2008-08-01
Overview
Irritable bowel syndrome (IBS), which is characterized by abdominal pain associated with altered bowel movements, is the classic “functional” gastrointestinal disorder. Patients with functional disorders experience symptoms, but no abnormality can be found on physical examination or standard medical tests. Functional disorders present challenges and can cause frustration for patients as well as doctors. The lack of a diagnostic test raises the question of how much testing should be done to exclude other conditions that can present with the same symptoms. Patients with IBS may feel discouraged if they receive messages such as “we don’t know what is wrong,” “nothing is wrong,” or “it is all in your head.” If a diagnosis of IBS is made, patients may feel uneasy that another serious disease is being missed, but if a focused medical work-up is done, the likelihood of missing other serious underlying disease is very low. IBS is a chronic condition with symptoms that can wax and wane, and no therapy is universally effective for all IBS patients. Successful management rests on providing education regarding the current understanding of IBS, reassurance of the good long-term prognosis, a supportive doctor-patient relationship, judicious use of behavior modifications and available therapies, and emphasis on leading as normal a life as possible even if symptoms cannot be eliminated completely.
How is IBS defined and diagnosed?
Clinicians
have recognized for a long time that some patients have a condition
with the hallmark symptoms of abdominal pain and altered bowel function,
without clear structural abnormalities of the gastrointestinal system. Lucid
descriptions of the symptom complex of abdominal pain and alteration in
bowel movements, sometimes with alternating diarrhea and constipation
in the same patient, can be found in the medical literature of the
1800’s. Several terms have been used through recent
decades, including nervous colon (the colon is the large intestine),
colonic spasm, and mucous colitis.
Because
there is no clinical test to identify patients with IBS, a consensus
definition of the disorder is needed in order to pursue clinical
research on this condition. Beginning in the 1980’s,
leading researchers in the field of functional gastrointestinal
disorders have engaged in the “Rome process” (named after the city where
the major meetings for this group have taken place), which addresses
multiple issues related to the study of the functional gastrointestinal
disorders. A major task of the Rome process is to define symptom-based diagnostic criteria for these disorders.
The
Rome III definition of IBS, proposed in 2006, is “a functional bowel
disorder in which abdominal pain or discomfort is associated with
defecation or a change in bowel habit, and with features of disordered
defecation.” The Rome III diagnostic criteria for IBS are:1
· Recurrent abdominal pain or discomfort* at least 3 days per month in the last 3 months associated with 2 or more of the following:
1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (appearance) of stool
· Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis
* “Discomfort” means an uncomfortable sensation not described as pain
The
Rome group has also proposed formal criteria for four IBS sub-types
depending on the frequency of “hard or lumpy stools” or “loose [mushy]
or watery stools.” The sub-types are “IBS with constipation,” “IBS with diarrhea,” “Mixed IBS,” and “Unsubtyped IBS.”
The
formal Rome criteria are often used to select patients with IBS for
clinical research studies, but the strict application of the criteria is
not practical in every-day clinical care of patients. The
“spirit” of the criteria is to capture patients with at least several
months of abdominal pain or discomfort associated with changes in stool. Thus,
some patients who are diagnosed with IBS by their doctor may fulfill
the spirit of the Rome III criteria, if not the precise letter.
Some patients experience abdominal pain/discomfort alone, or change in stool alone. These patients are distinguished from those with IBS. Rome
III criteria have been proposed for other conditions including
“Functional diarrhea,” “Functional constipation,” “Functional bloating,”
and “Functional abdominal pain syndrome.” The distinctions among these conditions are a matter of definitions, the result of a classification scheme based on symptoms. It
is not yet clear whether the same underlying abnormalities could
manifest as “IBS” or “Functional diarrhea” or “Functional abdominal pain
syndrome,” for instance, in large part because the underlying
abnormalities in all of these disorders are not well understood. In
clinical practice, some patients who experience abdominal
pain/discomfort alone or change in stool alone are diagnosed with IBS,
but this does not conform to the spirit of the Rome III definitions.
Some patients and clinicians have trouble accepting or making a diagnosis of IBS. Both may be troubled that the diagnosis is uncertain or that “IBS” is a “throw-away” term for something we do not understand. These
perceptions, and the lingering bias among some clinicians that IBS is
an “imaginary disease,” can pose great barriers to the successful
management of patients with IBS.
The first step in the care of patients with IBS is to make a diagnosis. In
clinical practice, this can be done in patients who fulfill the spirit
of the Rome criteria in whom other conditions that could explain the
symptoms have been excluded or are very unlikely. Although
IBS remains to some extent a “diagnosis of exclusion” (that is, it
cannot be diagnosed until other likely explanations for the symptom
complex have been ruled out), extensive testing is not necessary in most
patients before making the diagnosis of IBS.
How common is IBS and what is the spectrum of disease?
Studies in the population suggest that 10-20% of people experience symptoms that are consistent with those of IBS.2 In many countries, IBS is more common in women than in men. A
large proportion of persons with IBS symptoms are “non-patients”
because they manage their symptoms on their own, without seeing a
doctor. One need only walk into a pharmacy or health food
store and look at the shelves and shelves devoted to products for
treating digestive symptoms in order to appreciate how many millions of
people self-treat for various digestive complaints.
Whether
an individual person with IBS sees a doctor or not, and how specialized
a doctor a patient with IBS ultimately sees, are influenced by multiple
factors. These include access to care, personality
factors that make some persons more likely to seek medical care than
others, severity of symptoms, and co-existing conditions. Most patients with IBS can be managed successfully in primary care. Some
persons with IBS are seen by gastroenterologists, and a minority is
seen by gastroenterologists with subspecialty clinical or research
interests in the functional gastrointestinal disorders.
As
a group, patients with IBS are more likely than patients without IBS to
have co-existing anxiety or depression, which must be recognized in
order to provide adequate care. Patients with severe symptoms that are
difficult to treat are more likely to be seen in specialty and
subspecialty settings, and some of these patients may have significant co-existing anxiety or depression, history of physical or sexual abuse, or other chronic pain syndromes. It
is important for clinicians to remember, however, that many patients
with IBS do not have anxiety or depression, and that functional
gastrointestinal symptoms may not be “explained” by anxiety or
depression.
IBS can significantly impair quality of life and work productivity. Persons
with IBS may feel isolated, particularly if they feel embarrassed about
their symptoms and are reluctant to discuss them. It is important for persons with IBS to recognize that they are not alone—many millions of people have IBS. In
primary care, IBS is a common diagnosis, and in gastroenterology
practice, perhaps 50% of all consultations ultimately lead to a
diagnosis of a functional gastrointestinal disorder.
Are there any abnormalities in persons with IBS compared to persons without IBS?
Although
IBS is a functional disorder diagnosed by symptom-based criteria, and
for which there is no diagnostic test, this does not mean that no
“abnormalities” have been described in persons with IBS in research
studies. In fact, many biological differences have been reported in IBS patients as a group compared to persons without IBS.3, 4 The
very range of abnormalities that have been described suggests that what
we call “IBS” is an umbrella term for a collection of different
conditions, all of which manifest common symptoms. The
fact that subtypes of IBS are defined to capture patients with
predominant diarrhea, predominant constipation, alternation between
these, or neither suggests that the underlying physiological
abnormalities may be different between subtypes.
No
single “abnormality” has been found that can separate all patients with
IBS from those with other gastrointestinal diseases or persons without
disease. Some studies suggest that IBS patients are more likely to have certain patterns of muscular contractions in their intestines. IBS
patients may not handle intestinal gas in the same way as those without
IBS, possibly due to abnormalities in the motor function of the gut,
leading to symptoms of bloating and pain. In persons with
diarrhea, the gut’s contents may move faster than normal, and in those
with constipation, they may move more slowly.
IBS patients may have abnormalities in sensation from the internal organs (the viscera). A common experimental technique is to inflate a balloon inside an organ and assess the symptom response. For
a given level of balloon inflation in the rectum, for instance, IBS
patients may experience more severe symptoms than those without IBS. The
level of the abnormalities responsible for this “visceral
hypersensitivity” could include the gut itself, the nerves traveling to
the spinal cord, or centers in the brain responsible for processing
information and for the conscious experience of symptoms. Brain
imaging studies have reported different patterns of brain activity in
IBS patients compared to those without IBS when exposed to the same
visceral stimulation. Some patients with IBS exhibit
hypersensitivity not only in the intestines, but also in other regions
of the gastrointestinal system, and studies show that some patients
diagnosed with IBS may be diagnosed with other functional
gastrointestinal disorders at later times. Thus, at least
in some patients, sensory or other abnormalities may be generalized to
the entire gastrointestinal tract, and not specific to a single organ. It
remains to be determined how the hypersensitivity described in the
research setting relates to the symptoms that patients experience in
every-day life.
Multiple
studies have identified a subgroup of patients who seem to develop IBS
after a self-limited gastrointestinal infection (“post-infectious IBS”),
suggesting that the motor and sensory nerves of the gut may be altered
long-term by an acute infection, without the need for chronic infection.5 Recently,
much attention has been devoted to the possibility that IBS symptoms
could be due to overgrowth of bacteria in the intestines, possibly due
to subtle abnormalities in the motor function of the gut. Some propose that alteration in the gut’s bacterial flora could cause IBS.6 In
some studies, subtle abnormalities in the nerves of the bowel wall or
in the types of inflammatory cells present in the bowel have been
described in patients with IBS. Allergic reactions are being explored as a possible explanation of some symptoms.
In
interpreting all of the above research findings, it is important to
appreciate that the repertoire of symptoms that the gastrointestinal
system can produce (e.g., pain, diarrhea, nausea, etc.) is limited. It is therefore not surprising that different processes would manifest with similar symptoms. The
abnormalities described in some patients, those with the most severe
symptoms for instance, may not be present in others, such as those with
milder symptoms. It is conceivable that one day the use of
the term “IBS” will give way to new terminology that will capture more
precisely the underlying abnormalities present in subgroups of patients. But
until a viable clinical mechanism is developed to define meaningful
subgroups of patients for whom different treatment options are
available, the use of the umbrella term “IBS” is likely to continue.
At
present, it is not clinically applicable to test patients to determine
if they exhibit some of the abnormalities reported in research studies
of IBS. But the evidence is compelling that abnormalities not identified on standard medical tests may be present in patients. If
standard tests are normal, patients should not be given the message
that “nothing is wrong” or, worse yet, that they are imagining their
symptoms. With the exception of the very small number of
patients who willingly present with phony symptoms, a patient’s pain is
definitely real to that patient, whether a doctor can find an
explanation for it or not.
What causes IBS?
Given
the wide range of abnormalities described in persons with IBS, it has
been proposed that IBS should be understood in the context of the
biopsychosocial model.7 People without IBS may well recognize that their emotional and psychological state can affect gastrointestinal function (e.g., “butterflies
in the stomach,” diarrhea associated with times of nervousness or
anxiety, or lack of appetite during stressful times). This
powerful and complex brain-gut connection is believed to be a key to
the understanding of IBS, and is central to the biopsychosocial model of
IBS.
Conceptually,
early life influences including genetic predisposition and
environmental factors may affect social or psychological factors as well
as physiological processes in the body, and these may influence each
other. Ultimately, these interactions may lead to
symptoms, and psychosocial factors may then also affect a person’s
reaction to illness and their health-related behavior. Many
patients relate that they have “always had a nervous stomach” or have
had symptoms “as far back as I can remember,” suggesting that in them,
the determining factors were established early in life. In
the context of this model, one can appreciate how childhood physical or
sexual abuse could have long-standing impact on gastrointestinal
function, or how IBS and other illnesses such as anxiety or depression
could interact in determining health-related behavior.
Perhaps the clearest example of a “cause” for IBS is the acute infection reported in persons with post-infectious IBS. These
patients may have a history of normal bowel function and no pain before
a severe acute illness that may include nausea and vomiting, abdominal
pain, severe diarrhea, and fever. These infections sometimes occur during international travel. Once the acute symptoms resolve, these patients are left with longer-term bowel disturbance that is clinically diagnosed as IBS. It
is notable that research studies have found several factors that
influence the probability that a person will experience post-infectious
IBS after an acute infection, including the severity of the infection
but also the psychological profile of the person. This highlights the complexity of the brain-gut interactions and invokes the biopsychosocial model.
In the context of the biopsychosocial model, it may not be appropriate to talk about “THE cause” of IBS. Even
if different subgroups of IBS patients are eventually classified under
more specific categories (“mild inflammation of nerve cells” as a
hypothetical example) no single “cause” may be found for these various
conditions. The biopsychosocial model postulates that
multiple factors interact in determining the ultimate clinical
manifestations in a particular person.
What tests should be done before diagnosing IBS?
The
key diagnostic challenge in any medical encounter is arriving at the
correct diagnosis after considering all the relevant diagnostic
possibilities that could explain a patient’s symptoms. By
definition, patients must fulfill the spirit of the Rome criteria to be
diagnosed with IBS, but it is clear that patients with other diseases
may also fulfill the IBS Rome criteria. It is generally
accepted that persons with symptoms suggestive of IBS who also have
“alarm features” or “red flags” such as fever, bleeding, weight loss,
new symptoms at older age, or night-time symptoms interrupting sleep
should have appropriate testing to look for infection, inflammatory
bowel disease, or malignancy.
In young persons with possible IBS without alarm features, most experts agree that extensive testing is not required.2, 3, 8 In some cases, it may be reasonable to make a working diagnosis of IBS with no specific testing. A
sensible limited work-up can include basic blood tests (blood counts,
electrolytes which are the “salts” in the blood and may be abnormal in
severe diarrhea, and thyroid function tests), stool tests (for parasites
or Clostridium difficile infection in those with chronic diarrhea), and sigmoidoscopy with possible biopsy for those with diarrhea. This
set of tests may actually not yield a significantly higher number of
abnormalities in persons with suspected IBS than in those without, but
some abnormalities may be uncovered.
Recently,
several studies have found that celiac disease (also known as sprue or
celiac sprue) is more common in persons with suspected IBS than in the
general population.9 In celiac disease, the
lining of the small intestine may become damaged as a result of exposure
to gluten, a protein component of wheat, barley, and rye. The resulting symptoms may mimic IBS. Some
authorities advocate testing patients with suspected IBS for celiac
disease, which can be done with blood tests for antibodies. If
these tests are abnormal or if the suspicion is high enough despite
normal antibody tests, the next step is upper endoscopy with small
intestinal biopsies. Celiac disease is managed with a strict gluten-free
diet.
Although
it is unlikely that in those aged 50 years or older IBS-type symptoms
are a manifestation of colon cancer, colon cancer screening is widely
recommended starting at age 50. For this reason, a colonoscopy for screening purposes is appropriate in persons 50 years or older. For
those with diarrhea, biopsies should be done to evaluate for the
possibility of microscopic colitis, a condition in which the bowel looks
normal during colonoscopy but shows inflammation when samples are
studied under the microscope.
Multiple
studies show that if IBS is diagnosed after a limited initial work-up
such as described above, the likelihood that a different diagnosis will
be made in subsequent years is very small. Certainly, patients should be re-evaluated if new symptoms develop or if there are worrisome changes. But most of the time, the diagnosis of IBS will be correct. This
knowledge should give patients and doctors the confidence to move on to
a management plan, instead of dwelling on what other tests should be
done. An endless search for “what is wrong” can be
frustrating, expensive, and even harmful if it leads to unnecessary
medical interventions.
What treatments and management options are available for IBS?
Establishing a diagnosis of IBS is a key prerequisite to effective treatment. Education
and reassurance that symptoms are not due to other serious conditions
such as cancer or inflammatory bowel disease may be enough for some
patients who can tolerate or adjust to their symptoms. If exacerbating factors such as specific stressors or particular foods can be identified, then avoiding these may be useful. However, the search for a food “trigger” is usually a frustrating and disappointing endeavor for patients. General healthy habits such as exercising and sleeping enough may improve overall well-being in IBS patients.
The
decision as to whether to pursue a treatment trial rests on how
symptomatic a patient is, how much quality of life is impaired, and on
the patient’s willingness to engage in specific therapies. Treatments are aimed strictly at symptom control. Few treatments have been studied rigorously in clinical trials with excellent design and methods.10
Fiber supplements (e.g., psyllium,
methylcellulose, calcium polycarbophil) may help certain patients, for
instance some who have alternating diarrhea and constipation or those
with constipation and hard stools. However, fiber may worsen bloating and distension in some. Antidiarrheals such as loperamide (Imodium) or diphenoxylate/atropine (Lomotil) may help with loose, frequent stools. Constipation may be improved with fiber, milk of magnesia, lactulose, or polyethylene glycol (e.g., MiraLax, GlycoLax), but these may worsen bloating in some patients.
Pain and discomfort can be difficult to treat. Sometimes pain improves with treatment of constipation. Antispasmodics
or smooth muscle relaxants such as hyoscyamine (Levsin, Anaspaz, NuLev)
or dicyclomine (Bentyl) may help decrease the intensity of pain, and
these may work best when taken as needed for attacks of crampy pain or
“spasms.” Some physicians use a combination of atropine, hyoscyamine and phenobarbital (Donnatal). Anti-anxiety
medications such as diazepam (Valium), chlordiazepoxide (Librium) or
chlordiazepoxide/clidinium (Librax) can lead to dependence and should be
avoided if possible.
Low
doses of tricyclic antidepressants such as amitriptyline (Elavil),
nortriptyline (Pamelor), imipramine (Tofranil), and desipramine
(Norpramin) may improve symptoms.11 However,
they can have side effects including sedation, dry mouth, blurry vision,
and constipation, and the dose must be increased cautiously in
sensitive patients. The mechanism of action of these medications in IBS remains to be clarified, but they may affect the perception of symptoms. Some patients with IBS are also depressed, and treatment of depression is warranted in them. For
non-depressed patients, it is imperative that doctors explain to
patients the rationale for using low-dose tricyclic antidepressants,
namely that they may alleviate symptoms in those who can tolerate the
medications, and clarify that the prescription does not signal the
belief that the symptoms are “in the patient’s head” or that the patient
“is crazy.” While these pejoratives are also not
justified in patients who actually have psychiatric conditions, some
patients with IBS may feel offended if the rationale for prescribing an
antidepressant is not clear. The selective serotonin
reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), sertraline
(Zoloft), paroxetine (Paxil), citalopram (Celexa) and fluvoxamine
(Luvox) are less well studied in IBS. They tend to have fewer side-effects than the tricyclic antidepressants, but they may not be as effective for IBS. However, no definitive comparative trials have been done. Selective serotonin reuptake inhibitors may cause diarrhea.
In
recent years, three drugs have been approved for treatment of IBS in
the United States. Currently, the only widely available drug is
lubiprostone (Amitiza), which has been approved for treatment of IBS
with constipation in women 18 years or older, at a dose of 8 micrograms
twice a day (a lower dose than the dose approved for treatment of
constipation).
The two other drugs that have been approved in the United States for use in patients with IBS are not routinely available. Alosetron (Lotronex) improves the rate of achieving adequate relief of symptoms in women with diarrhea-predominant IBS. Serious
complications including ischemic colitis (damage to the colon due to
decreased blood flow) and obstipation (complete lack of bowel movements)
were reported with this drug, leading to its withdrawal from the
market. It is now available only through a restricted drug
distribution program for women with severe diarrhea-predominant IBS who
have not responded to other medications.
The
second drug approved specifically for IBS was tegaserod (Zelnorm) for
women with constipation-predominant IBS. The marketing of this drug was
suspended after review of clinical data revealed more cardiovascular
adverse events in patients treated with tegaserod than in those treated
with a placebo. Until recently, selected patients could be eligible to
participate in a restricted treatment program (“treatment IND”) for
women under the age of 55 years with constipation-predominant IBS or
chronic idiopathic constipation who did not have satisfactory response
to other available treatments, and/or patients who had satisfactory
improvement of their symptoms with prior tegaserod treatment. Patients
were excluded for a history, current diagnosis, or symptoms of
cardiovascular ischemic disease, the presence of any cardiovascular risk
factors according to National Institutes of Health guidelines, or
uncompensated depression, anxiety, or suicidal ideation or behavior.
The IND program is not currently available.
Notably, no agent has been approved for men with IBS. This may be in
part due to the small number of men studied in clinical trials, but
there may also be a different response in men than women. Why there
should be a different response to IBS medicines on the basis of gender
remains a mystery.
Some patients show improvement after treatment with the non-absorbable antibiotic rifaximin (Xifaxan),12 supporting the idea that bacterial overgrowth may play a role in their symptoms. However, long-term antibiotic treatment is not a desirable strategy. The
potential use of probiotics is intriguing, but which specific
preparation should be used and what its actual benefits are remain to be
established.
Several mental health interventions may help some patients with IBS, including cognitive behavioral therapy and hypnotherapy. These tend not to be widely available. Selected patients, particularly those with significant co-existing psychiatric diagnoses, may benefit from psychotherapy. Group therapy and support groups may be beneficial for some IBS patients.
As
a practical point, if patients wish to try interventions that are
harmless and not financially burdensome, they should not be discouraged. However,
the frustration with conventional treatments can be exploited by
providers of unproven therapies, including various “cleansing regimens”
or supplements. IBS patients should be aware that the allure of some non-conventional treatments may be misleading.
Some patients appreciate frequent contact with a clinician. This relationship may be crucial in avoiding unnecessary tests and interventions. The
ultimate focus of management should be to return to as normal daily
function as possible—that is, to lead a normal life even if some
symptoms persist.
What diet should IBS patients follow?
In
their search for the responsible food “trigger” for their symptoms,
some patients end up eating severely restricted diets that only
compromise their nutrition. Usually, no specific food can be identified as the culprit for symptoms. Dairy
may worsen the symptoms for some, high fat foods slow down intestinal
motor functions and can worsen bloating and discomfort, and some foods
and juices with high sugar content may cause bloating. A
short-term trial of excluding selected foods may be reasonable as a
test, but most patients with IBS should be encouraged to eat a healthy,
balanced diet in the long-term, and avoid foods only if there is clear
indication that this helps in their particular case. Common sense should guide dietary choices. Even
if some foods exacerbate symptoms, this is not harmful, and patients
must balance the pleasure of eating some foods against any potential
unpleasant symptoms.
The
special case requiring a very specific diet is when celiac disease is
diagnosed in persons previously suspected of having IBS. Celiac disease is managed with a strict gluten-free diet, which can be a challenge to observe. The
IBS-like symptoms are likely to improve on this gluten-free diet, but
some patients with excellent adherence to a strict celiac disease diet
have residual gastrointestinal symptoms.
What is the long-term outlook for IBS patients?
While the long-term course of any individual patient is unpredictable, it is common for IBS to be a chronic condition. Some patients have significant waxing and waning of symptoms, sometimes in relation to life events.13 For some patients, the symptom pattern changes to be more typical of other functional gastrointestinal disorders. Persons with IBS must appreciate that their overall prognosis is very good. Life expectancy in IBS is normal and there is not a higher than average risk of cancer or other serious disease. With
this understanding, IBS should be viewed as a condition to be managed
over the long term, as opposed to a source of anxiety and fear.
USEFUL LINKS
National Digestive Disease Information Clearinghouse (National Institutes of Health)
International Foundation for Functional Gastrointestinal Disorders
American Gastroenterological Association Patient Center
American College of Gastroenterology IBS Resource Center
Rome Foundation
REFERENCES
1. Longstreth
GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional
bowel disorders. Gastroenterology 2006;130:1480-91.
2. Drossman
DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on
irritable bowel syndrome. Gastroenterology 2002;123:2108-2131.
3. American
Gastroenterological Association medical position statement: Irritable
bowel syndrome. Gastroenterology 2002;123:2105-2107.
4. Talley NJ, Spiller R. Irritable bowel syndrome: a little understood organic bowel disease? Lancet 2002;360:555-64.
5. Neal
KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six
months after bacterial gastroenteritis and risk factors for development
of the irritable bowel syndrome: postal survey of patients. BMJ
1997;314:779-82.
6. Kassinen
A, Krogius-Kurikka L, Makivuokko H, Rinttila T, Paulin L, Corander J,
Malinen E, Apajalahti J, Palva A. The fecal microbiota of irritable
bowel syndrome patients differs significantly from that of healthy
subjects. Gastroenterology 2007;133:24-33.
7. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130:1377-90.
8. Spiller
R, Aziz Q, Creed F, Emmanuel A, Houghton L, Hungin P, Jones R, Kumar D,
Rubin G, Trudgill N, Whorwell P. Guidelines on the irritable bowel
syndrome: mechanisms and practical management. Gut 2007;56:1770-98.
9. Sanders
DS, Carter MJ, Hurlstone DP, Pearce A, Ward AM, McAlindon ME, Lobo AJ.
Association of adult coeliac disease with irritable bowel syndrome: a
case-control study in patients fulfilling ROME II criteria referred to
secondary care. Lancet 2001;358:1504-8.
10. Brandt
LJ, Bjorkman D, Fennerty MB, Locke GR, Olden K, Peterson W, Quigley E,
Schoenfeld P, Schuster M, Talley N. Systematic review on the management
of irritable bowel syndrome in North America. Am J Gastroenterol
2002;97:S7-26.
11. Drossman
DA, Toner BB, Whitehead WE, Diamant NE, Dalton CB, Duncan S, Emmott S,
Proffitt V, Akman D, Frusciante K, Le T, Meyer K, Bradshaw B, Mikula K,
Morris CB, Blackman CJ, Hu Y, Jia H, Li JZ, Koch GG, Bangdiwala SI.
Cognitive-behavioral therapy versus education and desipramine versus
placebo for moderate to severe functional bowel disorders.
Gastroenterology 2003;125:19-31.
12. Pimentel
M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral
antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome:
a randomized trial. Ann Intern Med 2006;145:557-63.
13. Halder
SL, Locke GR, 3rd, Schleck CD, Zinsmeister AR, Melton LJ, 3rd, Talley
NJ. Natural history of functional gastrointestinal disorders: a 12-year
longitudinal population-based study. Gastroenterology 2007;133:799-807.