IRRITABLE BOWEL SYNDROME: RECENT PROGRESS IN PATHOPHYSIOLOGY, DIAGNOSIS AND MANAGEMENT?

Abstract

Irritable bowel syndrome (IBS) is one of the most
common of all medical disorders, whether surveyed in
the community, in a primary care practice or at a
specialist gastroenterology referral centre.1,2 Its
prevalence has long been appreciated in the West; what
is new is a recent accumulation of evidence to indicate
that IBS is also highly prevalent in the East and even in
developing nations like Pakistan.3,4 These same studies
have also revealed some interesting differences in
demographics and mode of presentation between East
and West. Thus, female predominance, a hallmark of IBS
in Europe and North America, is not as striking in the
East and may not even exist in certain countries, where
male IBS subjects may be in the majority. Furthermore,
symptom patterns may vary, with lower abdominal pain
and a preoccupation with bowel habit being the foremost
pattern in the West, whereas upper abdominal symptoms
are common in the East where sufferers also seem less
exercised about bowel dysfunction. The latter reminds us
of the importance of overlap with another functional
disorder, functional or non-ulcer dyspepsia (FD). Some,
indeed, would refer to evidence such as this to emphasise
the degree of overlap between these conditions and
would question whether FD, a disorder which has proven
difficult to define clinically, is really a distinct entity but
rather a part of the spectrum of IBS, a much more
accepted clinical entity.5
While research continues, in a variety of areas,
on the pathophysiology of IBS, work on a possible
inflammatory component to IBS is currently attracting the
greatest attention. Three principal strands of evidence have
been explored: the role of enteric infection in initiating IBS
(post-infectious IBS, or PI-IBS), the possibility that
alterations, be they quantitative or qualitative, in the enteric
flora might be relevant to the genesis of symptoms in IBS
and, finally, the suggestion that low-grade inflammation
and immune activation may be a fundamental abnormality
in IBS. With regard to the former, there is now an
overwhelming body of epidemiological and clinical data to
support the concept of PI-IBS, an entity that clinicians
have recognised for decades.6 Though the risk of
developing PI-IBS following an episode of bacterial
gastroenteritis is low, afflicted patients may endure
prolonged and significant IBS-type symptoms and may
exhibit an associated persistent inflammatory response in
the rectal mucosa. Over the years a number of studies have
suggested that the colonic (or, more correctly, the faecal
flora) flora may demonstrate quantitative changes in IBS;
studies on the faecal flora in IBS have, however, provided
variable results, one of the few consistent findings being an
apparent suppression of the population of bifidobacteraia.
Given the limitations of faecal sampling as a reflection of
the colonic flora and of current culture techniques, per se,
more study is required on this issue. Very recent studies,
using molecular techniques, have, not only begun to reveal
the true diversity of the intestinal microbiota, but have
begun to establish, on a firmer footing, differences
between IBS and control subjects.7 Even more
controversial has been the suggestion that a significant
proportion of the IBS population harbour bacterial
overgrowth in their small intestines and that they can
expect a significant symptomatic response to course of
antibiotics.8 Critics of this hypothesis have drawn attention
to the poor specificity of the test (the lactulose breath
hydrogen test) used to diagnose bacterial overgrowth in
these studies, to the non-specificity of gastrointestinal
symptoms, in general, and to the far from spectacular
response to antibiotic therapy.9,10 Furthermore, others have
failed to reproduce this finding. This is an important issue,
as the prospect of long-term, or even repeated, courses of
antibiotics to subjects with a disorder as chronic and
relapsing as IBS, is a cause for some considerable concern.
The inflammatory concept, in contrast, continues to gather
momentum. It began with the demonstration, in biopsy
material from the rectum, colon and ileum, of evidence of
increased numbers of a variety of cells (lymphocytes, mast
cells) known to participate in an inflammatory response
and to produce cytokines and other biologically active
substances that could modulate enteric nerve and muscle
function.11 Since then, others have gone on to demonstrate
elevated levels of pro-inflammatory cytokines in the
peripheral blood of IBS patients and have even suggested
that some IBS patients may be genetically predisposed to
develop a low-grade, but sustained, inflammatory response
to certain stimuli, including those that may originate in the
lumen itself.12-14 In this way, a luminal stimulus could
initiate a local inflammatory response in the colon or small
intestine and, through the local or systemic release of
cytokines, generate the motor (spasm), sensory (visceral
hypersensitivity and hyperalgesia) and mucosal responses
that typify IBS. It is also feasible, based on evidence from
animal models as well as from man, to reconcile these
inflammatory findings with more central {aberrant
cerebral activation and disturbances in the hypothalamicpituitary-adrenal (HPA) axis} and even systemic
disturbances (fatigue, fibromyalgia) associated with IBS.
Whether these linkages between inflammation and other
physiological perturbations represent mere associations or,
indeed, even epiphenomena, or are truly causal remains to
be determined. For now, these findings have raised the
possibility that a targeted anti-inflammatory approach may
ameliorate symptoms or even cure IBS is tantalizing one;
evidence with a probiotic (Bifdobacterium infantis infantis
35624) with potent anti-inflammatory properties suggests
that journeys down this therapeutic avenue may prove
productive.12
J Ayub Med Coll Abbottabad 2009;21(1)
2 http://www.ayubmed.edu.pk/JAMC/PAST/21-1/Editorial.pdf
For now, the management of IBS continues to
pose significant challenges for the patient and the clinician,
alike. The importance of the physician-patient interaction
cannot be over-emphasised: it is critical that the physician
recognise the patient's symptoms, their impact on their
daily lives and any associated psychosocial dimensions.
With regard to the evaluation of the patient presenting with
IBS-type symptoms we have recently witnessed a seachange in attitude. The concept of IBS as a diagnosis of
exclusion (or even of exhaustion), arrived at only when a
range of biochemical, radiological and endoscopic tests
had eliminated other '˜pathologies', has now been cast
aside: in the right context and in the absence of symptoms
or signs suggestive of other diseases, a positive diagnosis
is, not only possible, but recommended.15,16 This approach
eliminates the need for the application of expensive,
invasive and, almost certainly worthless, investigations, to
all IBS patients. Given the heterogeneity of symptoms and
modes of presentation in IBS it should come as no surprise
that management strategies can seldom be generalised but
require considerable nuance and even individualization.
What may assist a patient with frequent bowel movements
or even diarrhoea may significantly impair the patient with
constipation in association with IBS. The concept of
tailored therapy based on predominant stool frequency
came to the fore with the development of IBS-targeted
therapies that either accelerated (tegaserod) or inhibited
(alosetron and cilansetron) gut transit. All of these agents
were designed to modulate serotonergic (5-
hydroxytryptamine, 5-HT) activity in the enteric nervous
system. The universal adoption of these agents has been
limited by regulatory issues (none of these agents has been
approved for use in the European Union) and, in the case
of the 5-HT3antagonists, by the spectre of ischemic colitis.
Tegaserod, in turn, was withdrawn because of rare cardiac
effects. The regulatory travails of all of these compounds,
on both sides of the Atlantic, have revealed the challenges
that face those that attempt to introduce, test and bring to
market, new therapies in IBS.17 It is, after all, a
heterogeneous disorder of uncertain cause for which we
have no validated biomarker and which is associated with
a placebo response that averages 40% in clinical trials.
Furthermore, IBS is regarded, by regulatory bodies, as a
very benign disorder; as such adverse events of any
magnitude or severity will not be tolerated. Most recently,
Food and Drug Administration in the US has imposed a
moratorium on new IBS studies pending definition,
validation and acceptance of an appropriate primary
outcome endpoint. These misgivings notwithstanding,
research continues on a variety of chemical entities that
may impact on IBS, be they located on sensory neurons,
on gut smooth muscle, the central nervous system, in the
intestinal lumen or inflammatory cells.