FUNCTIONAL GI DISORDERS
From University of Wisconsin School of Medicine and Public Health’s Functional GI Disorders
| BRAIN GUT AXIS/GENETICS —Lin Chang, MD, Professor of Medicine in Residence, Department of Medicine, Division
of Digestive Diseases, and Co-Director, UCLA Center for Neurovisceral Sciences and Women’s Health, the David Geffen
School of Medicine at the University of California, Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare
System
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| Familial association studies: Mayo Clinic questionnaire study on adults with gastrointestinal (GI) dysmotility and
sensory disorders showed increased odds ratio that patients with these conditions would have first-degree relative with GI
symptoms; follow-up study (included data directly from relatives) determined increased odds ratio in patients with irritable
bowel syndrome (IBS) for having first-degree relative with GI symptoms; question whether result due to genetic familial
clustering or to similar psychosocial patterns
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| Twin studies: 4 of 5 studies show increased concordance of IBS in monozygotic twins vs dizygotic twins; study showed
proportion of dizygotic twins with IBS who had mothers with IBS greater than proportion of dizygotic twins with IBS
who had co-twins with IBS (suggests environmental factor as important or more important than genetic component); twin
study of restricted intrauterine growth—looked at effect of genes and early adverse life events on development of IBS;
known that restricted development of specific fetal organs predisposes individuals to developing certain chronic illnesses
later in life (eg, cardiovascular disease, type 2 diabetes, hypertension); identical twins often differ in birth weight; questionnaire
study showed 5% prevalence of IBS overall, with concordance in monozygotic twins higher than in dizygotic
twins, and increased prevalence in girls; mean onset of IBS similar between sexes (18 yr of age in boys and 17 yr of age
in girls); genetic influence seen in girls, not boys (no monozygotic male twins with concordance for IBS; individuals with
IBS had lower birth weights (significant only if adjusted for gestational age); persons with very low birth weight (<1500
g) had earlier onset of IBS symptoms; integration of genetics and developmental and environmental factors may lead to
increased vulnerability to development of IBS
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| Model: genetic predisposition to development of functional GI disorders (FGID), and some early life event (stressor)
leads to compromise of adaptive systems, resulting in increased vulnerability to developing IBS; trigger later in life
(physical or psychologic) leas to actual development of symptoms; stressor and/or symptom-related anxiety perpetuate
symptoms; genetic influences at all levels
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| Genetic effects: evidence that serotonin receptor transporter (SERT) genetic polymorphisms associated with particular
clinical symptom subtypes (SERT short allele associated more with patients with IBS with diarrhea [IBS-D], but study
showed association with IBS with constipation [IBS-C]); evidence that genetic polymorphism in cholecystokinin and
adrenergic receptor (AR) potentially associated with certain subtypes, particularly IBS-C, and somatic symptoms; evidence
that genetic polymorphisms that encode for cytokines potentially abnormal in patients with IBS; potential genetic
effects on central nervous system regulatory pathways, eg, stress responsiveness, pain modulation; much psychiatric comorbidity
in patients with severe IBS; pharmacogenomics—do genetic polymorphisms predict certain treatment responses?
evidence that patients with long genetic polymorphism for SERT (greater reuptake of serotonin) have greater
slowing with 5-hydroxytryptamine type 3 (5-HT3) antagonist (alosetron) in IBS-D; evidence of increased drug response
in patients with functional dyspepsia with G-protein polymorphism
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| Brain–gut interaction: certain proinflammatory cytokines feed back to brain and drive stress circuitry; data from nonpostinfectious
IBS show abnormally elevated levels of proinflammatory cytokines in blood, not gut tissue; study looking at
genetic polymorphisms for proinflammatory cytokine tumor necrosis factor (TNF)-α found elevated levels of genotype
associated with high production of this cytokine in patients with IBS vs controls; study looking at genotypes of
anti-inflammatory cytokine interleukin-10 (IL-10) found lower number of patients had high-producing IL-10 polymorphism;
patients producing higher levels of TNF-α and lower levels of IL-10 potentially predisposed to developing
changes in immune function
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 | Genes tested for association with FGID: Mayo Clinic study—found α-2A AR and α-2c AR polymorphisms associated
with IBS-C and somatic symptoms, and showed association with high somatic symptom score with α-2c AR alone or in
combination with SERT and α-2A AR; loss of normal function of AR leads to altered central processing of sensory information
and modulation of descending pain inhibitory systems
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| Epigenetic programming: environment can change gene expression by DNA methylation and acetylation of histones;
maternal care can alter DNA methylation, affecting glucocorticoid expression (maternal separation animal model of IBS)
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| PSYCHOLOGIC AND BEHAVIORAL TREATMENTS —Kevin W. Olden, MD, Jerome S. Levy Professor of Medicine,
and Division Director, Gastroenterology and Hepatology, University of Arkansas School for Medical Sciences, Little Rock
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| Introduction: important that psychotherapist understand FGID; attention effect—concern in clinical trials that people
improving because of getting so much human contact (methods in place to try to control for this); question whether treating
psychologic disorder of patient directly affecting gut and gut symptoms, or just building better coping skills
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| Role of stress in IBS: life experience survey given to 100 patients with IBS vs 100 normal controls showed abnormal
scores in 66% of patients with IBS vs 25% of controls; scores not significantly different in patients with organic disease
vs those with IBS, indicating that people with chronic GI illness, regardless of cause, seek care and have more distress,
based on recent life stressors; severe life events more common in patients with IBS than in those with structural GI disorders;
stress predicts onset of symptoms, which creates symptom exacerbation and health care-seeking behavior and increases
intrusiveness and disability-generating aspect of IBS symptoms; cycle—person has FGID, and then has negative
experiences; this leads to depression, anxiety and less-than-optimal coping, which creates negative world view of disorder
and further disability and helplessness
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| Psychiatric comorbidity: acknowledge burden of illness (disability and negative quality of life [QOL]); screen for
psychiatric comorbidity (rating scales easy and objective); major depressive disorder, generalized anxiety disorder, and
panic disorder fairly prevalent, and specific screening for these produces high yield; somatoform disorders (understudied)
treated differently (patients more disabled and more refractory); screen for panic disorder and other anxiety disorders,
particularly posttraumatic stress disorder (PTSD; important because of abuse history in many patients); studies show generalized
anxiety disorder found in ≈34% to ≈37% of patients with IBS (significant overexpression, compared to mean in
general US population; 39% of patients with IBS meet criteria for mood disorder
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| Abuse: classic study showed that abuse significantly more likely in patients with FGID than in organic controls; impact—
psychiatric distress significantly elevated; more pain; more impairment in activities of daily living; more days in bed;
more visits to physicians; more symptoms; study of patients who had suffered physical or sexual abuse—showed psychotherapy
improved depression, pain, disability, and intolerance of rectal balloon distention; all parameters, including
balloon distention, improved with psychotherapy; childhood abuse—high frequency; people abused in childhood tend to
have more dysfunction in adulthood than those abused as adults; much more pain across all organ systems, much more
psychologic distress, and impaired functioning; “help-rejecting complainer” may have been abused, and that behavior
can lead to diagnosis; patient characteristics—tendency to catastrophize, ie, exaggerate threat to well-being, coupled
with less than optimal coping; selective attention (focus on physical problems and away from positive thoughts)
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| Interventions: patient education; relaxation therapy; cognitive behavioral therapy (CBT); coping skills; psychologic insight;
CBT—1) help patient recognize how beliefs about symptoms may perpetuate pain and negative activities; 2) introduce
relaxation and stress management techniques; 3) teach coping strategies; recent meta-analysis— odds ratio 12
(95% confidence interval) and number needed to treat 2 for improvement with CBT; sex—no convincing evidence for
significant differences between sexes in response to psychologic treatment for FGID (few studies; more men needed in
studies)
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| Referral to mental health professional: Rome criteria committee suggests referral if patient suicidal, pain refractory
to medical therapy, and QOL poor (eg, patient not working); speaker suggests referral early because studies show
patients with depressed mood or any axis I diagnosis less likely to respond to CBT
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| TRADITIONAL MEDICAL TREATMENT —William D. Chey, MD, Associate Professor of Medicine, University of
Michigan Medical School, Ann Arbor
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| Assessment: medical history; personality; supportive family structure; QOL and level of daily functioning; psychosocial
history; appropriate diagnostic tests (not routine diagnostic testing on every patient); confidence about diagnosis; institution
of appropriate therapy; severity—patients with mild symptoms often do not want anything more than reassurance
that they do not have cancer or other major disease; patients with moderate symptoms, by definition, have some impairment
in QOL and seek relief from more severe and frequent symptoms; patients with severe symptoms often have psychosocial
comorbidity or other non-GI comorbid conditions that drive health care-seeking and influence symptom
expression; patients have severe impairment in QOL and have difficulty with social and professional functioning
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| Treatment: mild symptoms—reassure patient and make sure he or she confident about what symptoms represent; discuss
potentially beneficial dietary and lifestyle measures; moderate symptoms—require follow-up; management of
stress; pharmacotherapy in selected cases; severe symptoms—often require medical therapy; consider behavioral therapy
when comorbid psychologic distress present; improved functioning, not cure, goal of therapy in all patients
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| Diet: no standardized diet for patients with FGID; certain foods known to trigger symptoms; food diary potentially helpful;
reasonable to recommend fiber for patients with constipation; dedicated time to eat and pass stool; study—patients with
IBS randomized to either strict elimination diet based on abnormal IgG levels to specific foods or sham elimination diet;
study showed that people able to adhere to strict elimination diet highly likely to get improvement in IBS symptoms
(many not able to adhere to this diet); celiac markers—prospective study evaluating utility of celiac markers in patients
who fulfill criteria for IBS showed 8.8% of patients with IBS have celiac antibodies vs 2.9% of controls, with no difference
in likelihood of biopsy-proven celiac disease; mismatch in likelihood of celiac antibodies (specifically antigliadin
antibodies); message that although biopsy-proven sprue potentially not different between populations, potential exists for
differences between these populations with regard to immunologic responses to different substances in foods
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| General measures: carefully review prescription and over-the-counter medications; exercise—no good evidence base
that exercise improves GI symptoms; exercise clearly good for other reasons (speaker recommends)
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| Pharmacologic therapies: fiber and bulking agents most commonly recommended agents; fiber—meta-analysis
shows fiber may improve orocecal and colonic transit; all trials had methodologic flaws; fiber shown to improve stool
consistency; 5 of 13 trials showed improvements in global IBS symptoms; data did not support efficacy in abdominal
pain or diarrhea; in some studies, bran was found to worsen problems with bloating or abdominal pain;
antispasmodics—most commonly prescribed medication in North America for patients with IBS; meta-analysis (trials
included had methodologic flaws) found several agents improved global IBS symptoms and/or abdominal pain, but when
studies stratified on basis of quality assessments, only otilonium bromide effective (odds ratio 1.9); no convincing evidence
that dicyclomine or hyoscyamine effective; antidiarrheals—loperamide commonly recommended (only agent
systematically evaluated in patients with IBS); 3 randomized trials (low to intermediate quality) showed decreased stool
frequency and improvements in stool consistency, but no improvement in abdominal pain or global IBS symptoms; side
effects—no robust data set on likelihood of side effects; data published as part of larger study show side effects reported
(1 in 7 for laxatives; 1 in 10 for antidiarrheals; 1 in 20 for antispasmodics; 1 in 4 for antidepressants; 1 in 10 for anxiolytics
or muscle relaxants); same study assessed how well patients felt they were doing and found ≈50% of patients felt they
were achieving satisfactory relief with usual medical care for IBS (proportion smaller if criterion >50% symptom reduction)
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| Neurotransmitters: some play role in motor function and sensation within GI tract; most of focus on serotonin, with
pharmaceutical development focused on 5-HT3 and 5-HT4 receptors
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| Tegaserod: 5-HT4 receptor agonist; augments peristalsis; accelerates gastric emptying, orocecal transit, and colonic transit;
potential effects on visceral perception and pain; some effects (animal models) on chloride and water secretion;
indications—women with IBS-C; men and women <65 yr of age with chronic idiopathic constipation; studies—trial
showed tegaserod more effective than placebo; post-hoc analysis showed patients with more severe baseline symptom
severity got greater benefit from tegaserod than individuals with less severe baseline symptoms; patients with IBS and
mixed bowel pattern—statistically significant benefits from tegaserod in both groups (IBS-C or IBS with mixed
bowel pattern) vs placebo; safety—diarrhea most commonly reported side effect; precaution on label for ischemic
colitis (data from post-marketing surveillance shows event rate comparable to that of general population); no clinically
relevant drug–drug interactions; pregnancy category B; withdrawal from US market (March 2007)—related to imbalance
in incidence of cardiovascular events and cerebrovascular accidents between individuals randomized to tegaserod
vs placebo in clinical trials (incidence 0.11% in tegaserod group vs 0.01% in placebo); patients with events had at
least one risk factor for coronary artery disease
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| Alosetron: 5-HT3 receptor antagonist; increases colonic compliance; decreases perception of visceral discomfort and
pain; decreases chloride and water secretion; slows colonic transit; available as part of restricted access program in
United States; indication—women with severe IBS-D with chronic (>6 mo) symptoms not responding to traditional
medical therapy; safety—ischemic colitis (increased rate with alosetron); constipation; no clinically relevant drug–
drug interactions; pregnancy category B
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Suggested Reading
Andresen V, Camilleri M: Irritable bowel syndrome: recent and novel therapeutic approaches. Drugs 66:1073, 2006;
Bach DR et al: Emotional stress reactivity in irritable bowel syndrome. Eur J Gastroenterol Hepatol 18:629, 2006;
Bengtson MB et al: Irritable bowel syndrome in twins: genes and environment. Gut 55:1754, 2006; Blanchard EB
et al: A controlled evaluation of group cognitive therapy in the treatment of irritable bowel syndrome. Behav Res Ther
45:633, 2007; Bray BD et al: Symptom interpretation and quality of life in patients with irritable bowel syndrome. Br J
Gen Pract 56:122, 2006; Cohen H et al: Post-traumatic stress disorder and other co-morbidities in a sample population
of patients with irritable bowel syndrome. Eur J Intern Med 17:567, 2006; Dellon ES, Ringel Y: Treatment of Functional
Diarrhea. Curr Treat Options of Gastroenterol 9:331, 2006; Dinan TG et al: Hypothalamic-pituitary-gut axis
dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology 130:304, 2006;
Eriksson EM et al: Body awareness therapy: a new strategy for relief of symptoms in irritable bowel syndrome patients.
World J Gastroenterol 13:3206, 2007; Hirata T et al: Pharmacological profile of ramosetron, a novel therapeutic
agent for IBS. Inflammopharmacology 15:5, 2007; Jones MP et al: Coping strategies and interpersonal support in patients
with irritable bowel syndrome and inflammatory bowel disease. Clin Gastroenterol Hepatol 4:474, 2006; Kolfenbach
L: Pathophysiology, diagnosis, and treatment of IBS. JAAPA 20:16, 2007; McLean PG et al: 5-HT in the enteric
nervous system: gut unction and neuropharmacology. Trends Neurosci 30:9, 2007; Pajala M et al: A prospective 1-year
follow-up study in patients with functional or organic dyspepsia: changes in gastrointestinal symptoms, mental distress and
fear of serious illness. Aliment Pharmacol Ther 24:1241, 2006; Park JM et al: Serotonin transporter gene polymorphism
and irritable bowel syndrome. Neurogastroenterol Motil 18:995, 2006; Spence MJ, Moss-Morris R: The cognitive
behavioural model of irritable bowel syndrome: a prospective investigation of patients with gastroenteritis. Gut
56:1066, 2007; Toner BB: Cognitive-behavioral treatment of irritable bowel syndrome. CNS Spectr 10:883, 2005.
Educational Objectives
| The goal of this program is to improve the management of functional gastrointestinal disorders (FGID), including irritable
bowel syndrome (IBS), by use of psychologic and behavioral treatments as well as traditional medical treatment. After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss the role of genetics and environment on the development of IBS.
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| 2. Explain the various genetic polymorphisms that have been studied and how they potentially affect the development
of IBS.
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| 3. Recognize the role of psychologic and behavioral therapy in the treatment of FGID.
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| 4. Discuss the assessment of a patient with FGID.
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| 5. Describe the role of diet and medical treatment in IBS.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this program, the following has been disclosed: Dr. Chang is a consultant for GlaxoSmithKline, Pharmos, Microbia,
Allergan, Prometheus, Takeda, and Forest and has done research for GlaxoSmithKline. Dr. Chey is on the Speakers’
Bureau for Novartis, Salix, and Takeda, and is a consultant for Novartis, Microbia, Pharmos, Procter and Gamble, Salix, and
Takeda.
Acknowledgements
Drs. Chang, Olden, and Chey were recorded at Functional GI Disorders, held April 15, 2007, in Milwaukee, WI, and
sponsored by the University of Wisconsin School of Medicine and Public Health, Office of Continuing Professional
Development and International Foundation for Functional Gastrointestinal Disorders, in cooperation with Functional
Brain–Gut Research Group. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation
in the production of this program.
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