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Gut feelings: visceral hypersensivity and functional gastrointestinal disorders
Kuiken, S.D.
Publication date
2004
Link to publication
Citation for published version (APA):
Kuiken, S. D. (2004). Gut feelings: visceral hypersensivity and functional gastrointestinal
disorders.
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Generall introduction Functionall gastrointestinal disorders (FIGDs) represent a major clinical problem, nott only because of the large quantity of patients presenting with these disorders, butt also because of the lack of therapeutic options due to the limited understanding off the pathophysiological mechanisms involved. The most frequent of these disorderss are the Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD). Dependingg on the definitions applied, reported prevalences within the general populationn range up to 22% and 50% for IBS and FD, respectively.1-2 Although the majorityy of patients do not seek medical help, FD accounts for 5% and IBS for 12%% of primary care consultations.1'2 Together, FIGDs form the largest diagnostic groupp seen in a gastroenterologist's practice, comprising 35 to 4 1 % of the symptomaticc outpatients' diagnoses.3'4
FIGDss are generally characterised by chronic or recurrent gastrointestinal symptoms,, in the absence of a detectable underlying organic cause.5 Because reliable biologicall markers are not available, the diagnosis is based on symptom-based criteriaa such as the Rome II criteria, which currendy serve as the gold standard.6 Accordingg to the Rome II criteria, IBS is defined as 'abdominal discomfort or pain associatedd with defecation or a change in bowel habit, and with features of disorderedd defecation'.5 FD is defined as 'persistent or recurrent pain or discomfort centredd in the upper abdomen'.7 Symptom patterns alone are unable to adequately discriminatee organic disease from FIGDs. Therefore, patients need to have been investigatedd to rule out relevant organic disease.
Becausee the pathophysiological mechanisms are largely unknown, treatment of FGIDss is often disappointing. To understand the difficulties that are encountered inn the management of FGIDs, it should be emphasised that these disorders are very heterogeneouss and probably represent different subgroups with distinct underlying pathophysiologies.. Therefore, it is unlikely that a single mechanism would be responsiblee for the development of symptoms. Consequently, it is unlikely that a singlee treatment would be successful in all patients with IBS or all patients with FD, respectively. .
Too optimise treatment outcome, several attempts have been made to define subgroupss of patients with IBS and FD based on their clinical presentation. Such recommendationss have also been incorporated in the Rome II consensus. For IBS, sub-classificationn has been proposed based on predominant bowel habits. IBS patientss may present with predominandy diarrhoea D) or constipation (IBS-C),, or may alternate between diarrhoea and constipation (IBS-A).5 Patients with F D aree sub-classified based on their most bothersome symptom into ulcer-like dyspepsiaa (predominantly pain), dysmotility-like dyspepsia (predominandy non-painfull symptoms) or unspecified dyspepsia (without a predominant symptom).7 In FD,, the relevance of these sub-classifications to clinical practice with respect to treatmentt remains controversial, mainly because the relationship with proposed underlyingg pathophysiological mechanisms is unclear. In IBS however, recent studiess have shown that the investigational serotonin agonists and antagonists were onlyy effective in IBS-C and IBS-D, respectively, suggesting that these different subgroupss indeed respond to different treatments.8'9
Subgroupp selection may also be based on the proposed mechanisms underlying thee generation of symptoms. These mechanisms show considerable overlap betweenn IBS and FD. Common mechanisms that have been proposed to play a role inn both IBS and FD include abnormal motility, visceral hypersensitivity, autonomic dysfunction,, altered central nervous system modulation and psychosocial factors includingg mental stress.1-2 More specifically, post-infectious neuro-immune modulationn of gut functions has been shown to play a role in the development of IBS,11 whereas H. pylori infection and dysregulation of acid secretion have been relatedd to symptoms in FD.2
Att present, the concept of visceral hypersensitivity provides the leading hypothesiss regarding the generation of symptoms in both IBS and FD. Several studiess have shown that patients with IBS exhibit hypersensitivity to distension of thee colon and recto-sigmoid,10-11 whereas patients with FD exhibit hypersensitivity too gastric distension,12-13 indicating that normal, physiological stimuli may be perceivedd with increased intensity or may even cause pain. In addition, gut hypersensitivityy may lead to alterations in gut motility by disturbing regulatory reflex pathwayss and secretory functions.14-15 The prevalence of visceral hypersensitivity amongg patients with IBS and FD is similar, roughly involving 50 to 60% of patients.1-22 In the remainder of patients, visceral sensitivity appears to be normal. Therefore,, it has previously been suggested that hypersensitive patients with IBS or F DD may represent a distinct subpopulation of FGIDs based on the underlying pathophysiology.11-144 The possible mechanisms involved in the development of viscerall hypersensitivity have been summarised in CHAPTER 1.
Fromm a therapeutic point of view, restoring normal sensitivity could provide an attractivee approach to treat these patients. Several drugs have been shown to successfullyy reduce visceral sensitivity in experimental studies, but the proof of the conceptt has not been well established in clinical practice. In addition, the relationshipp between visceral hypersensitivity and symptoms in FGIDs is still unclear. .
Thiss thesis focuses on visceral hypersensitivity as a target for the treatment of F G I D s .. CHAPTER 1 discusses the currently available evidence with respect to the clinicall efficacy of drugs that have been proposed to interfere with visceral sensitivityy in FGIDs. Associations between the presence of visceral hypersensitivity andd specific symptoms in FGIDs may further support its relevance to symptom generation.. In addition, such associations could help to classify or select hypersensitivee F G I D patients based on symptom patterns, for example to improve thee outcome of treatments aimed at reducing visceral sensitivity. Therefore, we studiedd the relationship between visceral hypersensitivity and symptoms in FGIDs. Inn CHAPTER 2, we assessed possible associations between dyspeptic symptoms and proximall gastric dysfunction (i.e. impaired relaxation to a meal and hypersensitivity too distension) in patients with FD. In CHAPTER 3, the relationship between IBS symptomss and hypersensitivity to rectal distension was evaluated.
T oo guide future treatments aimed at restoring normal sensitivity in FGIDs, it is importantt to identify the receptors and mediators implicated in visceral perception
inn h u m a n s . At present, m o s t of our understanding of the (patho-) physiology of the viscerosensoryy system is derived from animal studies, and c a n n o t simply be extrapolatedd to h u m a n s . Based o n the available experimental data, we further exploredd the roles o f N-methyl-D-aspartate ( N M D A ) receptors and nitric oxide ( N O )) in visceral sensitivity in man. I n CHAPTERS 4 and 5, w e studied the effects of twoo different N M D A receptor antagonists o n the gastric sensitivity in healthy volunteers.. T h e effects of the N O synthase inhibitor L - N M M A o n gastric and rectall sensitivity in healthy volunteers are described in CHAPTERS 6 and 7, respectively.. I n addition, t o study possible differential effects o f N O in (abnormal) hypersensitivee states, w e also studied the effect of L - N M M A o n rectal sensitivity in hypersensitivee IBS patients (CHAPTER 7). Finally, to further address the concept of targetingg visceral hypersensitivity in clinical practice, we studied the p r o p o s e d viscerosensoryy effects of the SSRI antidepressant fluoxetine o n s y m p t o m s in hypersensitivee and normosensitive IBS patients (CHAPTER 8).
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