# Toward a cause of IBS:Permeability of the mucosa



## SpAsMaN* (May 11, 2002)

http://cat.inist.fr/?aModele=afficheN&cpsidt=16349607Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, OntarioAuteur(s) / Author(s)MARSHALL J. K. (1) ; THABANE M. (1) ; GARG A. X. (2) ; CLARK W. (2) ; MEDDINGS J. (3) ; COLLINS S. M. (1) ; Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)(1) Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Ontario, CANADA(2) Department of Medicine, Division of Nephrology, University of Western Ontario, Ontario, CANADA(3) Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, Alberta, CANADAWEL Investigators, CANADARÃ©sumÃ© / AbstractBackground: Post-infectious irritable bowel syndrome is a common clinical phenomenon of uncertain aetiology. Aim: To test the association between intestinal permeability and irritable bowel syndrome symptoms 2 years after a large waterborne outbreak of bacterial gastroenteritis. Methods: Consecutive adults with Rome I irritable bowel syndrome and controls without irritable bowel syndrome attending a community clinic were enrolled. Intestinal permeability was measured as the ratio of fractional urinary excretions of lactulose and mannitol, and compared among cases vs. controls and predictors of abnormal intestinal permeability were assessed. Results: A total of 218 subjects (132 irritable bowel syndrome cases and 86 non-irritable bowel syndrome controls) completed the study protocol. About 27 (12%) had been diagnosed with the irritable bowel syndrome before the outbreak and 115 (53%) had been ill during the outbreak. Lactulose-mannitol ratios were increased among cases vs. controls (Mann-Whitney mean rank 118.8 vs. 95.3, P = 0.007), and cases were more likely to have a ratio >0.020 (P = 0.007). Among cases, those with increased intestinal permeability were more likely to report increased stool frequency. Both irritable bowel syndrome symptoms and male gender, but not diarrhoeal illness during the outbreak, were significant predictors of abnormal permeability. Conclusions: Irritable bowel syndrome symptoms are associated with a subtle increase in intestinal permeability irrespective of prior gastroenteritis. This may improve understanding of the aetiology of both sporadic and post-infectious irritable bowel syndrome.


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## SpAsMaN* (May 11, 2002)

http://www.blackwell-synergy.com/doi/abs/1...journalCode=ajg American Journal of GastroenterologyVolume 101 Issue 6 Page 1295 - June 2006doi:10.1111/j.1572-0241.2006.00667.x Volume 101 Issue 6 EDITORIAL Mucosal Barrier Defects in Irritable Bowel Syndrome. Who Left the Door Open? Giovanni Barbara, M.D.1 There has been recent interest into the potential role of cellular and molecular mechanisms in the pathophysiology of irritable bowel syndrome (IBS). Although the intestinal mucosa of IBS patients is endoscopically and histologically "normal," it contains an increased number of activated T lymphocytes and mast cells, along with evidence of an increased release of mediators known to signal to epithelial, neuronal, and muscle cells leading to intestinal dysfunction. In this issue, Dunlop et al. provide evidence of increased intestinal permeability in patients with diarrhea predominant IBS. There is now consistent evidence indicating that mucosal barrier defects allow the passage of an increased load of luminal antigens of dietary and bacterial origin which, in turn, elicit the activation of mucosal immune responses involved in the generation of diarrhea. Further work has now to be done to better understand the interplay among luminal factors, epithelial cells, and mucosal immunocytes in the pathogenesis of IBS.(Am J Gastroenterol 2006;101:1295â€"1298)


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## Nanobug (Nov 7, 2006)

Wonderful! It is with great pleasure that I see the beginning of the end of IBS as a functional disease. It's about time!


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## eric (Jul 8, 1999)

also"Some of the major research advances that support the integrated or biopsychosocial approach include: Genetic and early environmental influences on the functional GI disorders The role of neurotransmitter and neurohormonal signaling in intestinal/enteric functionThe use of animal modelsNewer research relating to altered neuroimmune function, cytokine (cell molecules involved in the immune system response) activation, and brain-gut interactions*Demonstration of post-infectious IBS as a brain-gut disorder*The role of brain imaging in understanding the modulation of visceral pain http://www.iffgd.org/symposium2005report.htmlThe intial abstracts are good researchers.







Nanobug, they have had abnormalities in IBS now for at least four years if not more. However, not one specific abnormality in every IBSer they could use as a biological marker. The strongest evidence right now is on serotonin dysregulation which the majority of IBSers present with, however other factors like those mast cells for example and different subgroups.Some of these connections also are like a domino effect. Things can effect other things. Which is also why state of the art treatments for IBS incorportate treating the whole person mind and body or brain and gut brain.


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## SpAsMaN* (May 11, 2002)

Eric:Functional gastrointestinal disorders and mast cells: implications for therapyhttp://www.blackwell-synergy.com/doi/full/...82.2005.00685.x


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## eric (Jul 8, 1999)

SpasmanThanks for posting that and will bookmark it.I have over the last couple years been studying the mast cells. Two important cells in IBS, enterochromaffin cells or EC cells and mast cells. Both very important. Also its important chronic stress can activate the mast cells. It can also re-activate previous inflammation.Thanks for posting that and I will look it over.


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## Nanobug (Nov 7, 2006)

> quote:However, not one specific abnormality in every IBSer they could use as a biological marker.


The reason could simply be the fact that IBS is not a disease but simply a set of symptoms for which no one has a clue about the causes. IBS, I'm convinced, just stands for "I have no clue what the heck is going on". If this weren't so, IBS wouldn't be defined tautologically. Eventually, and here I'm just guessing, IBS will stop existing when all the diseases that cause IBS symptoms are identified.


> quote:The strongest evidence right now is on serotonin dysregulation which the majority of IBSers present with


Well, fructose malabsorption is associated with mood disorders due to impaired tryptophan absorption. This looks like one possible *cause* for serotonin dysregulation in the gut.


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## eric (Jul 8, 1999)

FYI with permissionIRRITABLE BOWEL SYNDROMELin Chang, M.D.CNS: Center of Neurovisceral Sciences & Womenâ€™s Health, CURE: Digestive Diseases Research Center,Division of Digestive Diseases, David Geffen School of Medicine at UCLACorresponding Author:Lin Chang, M.D.Center for Neurovisceral Sciences & Womenâ€™s HealthCURE: Digestive Diseases Research CenterVA Greater Los Angeles Healthcare System11301 Wilshire Blvd., Building. 115, Room. 223Los Angeles, CA. 90073PREVALENCE AND EPIDEMIOLOGYIrritable bowel syndrome (IBS) is the most common functional gastrointestinal (GI) disorder with worldwide prevalence rates ranging from 9-23%. Functionaldisorders are conditions where there is an absence of anatomical or biochemical abnormalities on diagnostic tests which could explain symptoms. IBS is a chronicfunctional bowel disorder characterized by abdominal pain or discomfort and alterations in bowel habits. It is the most common disorder diagnosed by gastroenterologists andaccounts for up to 12% of total visits to primary care providers Gender appears to play an important role in IBS.Two-thirds of individuals with IBS are female with an estimated prevalence in women ranging from 14-24%. Of those who seek healthcare services including tertiary andambulatory care for IBS and other functional bowel disorders, women lead men by a ratio of 2-2.5:1 while others estimate the rate to be higher at 3-4:1. However, the gender distribution appears to be less than 2:1 among IBS non-patients (individuals with symptoms of IBS but who have not sought health care) in the community. It is not known if this increased female prevalence represents a reporting bias, i.e. if female patients are more willing thanmen to disclose that they have IBS-related symptoms, or if it represents a biological difference.Not all individuals with IBS symptoms seek medical care for their symptoms. Based on different epidemiological studies performed in different countries, 20-75% of individuals meeting symptom criteria for IBS will seekmedical care for their symptoms at some point in their lives. There are between 2.4 and 3.5 million annual physician visits for IBS in the United States, during which 2.2 million prescriptions are written. The cost to society in terms of direct medical expenses and indirect costs associated with loss of productivity and work absenteeismis considerable. It has been estimated that the total cost of IBS is 30 billion dollars per year which includes 20 billion dollars for indirect costs and 10 billion dollars for directcosts.SYMPTOMS OF IBSGastrointestinal (GI) symptoms. The hallmark symptoms of IBS are chronic abdominal pain and/or discomfort and alterations in bowel habits, such as diarrhea, constipationor alternating diarrhea and constipation. Abdominal pain has been reported as primarily crampy or as a generalized ache with superimposed periods of abdominal cramps,although sharp, dull, gas-like, or nondescript pains are also common. The intensity and location of abdominal pain in IBS are highly variable, even at different times within asingle patient. The abdominal pain and/or discomfort experienced by IBS patients is often severe enough to interfere with daily activities. Several factors exacerbate orreduce the pain of IBS. Many IBS patients reportincreased symptoms during periods of stress or emotional upset such as job or marital difficulties. Defecation may provide temporary relief from the abdominal pain of IBS,whereas ingestion of food may exacerbate the discomfort in a subset of patients.Based on bowel habits, patients are commonly subclassified into those having mainly diarrhea, mainly constipation, and those alternating between the two patterns. IBS patients with constipation may experienceinfrequent bowel movements (<3/week), hard stools, straining, and sensation of incomplete evacuation. IBS patients with primarily diarrhea report frequent bowel movements (>3/day), loose and/or watery stools frequent,and urgency. The prevalence of the difference subgroups based on bowel habits is similar. Other common IBS symptoms include bloating, visible abdominal distension, and mucus in the stool.Upper gastrointestinal symptoms are commonly reported by IBS patients with 25% to 50% of patients reporting heartburn, early satiety, nausea, abdominal fullness, and bloating. Up to 87% have reported intermittent upperabdominal discomfort or pain (dyspepsia) byapproximately 40% of patients.Extra-intestinal symptoms and overlap with othercommon pain syndromes. Many IBS patients also report extra-intestinal (non-gastrointestinal) symptoms such as fatigue, muscle pain, sleep disturbances, and sexual dysfunction. Up to two-thirds of IBS patients report extraintestinalsymptoms compared to less than 15% of healthyindividuals. These extra-intestinal symptoms may be due to IBS co-morbidity with other stress-related syndromes such as fibromyalgia, chronic fatigue syndrome, andinterstitial cystitis. Epidemiological studies have confirmed the clinical impression that IBS frequently overlaps with these other conditions in the same patient, suggesting shared pathophysiologic mechanisms.Psychological symptoms. Some IBS patients also have psychological distress symptoms such as anxiety and depression particularly in those with severe symptoms and health care seeking behavior. Somatization, anxiety anddepressive disorders are also more commonly seen in IBS patients than in healthy controls. Psychosocial trauma and early adverse life events (e.g., parental separation orphysical/verbal/sexual abuse history) may profoundly affect symptom severity, daily function, and health outcome. Although these adverse events such as abuse may be quite prevalent in IBS patients, a significantnumber have not discussed this with anyone and a smaller number will actually inform their physicians.3DIAGNOSIS OF IBSThe diagnosis of IBS is based on identifying characteristic symptoms and excluding organic disease. An early confident diagnosis permits tests to be minimized and reassures the patient that there is no lethal disease. Thereare no physical findings or diagnostic tests that confirm the diagnosis of IBS. Therefore, diagnosis of IBS involves identifying certain symptoms consistent with the disorderand excluding other medical conditions which may have a similar clinical presentation. The symptom-based Rome II diagnostic criteria for IBS (Table 1) emphasize a â€œpositivediagnosisâ€ rather than exhaustive tests to exclude other diseases. A validation study of the Rome criteria after excluding patients with symptoms suggestive of other medical conditions other than IBS (â€œalarm signsâ€ e.g.bloody stools, weight loss, family history of colon cancer, refractory and severe diarrhea) showed that 100% of individuals who met the diagnosis of IBS based on the Rome criteria truly had IBS rather than an alternativediagnosis. At 2 years follow-up, none of the IBS patients required a change in diagnosis.Other medical conditions which may present withsymptoms similar to those seen in IBS includeinflammatory bowel disease, GI infections, lactose intolerance, thyroid disease, microscopic or collagenous colitis and malabsorption syndromes such as celiac sprue(Table 2). A medical history and physical examination, laboratory and GI tests can help to exclude these other diagnoses. These tests include routine blood tests, stool studies for infection, and endoscopic procedures such asupper endoscopy, sigmoidoscopy and colonoscopy. In patients < 50 years of age who meet diagnostic criteria for IBS and have no â€œalarm signsâ€ suggestive of diseases other than IBS, initial screening tests such as a complete bloodcount to check for anemia and a chemistry panel can be obtained. Other screening tests to consider are a thyroid test (TSH) and a blood test for celiac sprue. However, further tests and procedures such as a colonoscopy are notgenerally recommended. Patients â‰¥ 50 years of age with IBS symptoms should undergo a screening colon examination with either a colonoscopy or flexible sigmoidoscopy and barium enema if these tests have not been done previously, regardless if they have alarm signs(see Figure 1).In some centers, the presence of bacterial overgrowth is often determined because this condition may cause symptoms similar to those of IBS. It is most commonly diagnosed by a lactulose hydrogen breath test. Two studiesfrom the same research group found that 78% to 84% of patients with IBS had bacterial overgrowth. In patients with evidence of bacterial overgrowth, those treated withan antibiotic such as neomycin had a greater reduction in their GI symptoms compared with placebo. Although these data are intriguing, there are some methodologic limitations in these studies and, therefore, the use ofwidespread hydrogen breath testing for bacterialovergrowth is still not generally advocated.PATHOPHYSIOLOGIC MECHANISMS OF IBSAlthough psychological and physiological abnormalities have been described, the overall pathophysiology of IBS is not well understood. Similar to other chronic medical conditions, a multi-component conceptual model of IBS,which involves genetic, physiologic, emotional, cognitive, and behavioral factors, has been formulated (Figure 2).Although all factors are closely nterconnected, the importance of individual factors in the generation of IBS symptoms may vary greatly between individuals.Previously, IBS was considered primarily a disorder of altered gut motility. Currently, increased bowel sensitivity (visceral hypersensitivity) and altered brain-gutinteractions are felt to play a principal role in the pathophysiology of IBS. Recently, it has been found that genetic and environmental factors are important in IBS but further studies are needed to understand the importance of these factors in the prevalence, symptoms, physiologic responses and response to treatment in IBS.Altered intestinal motor function. Altered intestinal motility has been found in IBS, particularly exaggerated contractions (motor response) in the lower (sigmoid) colonto psychological stress and food intake. These alterations may explain why many IBS patients experience typical IBS symptoms following meals and develop exacerbations during stressful life events. These changes in bowel motility are likely due to alterations in the autonomicnervous system outflow to the intestine.Increased gut sensitivity. There has been compelling evidence that IBS patients have enhanced perception of bowel (visceral) stimuli such as food or distensions of the gut wall. The initial clinical observations that led to the hypothesis that patients with IBS have visceral hypersensitivity included the presence of recurring abdominal pain as a principal symptom, the presence of tenderness during palpation of the sigmoid colon (leftlower abdominal area) during physical examination in many patients, and excessive pain often reported by patients during endoscopic examination of the sigmoidcolon. Published studies measuring visceral sensitivity suggest that a variety of abnormal sensations or perceptions in relation to bowel stimuli may be more frequent in IBS patients. At least two perceptual alterations can be distinguished, a hypervigilance (increased attention or vigilance) towards expectedaversive events arising from the bowel, and hyperalgesia (lowered threshold to pain) which is inducible by sustained painful visceral stimulation. These findings are paralleledby similar findings of target system hypersensitivity in other disorders such as fibromyalgia and myofascial pain disorder. In contrast to their enhanced perception ofvisceral pain, most IBS patients have normal or even decreased pain sensitivity and tolerance for painful cold and mechanical stimulation of somatic (skin and muscle).However, there is a recent study that has demonstrated increased somatic sensitivity to thermal heat in IBS patients. Patients with IBS who also have co-existing4 fibromyalgia have increased somatic sensitivity comparable to patients with fibromyalgia alone.Increased stress mediators in IBS. There is increasing evidence to support the prominent role of stress in the pathophysiology and in the clinical presentation of IBS symptoms. There are few published reports on alterationsin stress mediators, such as catecholamines and cortisol to stress or visceral stimulation in IBS. Several studies have reported increased in catecholamines (norepinephrine and epinephrine) and cortisol levels in IBS patients. However,it remains to be determined whether these neuroendocrine alterations play a direct role in gut function and symptom generation.Altered brain-gut communication in IBS. A unifying hypothesis to explain the functional bowel disorders is that they result from a dysregulation of the brain-gut axis. Anevolving theory is that normal gastrointestinal function results from an integration of intestinal motor, sensory, autonomic and CNS activity and GI symptoms may relate to dysregulation of these systems. Brain imaging studies such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have been performed in IBS patients to measure brain activation patterns to visceral stimuli. These studies suggest that brainactivation responses to visceral stimuli are distinctly different in IBS patients compared to healthy individuals.IBS patients may have different emotional and cognitive processing of sensory information from the gut compared to healthy individuals.Post-infectious IBS. Symptoms suggestive of IBS occur in approximately 7-30% of patients following acute GI infections, often persisting for years following complete resolution of the infection. A large cohort study identifieda self-reported history of acute gastroenteritis as a major risk factor for the development of IBS. Reported risk factors for the development of post-infectious IBS includefemale sex, the duration of the acute diarrheal illness and the presence of sustained psychosocial stressors around thetime of infection. Post-infectious IBS is not restricted to a particular organism and has been documented with avariety of bacterial infections (Salmonella, Campylobacterand E. coli) as well as parasitic infection. However, the role of acute viral gastroenteritis in this condition is unknown.In post-infectious IBS, low grade GI inflammation or immune activation may be a basis for altered motility, and/or nerve and mucosal (lining of bowel) function of thegut in IBS. Recent studies have also shown that in a subset of unselected IBS patients (no documented history of a preceding gut infection), there is evidence of increasedinflammatory cells in the colon mucosa. It remains to be determined if altered gut immune function is a general characteristic of IBS patients. The implication of stressfullife events in the development of post-infectious IBS suggests a convergence of central (brain) and peripheral (gut) mechanisms in the clinical presentation of this syndrome.Gender differences. In addition to IBS, many functional GI disorders and other chronic visceral pain disorders (e.g.interstitial cystitis and chronic pelvic pain) and somatic pain disorders (e.g. fibromyalgia, myofascial pain disorder) are more common in women than in men.Increasing evidence suggests that gender differences exist in the symptoms, pathophysiologic responses and responseto certain treatments in IBS. Female IBS patients are more likely to be constipated, complain of abdominal distension and certain extra-intestinal symptoms. Studies have alsosupported an influential role of ovarian hormones (e.g. estrogen and progesterone) on bowel function and pain sensitivity which can in part explain the gender differencesin IBS. Several investigators have reported a variation in GI symptoms during different phases of the menstrual cycle, particularly increased abdominal pain and loose stools at the perimenstrual (just prior to and at time ofmenses) phase.TREATMENTTreatment of IBS includes both non-pharmacologic andpharmacologic therapies. An important component of nonpharmacologictreatment for IBS is a successful physicianpatientrelationship. The physician should strive toestablish effective bi-directional communication with thepatient, gain the patientâ€™s confidence with a concise,appropriate medical evaluation and offer reassurance andeducation that IBS is a real medical condition with apotential impact on health related quality of life butwithout significant long/term health risk. Some IBSpatients, especially those presenting with new onset ofsymptoms, express relief that their symptoms are notcaused by a serious condition such as malignancy. Othercomponents of non-pharmacologic treatment of IBSinclude diet recommendations, lifestyle modifications, andpsychosocial intervention if needed.Patients with mild IBS symptoms comprise the mostprevalent group, and are usually treated by primary carepractitioners, rather than specialists. These patients haveless significant functional impairment or psychologicaldisturbance. These patients do not see a clinician veryoften, and usually maintain normal daily activities.Treatment is directed toward education, reassurance, andachievement of a healthier lifestyle and occasionalmedication. Dietary advice may include avoidingoffending foods which can trigger symptoms (e.g. lactoseor fructose products, fatty foods, caffeine, gas-producingfoods). Fiber supplementation has been shown to beeffective for symptoms of constipation.Pharmacologic therapy is best used in IBS patients withmoderate to severe symptoms refractory to physiciancounseling and dietary manipulations. First line treatmenthas traditionally been aimed at treating the most5bothersome symptom because of the lack of effectivetreatment for the overall improvement of multiplesymptoms in IBS patients. However, new therapies forIBS have been recently introduced and have been shown toeffectively treat multiple symptoms of IBS.Anticholinergic/Antispasmodic agents. After fiberpreparations, antispasmodic agents are the next mostcommonly prescribed group of medications for thetreatment of IBS. However, several studies do not providefirm evidence that anticholinergic agents are efficacious inthe IBS population as a whole. Only a few of theseantispasmodics have been shown to be more effective thanplacebo in relieving abdominal pain in high quality clinicalIBS trials but these are not currently available in the U.S.Antidiarrheal agents. In IBS patients with diarrhea,antidiarrheal agents such as loperamide and diphenoxylatecan be effective in decreasing bowel movement frequency,improving stool form by enhancing intestinal water and ionabsorption, and increasing anal sphincter tone at rest.These physiologic actions seem to explain theimprovement in diarrhea, urgency, and fecal soilingobserved in patients with IBS. These medications do nottypically relieve abdominal pain and may causeconstipation.Psychotropic medications. The rationale of using thisclass of drugs in IBS may relate to several factors, such asthe prominent co-morbidity of IBS with psychologicdistress symptoms and the effects of these agents on gutmotility and pain sensation. Among the classes ofantidepressant medications, the tricyclics have been mostextensively evaluated in IBS. At lower doses than thoseusually used to treat depression (starting at 10 mg and upto 75 mg nightly), amitriptyline and desipramine have beenfound to be significantly more effective than placebo inpatients with IBS. Antidepressants have analgesic (painrelief) properties, which may benefit patientsindependently of the psychotropic effects of the drugs.Treatment with tricyclics should begin with low doses(e.g., 10 mg/day) and increased as needed up to fulltherapeutic doses. Selective serotonin reuptake inhibitors(SSRIs, e.g. paroxetine, citalopram) and selective serotoninand noradrenergic reuptake inhibitors (SNRIs, e.g.venlafaxine) have not been well studied for treatment ofIBS, and are more expensive, but have less side effectsthan tricyclics and empirically may help reduce painfulsymptoms and improve general well-being and quality oflife.Novel serotonin agents. The prominent role of serotoninin GI motility and sensation has led to the development ofnovel serotonin agents such as alosetron and tegaserod inthe treatment of IBS. Most of serotonin (also known as 5-HT) in the body resides in the bowel wall withinenterochromaffin cells lining the gut (mucosa) and nervecell bodies. Serotonin is released from theenterochromaffin cells and acts on receptors on the nerveswithin the bowel wall. These nerves may be part of thenervous system which resides completely within the bowelwall, known as the enteric nervous system, or may benerves that transmit painful and non-painful informationby projecting from the bowel to the spinal cord and brain.Activation of these nerves by serotonin leads to the releaseof other neurotransmitters and through their actions, itplays a major role in gut motility, secretion and sensation.Alosetron (Lotronexï›š), which is a 5-HT3 antagonist, hasbeen shown to be effective in relieving pain, normalizingbowel frequency, and reducing urgency in non-constipatedIBS female patients. This medication was approved by theFDA last year but was later withdrawn because of theadverse events of constipation and ischemic colitis, thelatter being observed in 0.1%-1% of patients receiving themedication. Future studies are being planned to determineif there is a causal association of alosetron and ischemiccolitis. However, alosetron has recently been re-approvedand now is available for the treatment of women withsevere diarrhea-predominant IBS under the Restricted UseProgram. Alosetron is indicated only for women withsevere diarrhea-predominant IBS who have: chronic IBSsymptoms (generally lasting â‰¥ 6 months), no evidence ofanatomic or biochemical abnormalities of the GI tractwhich could explain their symptoms, and failed to respondto conventional therapy. IBS is considered severe if itincludes diarrhea and â‰¥ 1 of the following: frequent andsevere abdominal pain/discomfort, frequent bowel urgencyor fecal incontinence, or disability or restriction of dailyactivities due to IBS. Physicians must enroll in theRestricted Use Program in order to prescribe alosetron.Patients should discuss with their physicians about therisks and benefits of the medication before beingprescribed it. Both should sign the Patient-PhysicianAgreement form. The starting dose of alosetron is now 1mg orally once daily. If the patient does not experiencecomplete relief of their symptoms after 1 month, the dosecan be increased to 1 mg orally twice daily which was theoriginally approved dose. Any patient who experiencesincreased abdominal pain, blood in their stool and/orconstipation should immediately stop their medication andcontact their physician.Tegaserod (Zelnormï›š) is a partial 5-HT4 agonist, whichhas been shown to be effective in relieving the globalsymptoms of IBS with constipation. It has been recentlyapproved for the treatment of IBS with constipation inwomen. Tegaserod has been shown to accelerate GI transittime in IBS patients and therefore would increase stoolfrequency, and increase electrolyte secretion in the boweland thus improve stool form. In addition to its motilityenhancing properties, tegaserod has been shown to havepain inhibitory properties in animal studies and thereforemay reduce abdominal pain although human studies areneeded to confirm this effect. Unlike other currentlyavailable medications for IBS with constipation, tegaserodappears to be effective in treating the multiple symptomsof IBS. The subjectâ€™s global assessment of relief of IBSsymptoms, change in number of bowel movements,6abdominal pain and bloating are all reportedly improved infemale patients with IBS with constipation takingtegaserod as compared to placebo. The only adverse eventswhich were seen at a small but significantly higher rate inpatients taking tegaserod compared to placebo wereheadache and transient diarrhea.Psychological treatments. Referral for psychologicaltreatment can be recommended as part of a multicomponenttreatment program to help the patient bettermanage the symptoms, or to address psychosocialdifficulties (e.g., abuse, loss) that may be interfere withdaily function and ability to cope with the illness. Ingeneral, these treatments are reserved for patients withmoderate to severe symptoms, particularly if theyexperience psychological distress. However, the patientmust be motivated and see this type of treatment asrelevant to their personal needs. Psychological treatmentsused to treat IBS include psychotherapy (dynamic andcognitive-behavioral therapy), relaxation therapy,hypnotherapy, and biofeedback therapy. Psychologicaltreatments can also be combined. Review of well-designedtreatment studies of IBS supports the superiority ofpsychological treatment over conventional medicaltherapy. Follow-up studies (duration 9-40 months), havedemonstrated that psychological treatment maintainedsuperiority over placebo, indicating that these methodshave lasting value. The choice of treatment will depend onpatient requirements, available resources and theexperience of the therapist.CONCLUSIONSIBS is a common, chronic disorder characterized byexacerbations and remissions, which presents withsymptoms of abdominal pain and/or discomfort and alteredbowel habits. It has a chronic relapsing course and canoverlap with other functional GI (dyspepsia) and non-GI(fibromyalgia) disorders.The clinical diagnosis of IBS is based on identifyingsymptom criteria with a â€œpositive diagnosisâ€ and excludingorganic disease with minimal diagnostic evaluation.Clinicians should feel secure with the diagnosis of IBS, ifmade properly, because it is rarely associated with otherexplanations for symptoms. Although there are manyexpensive and sophisticated tests available for theevaluation of IBS symptoms, these are generally notneeded for patients with typical symptoms and no featuressuggestive of organic diseases.An integrated diagnostic and treatment approach firstrequires an effective physician-patient relationship. Acareful history will also identify the need for diagnosticstudies and treatments as determined by the nature andseverity of the predominant symptoms, and the degree andextent of influencing psychosocial and other factors.The fact that definite structural or biochemicalabnormalities for these disorders cannot be detected withconventional diagnostic techniques does not rule out thepossibility that neurobiological alterations will eventuallybe identified to explain fully the symptoms of mostfunctional disorders. Examples of such a shift inperspective from symptom-based disorders withoutdetectable abnormalities to medically treatable diseasesbased on specific neurobiological alterations includeaffective disorders (depression, anxiety) and migraineheadaches. Similar to other chronic illnesses, amulticomponent model that involves physiologic,affective, cognitive, and behavioral factors can beformulated for IBS. Although all factors are closelyinterconnected, the importance of individual factors in thegeneration of IBS symptoms may greatly vary betweenindividuals. Physiologic factors implicated in thegeneration of IBS symptoms include hypersensitivity ofthe GI tract to normal events, autonomic dysfunctionincluding altered intestinal motility response to stress andfood intake, alterations in fluid and electrolyte handling bythe bowel, and alterations in sleep.Many of the traditional therapies have been used to treatspecific IBS symptoms because they have not been shownto significantly relieve global symptoms, which wouldimprove an overall sense of well-being. However, thediscovery of novel serotonergic agents such as tegaserodand alosetron have been shown to be effective in treatingglobal symptoms in patients with IBS compared withplacebo. More recently published studies evaluating theefficacy of antidepressants, such as tricyclics and SSRIs,suggest that these medications may help improve generalwell-being in addition to treating psychological comorbidityin affected individuals but further studies areneeded. Psychological and behavioral therapies have alsobeen showed to be effective for IBS however it potentiallycan be limited by the availability of experienced therapists.Instituting a multidisciplinary approach using nonpharmacologicand pharmacologic therapeutic modalitiesmay result in the most effective outcome. Future studieswill further enhance our understanding of this conditionand lead to newer, more effective treatments.7Recommended Reading:1. Sandler RS, Everhart JE, Donowitz M, Adams E, Cronin K, Goodman C, Gemmen E, Shah S, Avdic A, Rubin R.(2002). The burden of selected digestive diseases in the United States. Gastroenterology 122(5):1500-11.2. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. (2002) AGA Technical Review on Irritable BowelSyndrome. Gastroenterology. 123:2108-2131.3. 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 JGastroenterol 2002 Nov;97(11 Suppl):S7-26.4. Evidence-based position statement on the management of irritable bowel syndrome in North America. Am JGastroenterol. 2002 Nov;97(11 Suppl):S1-5.5. Rome II. The Functional Gastrointestinal Disorders. Diagnosis, Pathophysiology and Treatment: A MultinationalConsensus. 2 nd edition. McLean, VA: Degnon Associates, 20006. Vanner SJ, Depew WT, Paterson WG, DaCosta LR, Groll AG, Simon JB, Djurfeldt M. (1999). Predictive valueof the Rome criteria for diagnosing the irritable bowel syndrome.Am J Gastroenterol. Oct;94(10):2912-7.7. Cash BD, Schoenfeld P, Chey WD. (2002).The utility of diagnostic tests in irritable bowel syndrome patients: asystematic review. Am J Gastroenterol. Nov;97(11):2812-9. Review.8. Pimentel M, Chow EJ, Lin HC. (2000) Eradication of small intestinal bacterial overgrowth reduces symptoms ofirritable bowel syndrome. Am J Gastroenterol. 95(12):3503-6.9. Talley NJ, Spiller R. (2002) Irritable bowel syndrome: a little understood organic bowel disease? Lancet17;360(9332):555-64.10. Mayer EA, Naliboff BD, Chang L, Coutinho SV. (2001). V. Stress and irritable bowel syndrome. Am J PhysiolGastrointest Liver Physiol 280(4): G519-24.11. Chang L and Heitkemper MM. (2002). Gender differences in Irritable Bowel Syndrome. Gastroenterology.123:1686-1701.12. Drossman DA, Creed FH, Olden KW, Svedlund J, Toner BB, Whitehead WE. (1999). Psychosocial aspects of thefunctional gastrointestinal disorders. Gut 45 Suppl 2:II25-30.13. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. (2000). Efficacy and safety ofalosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet.25;355(9209):1035-40.14. Berman SM, Chang L, Suyenobu B, Derbyshire SW, Stains J, Fitzgerald L, Mandelkern M, Hamm L, Vogt B,Naliboff BD, Mayer EA. Condition-specific deactivation of brain regions by 5-HT3 receptor antagonistAlosetron. Gastroenterology 2002 Oct;123(4):969-77.15. Talley NJ. (2003) Pharmacologic therapy for the irritable bowel syndrome. Am J Gastroenterol.98(4):750-8.16. Jackson JL, O'Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. (2000). Treatment of functionalgastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med. 108(1): 65-72.17. Jailwala J, Imperiale TF, Kroenke K. (2000). Pharmacologic treatment of the irritable bowel syndrome: asystematic review of randomized, controlled trials. Ann Intern Med. 18;133(2):136-47.18. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R. (2000). Regional cerebral activation inirritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology.118(5): 842-8.819. Muller-Lissner SA, Fumagalli I, Bardhan KD, Pace F, Pecher E, Nault B, Ruegg P. (2001). Tegaserod, a 5-HT(4)receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloatingand constipation. Aliment Pharmacol Ther. 15(10): 1655-66.Resources for Patients and Providershttp://www.uclacns.orghttp://www.uclamindbody.orghttp://iffgd.org9Medical HistoryIdentify symptoms with IBS Rome II CriteriaLimited diagnostic screening testsPhysical Exam, CBC, Chemistry panel, Thyroid function, Stool for occult bloodPresence of alarm signs,Age ? 50 yr,New onset orchange in symptomsAbsence of alarm signs,Age < 50 yrChronic stable IBSsymptomsReferralPredominant SymptombaseddiagnosticapproachFulldiagnosticworkup(Negative)Figure 1.Figure 1. Diagnostic evaluation of IBS patientsFigure 2. Multicomponent model of irritable bowel syndrome (IBS). Development of IBS symptoms can be explained by theinterrelation of cognitive, behavioral, emotional, and physiological components. Mayer EA. Am J Med. 1999;107(5A):12S-19SCognitivePhysiologicalEmotional BehavioralAnxietyDepressionEnvironmentalstressorsPain modulationAutonomic regulation of motilityNeuroendocrine responseIBSIllness behaviorCoping stylesFigure 210Table 1Table 2.Differential Diagnoses of IBSInflammatory bowel diseaseColorectal carcinomaMedicationsGastrointestinal infections (e.g., Giardia,Entamoeba histolytica,Yersinia, Strongiloides)Lactose IntoleranceEndocrine disorders (Hypo or hyperthyroidism,Diabetes)Medications (e.g., laxatives, magnesium-containingantacids)Microscopic or collagenous colitisBacterial overgrowthMalabsorption syndromes (e.g., celiac sprue,pancreatic insufficiency)Chronic intestinal idiopathic pseudoobstructionendocrine tumors (e.g., gastrinoma, VIPoma)ROME II Diagnostic CriteriaAt least 12 weeks, which need not be consecutive, in the preceding 12 months ofabdominal discomfort or pain that has two of three features:1) Relieved with defecation; and/or2) Onset associated with a change in frequency of stool; and/or3) Onset associated with a change in form (appearance) of stoolhttp://ibs.med.ucla.edu/PDFs/IBSReviewArticle.pdf


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## Nanobug (Nov 7, 2006)

> quote:The fact that definite structural or biochemicalabnormalities for these disorders cannot be detected withconventional diagnostic techniques does not rule out thepossibility that neurobiological alterations will eventuallybe identified to explain fully the symptoms of mostfunctional disorders.


This was the part of the article I got excited about!


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## eric (Jul 8, 1999)

They have now actually found structural abnormalities in IBS.IBS has been considered a brain gut axis dysfunction now for quite a few years.Part of that is because of pain and viceral hypersensivity. They also have some info on IBS and neurogenic inflammation. another part is also non gi symptoms associated with IBS. FYIwith permissionIBS ï¿½ Beyond the Bowel:The Meaning of Co-existing Medical ProblemsOlafur S. Palsson, Psy.D. and William E. Whitehead, Ph.D.UNC Center for Functional GI & Motility DisordersIrritable bowel syndrome (IBS) is a disorder that is defined by a specific pattern ofgastrointestinal (GI) symptoms in the absence of abnormal physical findings. The latestdiagnostic criteria for IBS -- the Rome II criteria created by an international team ofexperts -- require that the patient have abdominal pain for at least 12 weeks within thepast 12 months and that the pain meets two of the following three criteria: it is relievedafter bowel movement, associated with change in stool frequency, or associated withstool form. It is becoming clear, however, that these bowel symptoms do not tell thewhole story of symptoms experienced by IBS patients. People with this disorder oftenhave many uncomfortable non-gastrointestinal (non-GI) symptoms and other healthproblems in addition to their intestinal troubles.SYMPTOMS ALL OVER THE BODY IN IBSSeveral research reports have established that IBS patients report non-bowel symptomsmore frequently than other GI patients and general medical patients. For example, fourstudies that have asked IBS patients about a wide variety of body symptoms(1-4) all foundheadaches (reported by 23-45% of IBS patients), back pain (28-81%), and frequenturination (20-56%) to be unusually common in individuals with IBS compared to otherpeople. Fatigue (36-63%) and bad breath or unpleasant taste in the mouth (16-63%) werefound in three of these four studies to be more common among IBS patients, as well.Furthermore, a large number of other symptoms have been reported to occur withunusually high frequency in single studies. In our recent systematic review of the medicalliterature(5), we found a total 26 different symptoms, listed in Table 1, that are reported tobe more common in IBS patients than comparison groups in at least one study.Table 1. Non-gastrointestinal symptoms more common in irritable bowel syndromepatients than in comparison groups(5).1. Headache2. Dizziness3. Heart palpitations or racing heart4. Back pain5. Shortness of breath6. Muscle ache7. Frequent urinating8. Difficulty urinating9. Sensitivity to heat or cold10. Constant tiredness11. Pain during intercourse (sex)12. Trembling hands13. Sleeping difficulties14. Bad breath/unpleasant taste inmouth15. Grinding your teeth16. Jaw pain17. Flushing of your face and neck18. Dry mouth19. Weak or wobbly legs20. Scratchy throat21. Tightness or pressure in chest22. Low sex drive23. Poor appetite24. Eye pain25. Stiff muscles26. Eye twitchingOVERLAP WITH OTHER MEDICAL CONDITIONSResults from numerous studies (reviewed by Whitehead, Palsson & Jones, 2002(5)) alsoindicate that IBS overlaps or co-exists more often than would be expected with othermedical conditions that appear to have little logical connection with the gut. The mostresearched example of such an overlap is the co-existence of IBS with fibromyalgia, adisorder characterized by widespread muscle pain. Fibromyalgia affects an estimated 2%of the general population, but 28-65% of IBS patients have the disorder. Similar resultsare obtained when this overlap is examined the opposite way, by studying fibromyalgiapatients and looking for IBS -- 32-77% of fibromyalgia patients have IBS.Chronic fatigue syndrome (CFS) is another medical condition that has been found to havemany times the expected co-occurrence with IBS. CFS is thought to affect only 0.4% ofthe general population, but it has been reported in 14% of IBS patients. Conversely, 35-92% of chronic fatigue syndrome patients have IBS. Other conditions documented inmultiple studies to have excess overlap with IBS are temporomandibular joint disorder(TMJ), found in 16-25% of IBS patients(2,6), and chronic pelvic pain (35% of IBSpatients(7). In addition to these well established relationships, many other medicalconditions appear (judging from single study reports) to have an excess overlap with IBS,although the frequencies of most of them in IBS are much lower than for the disordersalready discussed. In fact, we recently(8) compared the frequencies of a broad range ofdiagnoses in the medical records of 3153 IBS patients in a large health maintenanceorganization in the U.S. Northwest to an equal number of non-GI patients in the sameHMO, and found that the IBS patients had a higher frequency of almost half of all non-GIdiagnoses, or 64 of the 136 sampled diagnoses.In summary, non-GI symptoms and co-existing medical problems seen in many IBSpatients far exceed what is typical for medical patients or GI patients in general. Thisraises important questions about what causes this phenomenon and what the implicationsare for IBS patients.WHAT EXPLAINS NON-GI SYMPTOMS AND CO-EXISTENCE OF OTHER DISORDERS IN IBS?There are several possible explanations for the preponderance of general symptoms anddisorders in IBS. Our research group is engaged in several research studies that may helpshed some light on this mystery, but it is still too early to come to definitive conclusions.We will list here some of the possible explanations, and discuss relevant data comingfrom work by our team and other investigators.1. A common physical cause? One explanation for the high rates of co-existingsymptoms and conditions in IBS patients would be that there is something biologicallywrong in IBS patients that also causes other symptoms or conditions. There are a numberof distinct physiological characteristics or ï¿½abnormalitiesï¿½ seen in many IBS patients,although none of them are found in all IBS patients. These include: heightened painsensitivity in the gut, increased intestinal contractions (motility) or hyper-reactivity inresponse to meals or stress (too much movement of the intestines ï¿½ this is the reason whyIBS was called spastic colon in the past), patterns of dysfunction in the autonomicnervous system (that part of the nervous system that helps regulate our inner bodyfunctions), and vague signs of immune activation seen in some IBS patients. Althoughone could suggest ways in which these physiological abnormalities would play a role insome other disorders that co-exist with IBS, there is little evidence so far of a commonpattern of physical abnormality that could link IBS and its most common coexistingconditions and symptoms. Patterns of autonomic dysfunction in IBS are not like the onesseen in fibromyalgia and chronic fatigue syndrome, for example. And, fibromyalgiapatients do not show the same gut pain sensitivity as IBS patients, while conversely, IBSpatients do not show the pain-sensitive tender points that are characteristic offibromyalgia(9-10). Furthermore, as can be seen from reviewing the symptom list in Table1, the non-GI symptoms that plague IBS patients are so varied and cover so manydifferent organ systems, that it would be hard to identify a specific biological connectionbetween them. On the contrary, it seems like the only overall commonality between thesesymptoms may be that they are non-specific ï¿½ they are, in other words, not clearsymptoms of any identifiable disease processes or diagnosable disorders. Indeed, thesymptoms that are most common among IBS patients are generally those that are alsocommon in the general healthy population ï¿½ they just tend to occur at a higher level inpeople with IBS.2. Physical expression of emotional discomfort?Another possible explanation for the high number of non-GI symptoms and disorders inIBS patients is the tendency to translate strong emotions into physical symptoms. This issometimes called somatization (ï¿½somaï¿½ is the Greek word for ï¿½bodyï¿½ and somatizationtherefore literally means ï¿½to express in the bodyï¿½). All people ï¿½somatizeï¿½ to some degree;it is normal to feel butterflies in your stomach, to blush or go pale, get a lump in yourthroat, or feel the heart beating in your chest when you get very emotional. Shaky hands,stiff neck or excess sweating are likewise quite ordinary when people are under a greatdeal of stress. However, some people are more vulnerable than others to letting negativeemotions express themselves physically. This is often thought to be an alternative andless healthy way of exhibiting or feeling emotional discomfort. Some people maydevelop a strong tendency to do this because they have a basic personality trait that shiesaway from interpersonal expressiveness. For others, it could be the result of growing upin the care of strict, repressive or abusive parents or caretakers, where normal expressionof negative emotions was not allowed or would have been dangerous. Getting a headacheor a stomach ache may be an alternative way to ï¿½give voiceï¿½ to negative emotions undersuch circumstances. It seems that excessive habitual suppression of ordinary verbal andemotional expressions of negative emotions, regardless of the reason for it, may lead tothe tendency to somatize. There is evidence that this tendency may be at work in IBS, atleast among some women with the disorder. Dr. Brenda Toner has found in twostudies(11-12) that women with IBS score higher than depressed women and healthywomen on questionnaires measuring of the tendency to avoid the expression of negativeemotions or views.3. Learned over-attention to body symptoms and excess disease attribution?All people ignore most of the sensations from their bodies most of the time. This isnecessary so that we are not overwhelmed by the vast amount of information our sensessupply to our brains every moment of our lives. For example, if you are reading thissitting down, you have probably not been at all aware of the sensations of the seat underyour body until right now. Our brains constantly sift through the mass of incoming bodyinformation and decide what is important for us to become consciously aware of, basedon such things as our past experiences and how likely the information is to indicate athreat to our health or well-being. Most minor symptoms (those that might beuncomfortable and bothersome if they would get our attention), are simply dismissed inour busy everyday lives, because other things win out in the moment-to-momentcompetition for our limited attention resources.More frequent attention to mild physical symptoms can be learned, however, and canbecome a habit. As with most things, such habitual over-attention is probably most easilylearned in childhood. It would seem reasonable, for example, that a child could get intothe habit of noticing physical symptoms more if his or her parents are always talkingabout their own symptoms. We have recently found(13) that the more medical problemsthe parents in the childhood home had, the more general physical symptoms adult IBSpatients report. The possible consequence of a childhood where the child grew up withparents or others who were seriously ill, is a tendency to interpret common normalphysical sensations as symptoms of serious illness. Such a serious view of symptoms canalso be modeled after the parentï¿½s approach to common illness. Dr. Whitehead andcolleagues found in a telephone survey of 832 adults 20 years ago(14) that people whoseparents paid more attention to cold or flu symptoms in childhood were more likely toview such symptoms as serious in adulthood and to visit doctors for them. They were alsomore likely to have IBS diagnosis.Evidence that IBS patients interpret physical sensations differently than others isemerging from brain imaging studies. This type of research takes a ï¿½snapshotï¿½ of theamount of activity in different parts of the brain in response to sensations, usingtechniques such as PET scans (positron emission tomography) and fMRI (functionalMagnetic Resonance Imaging). By examining which parts of the brain react the most topainful sensations, it is possible to deduce to some degree how the brain processes theinformation. In one such study, by Silverman and colleagues(15), IBS patients but notcontrol subjects reacted to physical sensations from a painful balloon inflation in therectum with increased blood flow in the left prefrontal cortex, a part of the brain knownto process personally threatening information. In contrast, this study and others(16-17)found that IBS patients do not show activity in the anterior cingulate cortex that isindicative of general discomfort in healthy subjects. IBS patients are also more likely torespond to physical stimuli in the GI tract by activating brain centers that handleemotional events. Collectively, this suggests that IBS patients may process bodyinformation associated with bowel sensations (and perhaps other physical sensations, aswell) differently than other people, interpreting them as personally threatening and moreemotionally relevant events rather than just ordinary discomfort. Such differentinterpretations of physical sensations would also explain hyper-attention to suchsensations.4. Faulty neurological filtering?After entering the spine (the information highway from the body to the brain),information destined for the brain about body pain is sent along nerves through gates thatcontrol how much of this information passes through. Our brains continually send signalsdown these spinal gates to cause them to block signals that are of too low intensity toprovide valuable information (you do not want to constantly know about all of yourminor aches and discomforts from regular body activity). This is one of the ways thebrain uses to limit the vast amounts of information constantly streaming in from millionsof nerve sensors throughout our bodies. A current popular hypothesis in the field of IBSresearch is that an inadequate amount of this ï¿½descending inhibitionï¿½ of incoming paininformation is, at least partly, to blame for the hypersensitivity to intestinal discomfortand pain seen in IBS patients. Some researchers have further suggested that the samekind of slack traffic control could be more widespread in IBS patients and may explainthe observed proneness to headaches, back pain or muscle aches. People who have moreopen pain gates because of faulty inhibition would theoretically be like the princess inï¿½The Princess and the Pea.ï¿½ who could feel a pea through 20 mattresses. The problemwith this as an explanation for symptom overabundance among IBS patients is that itwould explain only excess in pain-type symptoms, which are just one of many types ofoverabundant symptoms in IBS. There are also no direct data on IBS patients to provehow valid this view is.5. Result of greater psychological distress?As was explained earlier, it is normal for people who are emotionally distressed toexperience more physical symptoms. At least half of IBS patients who have consulteddoctors have been diagnosed with an affective (ï¿½emotionalï¿½) disorder ï¿½ generally eitherdepression or an anxiety disorder. Additionally, many people with IBS who have noaffective disorder diagnosis have significant symptoms of anxiety and depression. Onemight, therefore, ask whether the physical symptoms reported could simply be a sideeffect of psychological distress.We have addressed this question in two studies presented at the 2003 Annual Meeting ofthe American Gastroenterological Association(18-19). In the HMO data mentioned earlier(18), we found that having a psychological diagnosis was associated with increasednumbers of physical diagnoses that these IBS patients had received (from an average of7.1 to 9.7). However, we also found that even patients with no psychiatric diagnosis hadmore physical diagnoses per person than the other HMO patients (7.5 vs. 5.5), so thepresence of psychological problems is not the whole answer. In the other study(19), weexamined the relationship between depression and anxiety scores of 795 people with IBSand the number of physical symptoms they had experienced over the past month.Statistical methods that estimate how much of the variability in one measuredcharacteristic can be explained by other measured factors tell us that the psychologicalsymptoms roughly accounted for 25-30% of physical symptoms of these people. In short,psychological distress is almost certainly part of the explanation for greater bodysymptoms in IBS, but not nearly the whole story.Further research will have to determine which of the above explanations are applicable inIBS, but it is likely that more than one of them, and maybe some other factorsunrecognized so far, work together to account for the high frequency of symptoms anddisorders that co-exist with IBS.THE IMPACT OF EXTRA PHYSICAL SYMPTOMS AND DISORDERS ON IBS PATIENTS.What do these extra (ï¿½non-IBSï¿½) symptoms and co-existing medical conditions mean inpractical terms for patients with IBS? The first thing to note is that not all IBS patientsexperience additional health problems and symptoms, so it is not a concern for all peoplewith IBS. For those who do, however, symptoms and disorders beyond the bowel can addmeasurably to the overall burden of illness for the individual and also lead to greaterhealth care needs and health care costs for IBS patients.It is by now well established that IBS patients visit doctors more than the generalpopulation. Only recently has it been recognized, howver, that most of the extra healthcare visits that people with IBS make are not for their bowel problems. Levy et al.(20)reported that IBS patients had about twice as many doctor visits compared to otherpatients in the same HMO, but they found that 78% of the additional visits were due toproblems other than IBS. It seems quite likely that these extra non-GI doctor visits of IBSpatients are due to the tendency to experience more general body symptoms over time,based on study results we presented at the Annual Meeting of the AmericanGastroenterologicalAssociation last year(21). Usinga scale asking patients aboutthe 26 physical symptoms inTable 1, we found that thoseIBS patients who report anunusually high number of thesesymptoms over the past monthmissed six times as many daysfrom school or work due toillness (see Figure 1)compared to those with low ormoderate (normal) symptoms.The ï¿½high-symptomï¿½ IBSpatients also had twice as manydoctor visits and more hospitaldays (Figure 2), and their qualityof life was furthermoremeasurably poorer on theaverage.A general tendency to have alarge number of body symptomsis, therefore, very costly in termsof the IBS patientï¿½s overall wellbeingand ability to functionnormally in life, and increasessubstantially the health care costsfor these individuals. Thesefindings clearly underline theneed to find a way to help themany IBS patients who score unusually high on body symptom questionnaires to reducethat tendency.IS IT POSSIBLE TO REDUCE NON-GI SYMPTOMS IN IBS?It is unknown to what degree standard medical treatment for IBS, when successful, alsoresults in improvement in non-GI symptoms. The problem is that most IBS treatmentresearch has not examined how non-IBS symptoms change. Non-IBS symptoms havealso not been a focus of standard IBS treatment. An exception to this is psychologicaltreatment trials for IBS, which sometimes have included general physical symptomquestionnaires among the measures of treatment effects. We, therefore, know from ourtwo studies of hypnosis treatment for IBS(22) as well as from research in England(23) thathypnosis treatment for IBS regularly improves non-GI symptoms substantially in additionto its beneficial effects on bowel symptoms. Less is known about improvement in non-GIsymptoms from cognitive-behavioral therapy (CBT), which is the other widelyresearched psychological treatment for IBS. However, there is every reason to believethat CBT can reduce the tendency to experience a lot of general physical symptoms,based on a review of over 30 such treatment studies(24). These benefits of psychologicaltreatment for IBS point to extra value of such treatments for the subgroup of IBS patientswho have many non-GI symptoms.Research in coming years will hopefully identify other ways to improve the well-beingand life functioning of IBS patients by reducing non-GI symptoms. This is likely tobecome an integral part of managing IBS effectively in the subset of patients who suffermany symptoms and conditions beyond the bowel.References:1. Whorwell PJ, McCallum M, Creed FH, Roberts CT. Non-colonic features of irritable bowelsyndrome. Gut 1986; 27:37ï¿½40.2. Jones KR, Palsson OS, Levy RL, Feld AJ, Longstreth GF, Bradshaw BH, Drossman DA, &Whitehead WE. Comorbid disorders andsymptoms in irritable bowel syndrome (IBS) Comparedto other gastroenterology patients. Gastroenterology 2001:120:A66.3. Zaman MS, Chavez NF, Krueger R, Talley NJ, Lembo T. Extraintestinal symptoms in patientswith irritable bowel syndrome (IBS). Gastroenterology 2001; 120(Suppl 1):A636.4. Maxton DG, Morris J, Whorwell PJ. More accurate diagnosis of irritable bowel syndrome by theuse of ï¿½non-colonicï¿½ symptomatology. Gut 1991; 32:784ï¿½786.5. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowelsyndrome with other disorders: what are the causes and implications? Gastroenterology 2002 Apr;122(4):1140-56.6. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatiguesyndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 2000; 160: 221ï¿½227.7. Walker EA, Gelfand AN, Gelfand MD, Green C, Katon WJ. Chronic pelvic pain andgynecological symptoms in women with irritable bowel syndrome. J Psychosom Obstet Gynaecol1996; 17:39ï¿½46.8. Whitehead WE, Palsson OS, Levy RL, Von Korff M, Feld AD, Turner MJ. Excess comorbidityfor somatic disorders in irritable bowel syndrome (IBS) is related to hypervigilance.Gastroenterology 2003 (abstract in press).9. Chang L. The association of functional gastrointestinal disorders and fibromyalgia. Eur J SurgSuppl 1998 ;( 583):32-6.10. Chang L, Mayer EA, Johnson T, FitzGerald LZ, Naliboff B. Differences in somatic perception infemale patients with irritable bowel syndrome with and without fibromyalgia. Pain 2000 Feb;84(2-3):297-307.11. Toner BB, Garfinkel PE, Jeejeebhoy KN. Psychological factors in irritable bowel syndrome. Can JPsychiatry. 1990 Mar; 35(2):158-6112. Toner BB, Koyama E, Garfinkel PE, Jeejeebhoy KN, Di Gasbarro I. Social desirability andirritable bowel syndrome. Int J Psychiatry Med 1992; 22(1):99-103.13. Whitehead WE, Palsson OS, Jones KR, Turner MJ, Drossman DA. Role of parental modeling insomatization of adults with irritable bowel syndrome. Gastroenterology 2000; 122 (Suppl 1):A502.14. Whitehead WE, Winget C, Fedoravicius AS, Wooley S, Blackwell B. Learned illness behavior inpatients with irritable bowel syndrome and peptic ulcer. Dig Dis Sci 1982 Mar;27(3):202-8.15. Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebralactivity in normal and pathological perception of visceral pain. Gastroenterology 1997 Jan;112(1):64-72.16. Bonaz B, Baciu M, Papillon E, Bost R, Gueddah N, Le Bas JF, Fournet J, Segebarth C. Centralprocessing of rectal pain in patients with irritable bowel syndrome: an fMRI study.Am JGastroenterol 2002 Mar;97(3):654-61.17. Bernstein CN, Frankenstein UN, Rawsthorne P, Pitz M, Summers R, McIntyre MC. Corticalmapping of visceral pain in patients with GI disorders using functional magnetic resonanceimaging. Am J Gastroenterol 2002 Feb;97(2):319-27.18. Whitehead WE, Palsson OS, Levy RL, Von Korff M, Feld AD, Turner MJ. Comorbid psychiatricdisorders in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).Gastroenterology 2003 (abstract in press).19. Palsson OS, Levy R,Von Korff M, Feld A, Turner MJ, Whitehead WE. Comorbidity andpsychological distress in irritable bowel syndrome (IBS). Gastroenterology 2003 (abstract inpress).20. Levy RL, Whitehead WE, Von Korff MR, Feld AD. Intergenerational transmission ofgastrointestinal illness behavior. Am J Gastroenterol 2000; 95:451ï¿½456.21. Palsson, O.S., Jones K.R., Turner M.J., Drossman D.A., & Whitehead, W.E. (2002). Impact ofsomatization and comorbid medical conditions on health care utilization, disability, and quality oflife in irritable bowel syndrome (IBS). Gastroenterology, 122 (Suppl 1): A501-502.22. Palsson OS, Turner MJ, Johnson DA, Burnelt CK, Whitehead WE. Hypnosis treatment for severeirritable bowel syndrome: investigation of mechanism and effects on symptoms. Dig Dis Sci 2002Nov; 47(11):2605-14.23. Gonsalkorale WM, Houghton LA, Whorwell PJ. Hypnotherapy in irritable bowel syndrome: alarge-scale audit of a clinical service with examination of factors influencing responsiveness. Am JGastroenterol 2002 Apr; 97(4):954-61.24. Kroenke K, Swindle R. Cognitive-behavioral therapy for somatization and symptom syndromes: acritical review of controlled clinical trials. Psychother Psychosom 2000 Jul-Aug; 69(4):205-15.


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## eric (Jul 8, 1999)

FYIAmerican Gastroenterological Association Teaching project slides IBS Originally posted on May 15, 2003 https://www.gastroslides.org/Main/browse_deck.asp?tpc=4Irritable Bowel Syndrome 2004 Update Originally posted on May 15, 2003 https://www.gastroslides.org/Main/browse_deck.asp?tpc=9


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## eric (Jul 8, 1999)

Med Sci Monit. 2004 Apr;10(4):RA55-62. Related Articles, Links Irritable bowel syndrome: a model of the brain-gut interactions.Mulak A, Bonaz B.Department of Gastroenterology and Hepatology, Wroclaw Medical University, Wroclaw, Poland. agata.mulak###wp.plBrain-gut interactions are increasingly recognized as underlying pathomechanisms of functional gastrointestinal disorders. Bi-directional communication between the central nervous system (CNS) and the enteric nervous system (ENS) occurs both in health and disease. Various CNS- and gut-directed stressors stimulate the brain-gut axis. Processes modulating responsiveness to stressors along the brain-gut axis involve neural pathways, the immunological, and endocrinological mechanisms. Disturbances at every level of neural control of the gastrointestinal tract can affect modulation of gastrointestinal motility, secretion, immune functions as well as perception and emotional response to visceral events. ENS function, central processing, and autonomic regulation play an important role in the brain-gut dialogue. Stress and emotions may trigger neuroimmune and neuroendocrine reactions via the brain-gut axis. Various non-site specific neurotransmitters influence gastrointestinal, endocrine and immune function, as well as human behavior and emotional state, depending on their location. The physiology of the digestive tract, the subjective experience of symptom, health behavior, and treatment outcome are strongly affected by psychosocial factors. Recently, a biopsychosocial model of IBS containing physiological, emotional, cognitive and behavioral components has been proposed. Rapid progress in neurogastroenterology, using new brain imaging techniques, should bring better understanding of the brain-gut axis and open new therapeutic perspectives.PMID: 15260348This is part of the connection between stress and those mast cells in the gut, but other issues as well.Harvard Health"The Mind and the Immune Systemï¿½Part IOne of the standing mysteries of medicine is the relationship between the mind and physical healthï¿½how feelings, thoughts, attitudes, and behavior are related to physical illness, how psychological and social stress affect the likelihood of developing a disease or the ability to resist it, and how counseling for emotional problems can aid recovery from illness. One of the clues to this mystery lies in the immune system, the network that defends us against microbes and other invaders. Interest in the connections between the brain and the immune system has given birth to the discipline of psychoneuroimmunology. These systems communicate through the sympathetic nervous system and the endocrine glands, especially the hypothalamic-pituitary-adrenal (HPA) axis. Like the immune system, both are dedicated to the defense of the body against stress and danger, and both are directed from the same part of the brain, the hypothalamus. All threeï¿½the immune system, sympathetic nervous system, and HPA axisï¿½respond to some of the same transmitter chemicals. ""The sympathetic nervous system is part of the autonomic nervous system, which controls involuntary functions like heart rate, digestion, and breathing. The sympathetic nerves serve as an emergency response network, heightening the bodyï¿½s readiness to accept a challenge or escape in the face of danger. The sympathetic nerves are connected to various organs of the immune system, such as the thymus gland, the bone marrow, the spleen, and lymph nodes. Immune cells, including T cells, monocytes, and B cells, have receptors for the neurotransmitters released by sympathetic nerves. Damage to the hypothalamus and loss of sympathetic transmitters impairs the functioning of the immune system. An injection of antigens (foreign substances that activate the immune system) affects the concentration of sympathetic neurotransmitters in the brain. "


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