severity and frequency of
abdominal pain.38 Nevertheless, it is significant that only
1 of 5 markers of mast cell morphology was associated
with IBS, sample size was small, and the correlation is
influenced by the fact that 3 out of 13 patients with IBS
had no pain (which, based on current criteria, raises the
question of whether they indeed had IBS).
The third line of evidence to be examined is the
response of IBS to anti-inflammatory treatment. A
controlled trial has shown that, among carefully selected patients with PI-IBS, a 30-mg dose of prednisone
taken twice daily was not significantly better than
placebo and that, whereas placebo resulted in the customary significant 30% change in median symptom
score relative to baseline, no change in score was noted
in the prednisone treatment group.39 Controlled studies with other anti-inflammatory agents are needed.
NEW MECHANISTIC INSIGHTS IN
IRRITABLE BOWEL SYNDROME
WHAT IS THE ROLE OF SEROTONIN?
Some have suggested that IBS is a disorder of sero-
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tonin, quoting recent evidence that modulation of
serotonergic mechanisms significantly impacts the
manifestations of IBS. In some respects, this is a borrowed concept, as serotonin is a key player in the secretion and dysmotility of the carcinoid syndrome,40 in
which 5-hydroxytryptamine3 (5-HT3) antagonists
reduce the colonic response to feeding,41 diarrhea, and
the need for rescue antidiarrheal agents.42
There are other more direct lines of evidence to
address the potential role of serotonin. First, plasma 5HT levels are elevated in patients with IBS.43,44 Postmeal symptoms can be prominent in IBS patients,45
and Houghton et al attempted to correlate postprandial symptoms and increased plasma 5-HT.44 However,
it appears that the peak in plasma 5-HT levels does not
coincide with the time (60 to 90 minutes after a meal)
at which patients with IBS typically experience pain,
diarrhea, and urgency.46
Second, enteroendocrine cells in rectal biopsies of
PI-IBS patients show significantly increased numbers
of 5-HT–containing cells. These quantitative differences were more impressive in one study31 than in a
subsequent study from Spiller’s group32; and overlap
with numbers in disease control groups or non–PI-IBS
suggests that prior infection may not be a key factor.
A third line of study assessed factors involved in the
control of 5-HT in IBS via examination of mucosal
biopsy specimens from patients with IBS, healthy
patients without IBS, and disease controls (who had
ulcerative colitis). Coates et al47 showed that the number of enteroendocrine E cells containing 5-HT was
normal, in contrast to other studies,31,32 and the release
of 5-HT from mucosal biopsy specimens under baseline conditions or in response to stimulation was normal.47 However, the mucosal content of the 5-HT
reuptake protein, serotonin transporter (SERT), was
reduced, as shown by SERT messenger RNA content
and immunohistochemistry.47 These changes paralleled
the findings in nonsevere ulcerative colitis, and it is
unlikely that the diarrhea itself induced the changes,
because results were similar in D-IBS and C-IBS. The
mechanisms causing these changes and their functional importance remain the subject of continued
research. Certainly, differences in SERT function
appear to influence the response to therapy in IBS,48
and further studies are forthcoming.
Fourth, serotonergic agents, including 5-HT3
antagonists49 and 5-HT4 agonists,50 are effective in the
treatment of multiple symptoms of IBS.
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WHAT IS THE ROLE OF GENETICS IN
IRRITABLE BOWEL SYNDROME?
Three lines of evidence suggest there may be a role for
genetics in IBS, but the data are inconclusive at present.
First, familial aggregation studies suggest that family members of individuals with IBS are more likely to
suffer from IBS than are their spouse controls.51,52
Second, twin studies also document a difference
between risk of IBS in monozygotic twins compared
with dizygotic twins53,54; however, the fact that mothers
of mono- and dizygotic twins have similar prevalence of
IBS suggests that heredity and social learning or other
environmental factors interact as risk factors in development of IBS. One study from the United Kingdom did
not confirm increased IBS prevalence in twins.55
Third, genetic epidemiology studies provide some
evidence of a genetic association in IBS. However,
these data are to be viewed as preliminary and the pitfalls of such association studies, which may be underpowered, should be kept in mind.
Fewer IBS patients have high interleukin (IL)-10
producer (G/G) genotype than do controls.56 Reduced
IL-10 production in these patients may lead to an
inability to down-regulate inflammation, which may
be a factor in the development of IBS.
Holtmann et al have shown that a polymorphism
in the gene for the G protein involved in mediating
the effects of several neurotransmitters and hormones,
G-protein ß subunit gene (GNß3 C825T) genotype,
is significantly associated with the report of dyspepsia
and, to a lesser extent, IBS in patients presenting to a
clinic in Germany.57
Adrenergic and serotonergic genotypes were investigated in 276 IBS patients and 120 community controls.
A 44-base pair deletion in the gene for the promoter for
SERT (SERT-P) previously has been shown to influence
the function of the SERT protein produced.58 Thus, the
wild-type L/L polymorphism results in normal function,
whereas the presence of the short allele (S/L or S/S)
results in impaired function.58 Kim et al59 showed in 90
C-IBS patients a significant association with α2A
adrenoceptor polymorphism, and the combination of
the α2 adrenoceptor and SERT-P polymorphism was
associated with high somatic scores in patients with
lower functional GI disorders (FGIDs). SERT-P alone
was not a risk factor for D-IBS in the Mayo Clinic
study,59 and a summary of studies to date60 suggests there
is no significant association with IBS or its subtypes in
studies from North America and Korea.61,62 A positive
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association with D-IBS in Turkey63 should be viewed
with caution, given the ethnic differences in the genetic
distribution of the polymorphism and the small sample
studied (n=18). In summary, the reduced mucosal SERT
in C-IBS and D-IBS observed by Coates et al47 does not
appear to be genetically determined, based on reports in
the literature to date.
“IRRITATED BOWEL” SYNDROME
Changes in the intraluminal milieu may result in
symptoms that may be alleviated by treatments directed at the intraluminal factors.
Symptom overlap exists between idiopathic bile acid
catharsis and rapid ideal transit that results in failure of
bile acid absorption. Bile salt retention is reduced in
patients who have functional diarrhea with or without
associated pain.64 Patients with IBS show higher intestinal
secretion in response to perfused bile acids in the ileum,
compared with controls.65 Retarding transit with loperamide reduces the risk of bile salt loss.66 It therefore is
not surprising that bile salt binding with cholestyramine
may be effective in the treatment of IBS with diarrhea.
Perfusion of the mammalian or human colon with
di-α-hydroxy bile acids such as chenodeoxycholic acid
or short-chain fatty acids results in high-amplitude
propagated contractions or rapid transit in a healthy
colon.67-70 Studies have not been conducted in IBS
patients. However, the relatively low concentrations of
bile acid (1 mmol/L) required to induce highly
propulsive propagated sequences71 suggest that relatively modest levels of malabsorption may be sufficient
to perturb colonic motility. The concentrations of longchain fatty acids (eg, oleic acid) required to accelerate
colon transit are relatively high, but certainly would be
in the range associated with moderate fat malabsorption.67 Such colonic concentrations of longer-chain
fatty acids are unlikely to be achieved in patients with
IBS, although formal studies with long- and shortchain fatty acids are required.
DOES A CHANGE IN INTRALUMINAL MILIEU OR BACTERIAL
ECOLOGY IN THE INTESTINE IMPROVE BOWEL FUNCTION
AND SYMPTOMS OF IRRITABLE BOWEL SYNDROME?
Small studies suggest that probiotics or antibiotics
aimed at changing bacterial counts may indeed alter
symptoms, although the mechanism is still unclear.
Nobaek et al showed that alteration of intestinal
microflora via probiotics was associated with reduction
in abdominal bloating and pain in patients with IBS.72
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Similarly, Kim et al showed that, in patients with IBS, the
combination probiotic, VSL#3, resulted in improvement
of the symptoms of bloating and flatulence in 2 separate
studies, but there was no other symptom or global relief.73
In the second study, there was a slight, but significant
retardation of colonic transit without significant alteration of bowel function.74 Quigley et al have preliminarily reported a benefit with Bifidobacteria- but not with
Lactobacillus-containing probiotics.75 This benefit was
associated with restoration of normal IL-10/IL-12 ratios
in plasma, suggesting that the probiotic normalized
immune function in these patients.75
Finally, change in the bacterial ecology with the nonabsorbable antibiotic, neomycin, results in short-term
improvement in the composite score for IBS and bowel
dysfunction.76 These effects were observed in a 7-day trial.
Interestingly, patients whose lactulose-hydrogen breath
test normalized had greater improvement than those with
no response in breath hydrogen. The author’s interpretation is that this represents an effect on bacterial overgrowth in the small bowel in IBS. Whereas this
interpretation may be questioned and longer-term studies and outcomes of treatment with bacterial modification need to be evaluated, the role of the intestinal milieu
and the effects of bacteria and endogenous factors such as
bile acids and fatty acids in the mechanisms and treatment of IBS deserve further study.
Although there is increasing evidence that IBS represents an enteric neurologic disorder that alters bowel sensation, secretion, and motility, it is important to
continue to study inflammation and the potential for
intraluminal factors resulting in dysregulation of those
functions. Central mechanisms may enhance visceral
sensation or the interpretation of ascending visceral signals as unpleasant because of the disturbances in the limbic system, which is involved in the affective response to
pain. At this time, the role of genetics is uncertain. These
data suggest that therapies should continue to be directed at these pathophysiologic mechanisms in the gut and
central control. However, it is conceivable that further
understanding of the bowel ecology in health and disease
may open new avenues for treatment of IBS.
CHRONIC CONSTIPATION
Constipation is a common symptom affecting
between 2%77,78 and 27%79 of the population in Western
countries and between 10% and 15% in the United
States.80 In the United States, it results in more than 2.5
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million visits to physicians, 92 000 hospitalizations,78
and laxative sales of several hundred million dollars a
year. Constipation is more prevalent in women than in
men,7 in nonwhite than in white persons,5 in children
than in adults,6 and in older than in younger adults.81-84
Severe constipation (eg, bowel movements only twice a
month) is seen almost exclusively in women.7 Physical
inactivity, low income, limited education, a history of
sexual abuse, and symptoms of depression all are risk
factors for constipation.81
There is no single definition of constipation. Most
patients define constipation as having 1 or more of the
following symptoms: hard stools, infrequent stools
(typically fewer than 3 per week), the need for excessive straining upon defecation, a sense of incomplete
bowel evacuation, and excessive time spent on the toilet or in unsuccessful defecation.83,84 An epidemiologic
study of constipation in the United States identified
the condition as an inability to evacuate stool completely and spontaneously 3 or more times per week.77
A consensus definition of constipation (the Rome II
criteria) used in current research is provided in Table 1.3
CAUSES AND PATHOPHYSIOLOGY
Constipation frequently is multifactorial and can
result from systemic or neurologic disorders or medications. Constipation can be classified into 3 broad
categories: normal-transit constipation, slow-transit
constipation, and disorders of defecatory or rectal
evacuation. More than 1 mechanism may contribute
to constipation. In a study of more than 1000 patients
with chronic constipation (CC),85 normal transit
through the colon was the most prevalent form (occurring in 59% of patients), followed by defecatory disorders (25%), slow transit (13%), and a combination of
defecatory disorders and slow transit (3%).
NORMAL-TRANSIT CONSTIPATION
Normal-transit constipation (or “functional” constipation) is the most common form of constipation that
clinicians see. In patients with this disorder, stool traverses at a normal rate through the colon and the stool
frequency is normal, yet patients believe they are constipated.6 In this group of patients, constipation is likely to
be the result of a perceived difficulty with evacuation or
the presence of hard stools. Patients may experience
bloating and abdominal pain or discomfort, and they
may exhibit increased psychosocial distress6; some may
have increased rectal compliance, reduced rectal sensa-
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tion, or both.86 Symptoms of constipation
typically respond to therapy with dietary
fiber alone or with the addition of an
osmotic laxative.87
Lack of a response to these therapies
may reflect a disturbance of evacuation or
transit that requires further management.
DEFECATORY DISORDERS
Defecatory disorders are most commonly
the result of dysfunction of the pelvic floor or
anal sphincter. Other terms used to describe
defecatory disorders include anismus; pelvicfloor dyssynergia; paradoxical pelvic-floor
contraction; obstructed constipation; functional rectosigmoid obstruction; the spastic
pelvic floor syndrome; and functional fecal
retention in childhood. Functional fecal
retention in children may result in secondary
encopresis88 as a result of leakage of liquid
stool around impacted stool, which can lead
to an initial misdiagnosis of diarrhea.
Prolonged avoidance of the pain associated
with either the passage of a large, hard stool or
an anal fissure or hemorrhoid may result in
defecatory disorders.89 Structural abnormalities, such as rectal intussusception, rectocele,
obstructing sigmoidocele, and excessive perineal descent, are less common causes of
defecatory disorders. Some patients with
defecatory disorders have a history of sexual
or physical abuse or an eating disorder.
Failure of the rectum to empty effectively
may be the result of an inability to coordinate the abdominal, rectoanal, and pelvicfloor muscles during defecation.5,90
These dysfunctions can be identified
clinically and with the use of defecography
as reduced descent of the perineum (less
than 1 cm) and a reduced change in the
anorectal angle (usually less than 15
degrees) during simulation of straining to
defecate (Table 2). Ignoring or suppressing
the urge to defecate may contribute to the
development of mild constipation91 before
the evacuation disorder becomes severe.
SLOW-TRANSIT CONSTIPATION
Slow-transit constipation occurs most
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Table 1. Rome II Criteria for Constipation*
Adults
2 or more of the following for at least 12 weeks (not necessarily consecutive) in the
preceding 12 months:
• Straining during >25% of bowel movements
• Lumpy or hard stools for >25% of bowel movements
• Sensation of incomplete evacuation for >25% of bowel movements
• Sensation of anorectal blockage for >25% of bowel movements
• Manual maneuvers to facilitate >25% of bowel movements (eg, digital evacuation
or support of the pelvic floor)
• <3 bowel movements per week
• Loose stools not present, and insufficient criteria for IBS
Infants and Children
• Pebble-like, hard stools for a majority of bowel movements for at least 2 weeks
• Firm stools <2 times per week for at least 2 weeks
• No evidence of structural, endocrine, or metabolic disease
*Reprinted with permission from Thompson WG, Longstreth GF, Drossman DA, Heaton KW,
Irvine EJ, Muller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut.
1999;45:(suppl II):43-47.3
Table 2. Diagnostic Findings in Patients With Defecatory Disorders
History
• Prolonged straining to expel stool
• Unusual postures on the toilet to facilitate stool expulsion
• Support of the perineum, digitation of rectum, or posterior vaginal pressure to facilitate rectal emptying
• Inability to expel enema fluid
• Constipation after subtotal colectomy for constipation
Rectal examination (with patient in left lateral position)
• Inspection
• Anus pulled forward while the patient is bearing down
• Anal verge descends <1.0 cm or >3.5 cm (or beyond the ischial tuberosities) while
the patient is bearing down
• Perineum balloons down while the patient is bearing down, and rectal mucosa partially prolapses through anal canal
• Palpation
• High anal-sphincter tone at rest
• Anal-sphincter pressure during voluntary contraction is only slightly higher than tone
at rest
• Perineum and examining finger descend <1.0 cm or >3.5 cm while patient simulates straining during defecation
• Puborectalis muscle is tender on palpation through the rectal wall posteriorly, or
palpation produces pain
• Palpable mucosal prolapse during straining
• Defect in anterior wall of the rectum, suggestive of rectocele
Anorectal manometry and balloon expulsion (with patient in left lateral position)
• Average tone of anal sphincter at rest, >80 cm water (or >60 mm Hg)
• Average pressure of anal sphincter during contraction, >240 cm water (or >180
mm Hg)
• Failure to expel balloon
*Reprinted with permission from Lembo T, Camilleri M. Chronic constipation. N Engl J Med.
2003;349:1360-1368.20 Copyright © 2003. Massachusetts Medical Society. All rights reserved.
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Figure 3. Distribution of Interstitial Cells*
Normal
Slow transit constipation
Distribution of interstitial cells of Cajal in whole transverse mounts of the sigmoid colon in a normal-appearing disease control section of the sigmoid
colon (left) and the sigmoid colon of a patient with slow-transit constipation.
*Reprinted with permission from He et al.96
commonly92 in young women who have infrequent
bowel movements (1 or fewer per week). Often,
this condition begins in puberty. Associated symptoms are an infrequent urge to defecate, bloating,
and abdominal pain or discomfort. In patients with
a minimal delay in colonic transit, dietary and cultural factors contribute to symptoms. In these
patients, a high-fiber diet may increase stool
weight, decrease colon-transit time, and relieve
constipation. Patients with more severe slow-transit
constipation have a poor response to dietary
fiber87,92 and laxatives. Such patients have more
delayed emptying of the proximal colon15 and
fewer high-amplitude peristaltic contractions after
meals, which normally induce movement of content through the colon. Colonic inertia, a related
condition, is characterized by slow colonic transit
and the lack of an increase in motor activity after
meals or after the administration of bisacodyl,92
cholinergic agents, or anticholinesterases such as
neostigmine.93
Histopathologic studies in patients with slowtransit constipation have shown alterations in the
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number of myenteric plexus neurons expressing the excitatory neurotransmitter, substance P,94 abnormalities in
the inhibitory transmitters, vasoactive intestinal peptide,
and nitric oxide,95 and a reduction in the number of
interstitial cells of Cajal,96 which are thought to regulate
gastrointestinal motility (Figures 3 and 4).
Hirschsprung’s disease is an extreme form of slowtransit constipation with similar enteric neuropathologic
features. In Hirschsprung’s disease, ganglion cells in the
distal bowel are absent, a result of an arrest in the caudal
migration of neural-crest cells through the gut during
embryonic development; and the bowel narrows at the
area that lacks ganglion cells. Though most patients with
this disorder present in infancy or early childhood, some
patients with a relatively short segment of involved colon
do not show symptoms until later in life.97 Hirschsprung’s
disease is associated with mutations in the RET protooncogene or the gene for the endothelin-B receptor.98
The role of colonic absorption of fluids and electrolytes in the etiopathogenesis of constipation is unclear.
Sodium-hydrogen and sodium-potassium exchanges
occur in the proximal and distal colon under mineralo-
Figure 4. High Magnification of Interstitial Cells of Cajal in the
Circular Muscle of Human Sigmoid Colon*
High-magnification confocal microscopy of the interstitial cells of Cajal from human sigmoid
colon. A and C are single slices; B and D are reconstructions of 20 consecutive single slices.
A and B are from a healthy-appearing disease control colon; note multiple fine processes
and the network of interconnecting interstitial cells of Cajal. C and D are from a patient with
slow-transit constipation. Note the irregular markings and loss of fine processes (bar =
10 microns).
*Reprinted with permission from He et al.96
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corticoid control; however, there appear to be no reports
of disturbances in these exchanges or the related aquaporins in common constipation disorders. On the other
hand, fluid and electrolyte handling in the colon is
extremely important in determining stool consistency.
The colon has a vast capacity to reabsorb water and electrolytes.99,100 Conversely, patients with constipation tend
to benefit from fiber, osmotic laxatives, stool softeners,
and stimulant laxatives (eg, bisacodyl). In disease states
such as carcinoid diarrhea, small intestinal secretion may
contribute to the accelerated emptying of the proximal
colon.40 The induction of small intestinal secretion via
osmotic or pharmacologic agents appears to result in
acceleration of small bowel or colonic transit, such as with
lactulose101 or lubiprostone, a novel chloride channel activator.102 This combination of secretion and accelerated
transit is associated with relief of chronic constipation.103
CONCLUSION
IBS and constipation are commonly encountered
clinical disorders; their pathophysiology and mechanisms are more clearly understood, and novel treatments based on this greater understanding will lead to
optimized treatment.
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Whitehead WE, eds. The Functional Gastrointestinal
Disorders: Diagnosis, Pathophysiology and Treatment: A
Multinational Consensus. McLean, Va: Degnon
Associates; 2000.
2. Drossman DA. The functional gastrointestinal disorders and
the Rome II process. Gut. 1999;45(suppl II):1-5.
3. Thompson WG, Longstreth GF, Drossman DA, Heaton KW,
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