Pharmacogenomics and functional gastrointestinal disorders.

Functional gastrointestinal disorders, including irritable bowel syndrome and functional dyspepsia, are highly prevalent disorders affecting approximately one in four people in Western societies. This article reviews examples of the role of pharmacogenomics in the safety and efficacy of medications used in the management of such disorders. These include variations in the effects of medications metabolized by cytochrome P450 enzymes (e.g., 2D6 and 2C19), and the effects of genetic polymorphisms in the promoter of the serotonin transporter protein, which influence the response to alosetron in patients with diarrhea-predominant irritable bowel syndrome. These observations suggest that pharmacogenomics will introduce a new era in pharmacotherapeutics in gastroenterology.

Family study of affective spectrum disorder.

BACKGROUND: Affective spectrum disorder (ASD) represents a group of psychiatric and medical conditions, each known to respond to several chemical families of antidepressant medications and hence possibly linked by common heritable abnormalities. Forms of ASD include major depressive disorder (MDD), attention-deficit/hyperactivity disorder, bulimia nervosa, cataplexy, dysthymic disorder, fibromyalgia, generalized anxiety disorder, irritable bowel syndrome, migraine, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and social phobia. Two predictions of the ASD hypothesis were tested: that ASD, taken as a single entity, would aggregate in families and that MDD would coaggregate with other forms of ASD in families. METHODS: Probands with and without MDD, together with their first-degree relatives, were interviewed using the Structured Clinical Interview for DSM-IV and a supplemental interview for other forms of ASD. The familial aggregation and coaggregation of disorders were analyzed using proband predictive logistic regression models, including a novel bivariate model for the presence or absence of each of 2 disorders in a relative as predicted by the presence or absence of each of 2 disorders in the associated proband. RESULTS: In the 178 interviewed relatives of 64 probands with MDD and 152 relatives of 58 probands without MDD, the estimated odds ratio (95% confidence interval) for the familial aggregation of ASD as a whole was 2.5 (1.4-4.3; P =.001) and for the familial coaggregation of MDD with at least one other form of ASD was 1.9 (1.1-3.2; P =.02). CONCLUSIONS: Affective spectrum disorder aggregates strongly in families, and MDD displays a significant familial coaggregation with other forms of ASD, taken collectively. These results suggest that forms of ASD may share heritable pathophysiologic features.

Mitochondrial inheritance in depression, dysmotility and migraine?

BACKGROUND: Several studies have reported a high degree of association of the common conditions of depression, bowel dysmotility and migraine. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) sequence variants have been linked individually to each of these three conditions, providing a plausible hypothesis for the reported association. If this hypothesis is correct, the matrilineal relatives (who all share essentially the same mtDNA sequence) of patients with mitochondrial disease secondary to inherited mtDNA mutations would be expected to have an elevated prevalence of each of these three conditions. METHODS: Families were recruited by an advertisement posted on the United Mitochondrial Disease Foundation website and invited to participate in an on-line questionnaire if at least one member was diagnosed with mitochondrial disease by a physician. Based upon the reported family histories, families were assigned by the investigators to either the probable maternal inheritance (PMI) group (55 families) or the probable non-maternal inheritance (PnMI) group (111 families). RESULTS: Bowel disorders, migraine and depression were reported at very high prevalence in the PMI mothers (60%, 54% and 51%, respectively), but were present at significantly lower prevalence rates among the PnMI mothers (16%, 26% and 12%; P<0.0001 for each) and the fathers of both groups (range 9-16%; P < 2 x 10(-6) for each). Similar data was obtained comparing the prevalence rates among maternal and paternal grandmothers, aunts and uncles. LIMITATIONS: Our data was obtained from families ascertained by the presence of a severely affected individual, and may not be applicable to families lacking this proband. CONCLUSIONS: Depression, bowel dysmotility and migraine are common manifestations in individuals with mtDNA sequence-related mitochondrial dysfunction, which supports our hypothesis that mitochondrial dysfunction is a major common factor underlying the association of these three conditions.

Emerging disease model for functional gastrointestinal disorders.

In response to perceived or experienced change that is considered threatening to the individual, the central nervous system mounts a stereotypic response that decreases the sensitivity to pain, modulates the autonomic nervous system outflow, and activates the hypothalamic-pituitary-adrenal (HPA) axis. This response of the "emotional motor system" may or may not be associated with the conscious experience of feelings of fear or anxiety. Alterations in these response systems (either up- or downregulation) may produce symptoms, such as viscero-somatic hypersensitivity, altered bowel habits, or increased anxiety.

Familial association in adults with functional gastrointestinal disorders.

OBJECTIVE: To evaluate the association between functional gastrointestinal (GI) symptoms and a family history of abdominal pain or bowel problems. SUBJECTS AND METHODS: A valid self-report questionnaire that records GI symptoms and spouse's and first-degree relatives' history of abdominal pain or bowel troubles and includes the psychosomatic symptom checklist (a measure of somatization) was mailed to an age- and sex-stratified random sample of Olmsted County, Minnesota, residents aged 30 to 64 years. A logistic regression model that adjusted for age, sex, and somatic symptom score was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of a positive family history for each functional GI disorder. RESULTS: Six hundred forty-three (72%) of 892 eligible subjects returned the survey. Reporting a first-degree relative with abdominal pain or bowel problems was significantly associated with reporting of irritable bowel syndrome (OR, 2.3; 95% CI, 1.3-3.9) and dyspepsia (OR, 1.8; 95% CI, 1.05-3.0) but not constipation, diarrhea, or gastroesophageal reflux. The reporting of a spouse with abdominal pain or bowel problems was not associated with any of these disorders. CONCLUSIONS: A history of abdominal pain or bowel troubles in first-degree relatives was significantly associated with irritable bowel syndrome and dyspepsia. Whether the familial associations represent similar exposures in a shared environment, heightened familial awareness of GI symptoms (reporting bias), or genetic factors remains to be determined.

Is irritable bowel syndrome more likely to be persistent in those with relatives who suffer from gastrointestinal symptoms? A population-based study at three time points.

BACKGROUND: We tested the hypothesis that subjects with relatives who suffered from abdominal pain or bowel dysfunction would be at an increased risk of more persistent irritable bowel syndrome. METHODS: A valid, self-report questionnaire was mailed to an age- and gender-stratified random sample of residents, aged 30-64 years, in Olmsted County, MN, USA, on three occasions over a 4-year period. Persistent irritable bowel syndrome was defined as the presence of irritable bowel syndrome on at least two of the three surveys, and fluctuating irritable bowel syndrome was defined as the presence of irritable bowel syndrome on only one of the surveys. RESULTS: Subjects were less likely to have persistent irritable bowel syndrome over the age of 50 years [odds ratio (OR), 0.20; 95% confidence interval (CI), 0.09, 0.47]. A positive family history was reported by 23%. A family history of gastrointestinal symptoms was independently associated with persistent irritable bowel syndrome (vs. no irritable bowel syndrome: OR, 2.5; 95% CI, 1.3, 4.9) and fluctuating irritable bowel syndrome (vs. no irritable bowel syndrome: OR, 2.4; 95% CI, 1.3, 4.4). However, subjects reporting a positive family history were not more likely to report persistent vs. fluctuating irritable bowel syndrome (OR, 1.2; 95% CI, 0.5, 2.9). The use of non-steroidal anti-inflammatory drugs (OR, 2.3; 95% CI, 1.2, 4.3) and a history of food sensitivity (OR, 3.6; 95% CI, 1.9, 6.9) were the only other predictors of persistent irritable bowel syndrome. CONCLUSIONS: A history of abdominal pain or bowel troubles in first-degree relatives appears to be independently associated with both persistent and fluctuating irritable bowel syndrome.

Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distension: role of afferent C-fibers and 5-HT3 receptors.

Experimental animal models have been established to gain insight into the pathogenesis and the mechanisms of visceral hyperalgesia in the irritable bowel syndrome (IBS). However, data about the mechanisms and pathways involved in the induction of neuronal activity in forebrain and midbrain structures by a physiological GI stimulus, like colonic distension (CD), in the range from non-noxious to noxious intensities are scarce. Thus, the effect of proximal CD with non-noxious (10 mmHg) and noxious (40 and 70 mmHg) stimulus intensities on neuronal activity in brain nuclei, as assessed by c-fos expression, was established. In additional studies, the role of vagal and non-vagal afferent sensory C-fibers and 5-HT(3) receptors in the mediation of visceral nociception was investigated in this experimental model at noxious colonic distension (70 mmHg). At CD, the number of c-Fos like immunoreactivity (c-FLI)-positive neurons increased pressure-dependently in the nucleus of the solitary tract (NTS), rostral ventrolateral medulla (RVLM), nucleus cuneiformis (NC), periaqueductal gray (PAG), and the amygdala (AM). In the dorsomedial (DMH) and ventromedial nucleus (VMH) of the hypothalamus, as well as in the thalamus (TH), neuronal activity was also increased after CD, but independently of stimulus intensities. A decrease of the CD-induced c-fos expression after sensory vagal denervation by perivagal capsaicin treatment was only observed in brainstem nuclei (NTS and RVLM). In all other activated brain nuclei examined, the CD-related induction of c-fos expression was diminished only after systemic neonatal capsaicin treatment. In the NTS and RVLM, a trend of decrease of c-fos expression was also observed after systemic neonatal capsaicin treatment. In order to assess the role of the 5-HT(3) receptor in CD-induced neuronal activation of brain nuclei, animals were pretreated with the 5-HT(3) receptor antagonist granisetron (1250 microg/kg, i.p. within 18 h before CD). Pretreatment with granisetron significantly reduced the number of c-FLI-positive cells/section in the NTS by 40%, but had no significant effect on the CD-induced c-fos expression in other brain areas. The data suggest that distinct afferent pathways and transmitters are involved in the transmission of nociceptive information from the colon to the brain nuclei activated by proximal colonic distension. Activation of NTS neurons at such a condition seems to be partially mediated via capsaicin-sensitive vagal afferents and 5-HT(3) receptors. In contrast, activation of brain nuclei in the di- and telencephalon by nociceptive mechanical stimulation of the proximal colon, as assessed by c-fos expression, is partially mediated by capsaicin-sensitive, non-vagal afferents, and independent of neurotransmission via 5-HT(3) receptors. The modulation of CD-induced c-fos expression exclusively in the NTS by granisetron points to a role of 5-HT(3) receptor antagonists in the modulation of vago-vagal sensomotoric reflexes rather than an influence on forebrain nuclei involved in nociception.

Irritable bowel syndrome and family history of psychiatric disorder: a preliminary study.

A series of 70 consecutive patients with irritable bowel syndrome (IBS) were interviewed concerning their family history of psychiatric disorders. A series of 60 consecutive patients with major depression (MDE) were also interviewed, as were a control group of 46 relatives of patients with organic brain disease. The results showed that both IBS and MDE groups had a similar, higher prevalence of relatives with psychiatric illness than controls, and that this was due to a higher prevalence of anxiety and depressive disorder in the relatives. The implications of these findings are discussed.

[Intestinal infection and irritable bowel syndrome].

OBJECTIVE: To determine whether intestinal infection plays a role on the pathogenesis of irritable bowel syndrome (IBS). METHODS: 295 patients who had no previous history of functional bowel disorder had received treatment for dysentery (n = 235) or for acute bowel infection at the hospital between April-October, 1998, were followed up for 1 - 2 years and evaluated for their subsequent bowel habits. A cohort study of 243 subjects using their siblings, husbands or wives who did not have dysentery or acute bowel infection at the same period was taken as control. Furthermore, the contents of mRNAs of IL-1alpha, IL-1beta and IL-1ra in the mucosa at the terminal ileum and recto-sigmoid junctions were determined and compared using RT-PCR method in 30 IBS patients and 12 controls. RESULTS: (1) Sixty-six (22.4%) patients were reported to have functional bowel disturbance, and 24 (8.1% total and 10.2% among cases of dysentery) developed IBS in the study group, whereas, only 7.4% had altered bowel habit and 0.8% had IBS in the control group (P < 0.01). (2) The risk of having functional bowel disturbance was higher in patients who suffered from a longer duration (> 8 d, OR = 3.5) of dysentery. (3) The IL-1beta mRNA level in the mucosa of terminal ileum and recto-sigmoid junction of IBS patients with dysentery was higher than that of controls and IBS patients without dysentery (P < 0.01). CONCLUSION: Intestinal infection plays a role on the pathogenesis of IBS through some immunological factors.

Current concepts of the irritable bowel syndrome.

The irritable bowel syndrome is one of the most common clinical problems encountered by the generalist and gastroenterologist. The goal of this review is to critically evaluate, based on available peer-reviewed literature, the current status of our understanding of the pathophysiology of the irritable bowel syndrome. The epidemiology of this disorder, including the characteristics of its presentation, natural history and associated phenomena, have been clarified. Differences between those who seek specialist care ('the consulters') and those in the community are now recognized. While, in both, symptoms may be similar in nature and severity; 'the consulters' are differentiated by how they react to their complaints. In terms of pathophysiology, the focus has moved to visceral sensation and central perception and has led to the identification of visceral hypersensitivity, visceral hyperalgesia and abnormal central perception of visceral events. This is not to dismiss dysmotility; subtle abnormalities in gas transit may be closely associated with the induction of certain symptoms. On the psychological front, attention now focuses on such complex issues as somatosization, abuse and response to major life events. Interactions between enteric flora, mucosal inflammation, immune phenomena and the enteric neuro-muscular apparatus also attract interest; the entity of post-infectious irritable bowel is now clearly recognized and there is experimental evidence to suggest a role for inflammation. While the precise aetiology of irritable bowel syndrome remains uncertain, considerable progress has been made, with recent advances in pathophysiology offering hope for the development of new therapeutic approaches.

Systematic evaluation of the causes of chronic watery diarrhea with functional characteristics.

UNLABELLED: BACKGROUND Causes of chronic watery diarrhea are multiple. There is not definite scientific evidence about AND AIMS: which are the recommended explorations to be performed in the diagnostic workup of patients with functional diarrhea. The aim was to assess prospectively the presence of gluten-sensitive enteropathy, bile acid malabsorption, and sugar malabsorption in consecutive patients with chronic watery diarrhea of obscure origin fulfilling Rome II criteria of functional disease. METHODS: A total of 62 patients with chronic watery diarrhea, defined as more than 3 loose or liquid bowel movements a day for at least 4 wk and a stool weight >200 g/day were included. The following tests were performed: (a) HLA-DQ2/DQ8 genotyping, and if positive, endoscopic biopsies from distal duodenum were obtained, and intestinal damage assessed; (b) SeHCAT (Se-homotaurocholate) abdominal retention test; (c) small bowel follow-through; and (d) hydrogen breath test (lactose, fructose + sorbitol). Gluten- or sugar-free diet, or cholestyramine was administered according to results. Functional disease was diagnosed if all tests performed were normal or if either there was no response to specific therapy or diarrhea relapsed during a 12-month follow-up. RESULTS: Bile acid malabsorption was considered to be the cause of diarrhea in 28 (45.2%) patients, sugar malabsorption in 10 (16.1%), gluten-sensitive enteropathy in 10 (16.1%), and both bile acid and sugar malabsorption in 2 patients. Twelve (19.4%) patients remained without a specific diagnosis and were considered as functional bowel disease. Diarrhea stopped in the 50 patients after specific treatment, decreasing the daily stool number from 5.4 +/- 0.3 to 1.5 +/- 0.1 (P < 0.0005), without relapse after the 12-months follow-up. CONCLUSIONS: The diagnosis of functional disease in patients with chronic watery diarrhea should be performed with caution since in most cases there is an organic cause that justifies diarrhea.

Irritable colon syndrome of infancy.

Irritable colon syndrome of infancy is the most frequent cause of chronic diarrhea in children between eight months and three years of age who are still gaining weight at a normal rate. The diarrhea occurs in response to a wide variety of stimuli, and a strong family history of functional bowel disorders is common. The usual dietary regimens for diarrhea perpetuate the problem. A regular diet, without snacks, is recommended, with fluids restricted to unchilled beverages taken with meals.

Genetic heterogeneity in primary ankylosing spondylitis.

We studied 115 white patients suffering from primary ankylosing spondylitis (AS). HLA-B27 was present in 105 patients (92%) and 8% of controls (pc < 0.001). Four of the 10 B27 negative patients were noted to possess HLA-Bw16 (40%), compared to 3.09% of 444 B27 negative controls (pc < 0.014). These findings suggest the existence of genetic heterogeneity in primary AS. Moreover, since Bw16 is also known to be associated with psoriasis and enteropathic spondylitis, our data support the clinical suggestion that disease-susceptibility alleles for psoriasis and for chronic inflammatory bowel diseases may be important in the development of primary AS as well, even in the absence of HLA-B27.

A role for inflammation in irritable bowel syndrome?

Attention has been directed to the putative role of low grade mucosal inflammation in irritable bowel syndrome (IBS) on the basis of evidence showing that some patients with IBS have an increased number of inflammatory cells in the colonic and ileal mucosa. Previous episodes of infectious enteritis, genetic factors, undiagnosed food allergies, and changes in bacterial microflora may all play a role in promoting and perpetuating this low grade inflammatory process. Human and animal studies support the concept that inflammation may perturb gastrointestinal reflexes and activate the visceral sensory system even when the inflammatory response is minimal and confined to the mucosa. Thus abnormal neuroimmune interactions may contribute to the altered gastrointestinal physiology and hypersensitivity that underlies IBS. A brief review of the human and animal studies that have focused on the putative role of intestinal inflammation and infections in the pathogenesis of IBS is given.

Prevalence of inflammatory bowel disease among relatives of patients with ulcerative colitis.

The familial occurrence of inflammatory bowel disease (IBD) was investigated among 963 patients with ulcerative colitis (UC) diagnosed in 1955-1979 in Stockholm County. For 76 patients who had a relative with IBD a pedigree was drawn. The diagnoses of the diseased relatives were verified. There was a general prevalence of 7.9% for IBD among relatives. In 80% one relative was affected, in most cases a first-degree relative with UC. Sibship was the commonest relationship. No concordance for UC was found among three pairs of monozygotic twins. The prevalence of UC in first-degree relatives was 15 times higher than in non-relatives. The age of onset was significantly lower among patients with a family history for UC; they also had a higher incidence of total colitis. The prevalence of Crohn's disease in first-degree relatives of patients with UC was almost 3.5 times higher than in non-relatives.

The relationship between irritable bowel syndrome and psychiatric illness. A family study.

Although irritable bowel syndrome (IBS) is a common disorder among gastrointestinal clinic outpatients, it continues to be a diagnosis of exclusion. In treatment-seeking populations, IBS has been frequently associated with psychiatric illness, and this co-occurrence has added to controversy about the validity of the IBS diagnosis. This study is a preliminary effort to examine the nature of this relationship by using the family study design. The probands consisted of 20 patients with IBS and 20 patients who had undergone laproscopic cholecystectomy. Their first-degree relatives were interviewed to obtain lifetime diagnoses of functional gastrointestinal and psychiatric syndromes. Significantly more IBS probands had lifetime psychiatric illness than the cholecystectomy probands. The lifetime prevalence of IBS as well as other functional gastrointestinal syndromes was not significantly different between the groups of relatives. However, significantly more relatives of the IBS probands had lifetime psychiatric illness than the relatives of the cholecystectomy probands. Among the relatives with functional gastrointestinal disorders, significantly more had psychiatric illness. This preliminary study provides support for a relationship between IBS and psychiatric illness by the finding of an increased prevalence of psychiatric disorders among the relatives of patients who have IBS.