FUNCTIONAL GI DISORDERS
From Diagnosis and Management of Functional GI Disorders: From Child to Adult, sponsored by the David Geffen
School of Medicine at the University of California, Los Angeles, and the Center for Neurovisceral Sciences and
Women’s Health
| GENETIC FACTORS IN IRRITABLE BOWEL SYNDROME (IBS)—Anthony Lembo, MD, Assistant Professor of Medicine,
Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA
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| Genetic contribution to IBS: prevalence—varies throughout world; however, in United States, prevalence similar in
whites, blacks, and Hispanics; prevalence higher in women; prevalence similar in all age groups, regardless of environmental
differences (supports genetic role); familial clustering—study of 100 patients with IBS found 33% had family
history of IBS, compared to 2% of controls; another study found presence of IBS in first-degree relative 1 of 5 parameters
that distinguished IBS from organic disease; familial aggregation—Mayo Clinic study of Olmstead County, MN, residents
30 to 64 yr of age; used bowel disease questionnaire (BDQ) to assess gastrointestinal (GI) symptoms and abdominal
pain or bowel disturbance in spouse and first-degree relatives; significant increased risk for IBS or dyspepsia in first-
degree relatives but not in spouses with GI symptoms; in families—study looked at 181 IBS patients; spouses and relatives
given BDQ and interviewed; prevalence of IBS 17% in patients’ relatives, compared to 7% in relatives of spouses;
twin studies—concordance rate reflects genes and shared environment; study looked at 686 twins from Australian twins
registry; 33 (4.8%) diagnosed with functional bowel disease (FBD) by primary care provider; concordance rate 33% in
monozygotic twins and 13.3% in dizygotic twins; development of IBS partly genetically driven; Virginia twins registry
study surveyed patients for diagnosis of IBS; prevalence of IBS 2.6%; similar concordance rate to previous study;
monozygotic twins had significantly greater likelihood of IBS than dizygotic twins; maternal IBS strong predictor of disease;
Lembo looked at twins from Minnesota Twins Registry; prevalence of IBS symptoms ≈14%; greater concordance
rate in monozygotic than dizygotic twins; multivariate analysis showed anxiety weak predictor for concordance; genetic
factors strongest predictor of IBS; study of twins from United Kingdom (UK) twin registry found similar concordance
rate between monozygotic and dizygotic twins
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| Candidate genes: gene polymorphisms—gene considered polymorphic when variants exist that can alter activity of protein;
associated with number of complex diseases, eg, asthma, hypertension
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 | Serotonergic inactivation: reuptake via transporter proteins (serotonergic reuptake transport [SERT] proteins) important
in IBS; inactivation of SERT gene in animal model produces alterations in bowel function; study using biopsies from
patients with IBS, compared to patients with inflammatory bowel disease (IBD) and normal controls, found patients
with IBS had significantly lower amount of SERT protein than normal subjects; polymorphisms—insertion referred
to as long gene (L) and deletion as short gene (s); greater biologic activity associated with L/L than L/s or s/s; studies
looked at prevalence of SERT polymorphism and concluded SERT polymorphism not cause of IBS; however, polymorphisms
may contribute to IBS subtypes, eg, diarrhea-predominant IBS (IBS-D)
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| 5-HT2A receptor gene: important in psychiatric disorders, eg, depression, schizophrenia, obsessive-compulsive disorder (OCD);
study looked at number of different genes in 54 IBS patients and in 102 controls and found increased odds ratio for 1 of 2
polymorphisms of 5-HT2A in IBS; another study showed no correlation
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| α2 -adrenergic receptor gene: important in GI function; study looked at clonidine (0.1 mg) in patients with IBS and found
symptoms improved, but clonidine associated with side effects; study looked at 276 IBS patients and 120 controls; found no
association between polymorphisms and development of IBS; however, deletion of α2A receptor and α2C receptor associated
with constipation-predominant IBS (IBS-C) subtype; α2C receptor associated with high somatic symptom score
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| Inflammation and IBS: ratio between tumor necrosis factor alpha (TNF-α proinflammatory cytokine) and interleukin-10
(IL-10; anti-inflammatory cytokine) important; study found high producers of IL-10 genotype (G/G polymorphism) less prevalent
in IBS population; high producers of TNF-α polymorphism and low producers of IL-10 genotype more prevalent in IBS
and in IBS-D, compared to other IBS subtypes; no association between postinfectious IBS and these polymorphisms
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| Pharmacogenetic studies: study gave 30 patients with IBS-D alosetron 1 mg bid for 6 wk; measured colonic transit using
scintigraphy at baseline and at 6 wk; assessed SERT polymorphism in 23 patients; significant difference between L/s
and L/L in response to alosetron; L/L polymorphism makes more SERT protein and less serotonin, and alosetron has
greater efficacy in slowing colonic transit; effect on GI transit dependent on presence of L/L or L/s polymorphisms
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| TRADITIONAL AND NOVEL TREATMENT OF IBS IN ADULTS —Lin Chang, MD, Associate Professor of Medicine,
David Geffen School of Medicine at the University of California, Los Angeles
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| Practical approach to traditional treatment: fiber supplementation—bulking agents not more effective than placebo
at relieving global IBS symptoms; useful for symptoms of mild constipation; start with low dose if patient not used
to high-fiber diet; recommend high-fiber diet; antispasmodic agents—insufficient data on global relief of symptoms;
helpful in reducing postprandial abdominal pain, but not effective for chronic pain; loperamide—antidiarrheal agent;
not more effective than placebo in relieving global symptoms of IBS; useful in relieving diarrhea, but not pain; recommend
proactive use; use liquid loperamide in patients with IBS with alternating diarrhea and constipation (IBS-A); behavioral
therapy—more effective than placebo at relieving individual IBS symptoms; recommend in interested and
motivated patients; single therapy in patients with more mild symptoms; adjuvant therapy in patients with moderate to severe
symptoms; match therapist to patient
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| Emerging therapies for IBS: clonidine—study used 0.05 mg or 0.1 mg, compared to placebo; patients with severe symptoms
had greater response to 0.1 mg of clonidine, compared to lower dose and placebo arms; difference seen in composite
stool score; consider in patients with IBS-D; may have analgesic properties; small intestinal bacterial overgrowth—study
found bacterial overgrowth in 80% of patients; placebo-controlled trial found patients taking neomycin had better chance of
symptom improvement than those on placebo; placebo-controlled trial of rifaximin (broad-spectrum nonabsorbable antibiotic)
found low response rates, but significantly higher response rate with rifaximin than with placebo; patients with IBS-D more
likely to respond; consider testing for bacterial overgrowth in patients who experience bloating; elimination diet—50% to
60% response rate in studies; randomized controlled trial measured IgG antibodies to food and used elimination diet; 10% reduction
in IBS symptoms in group getting elimination diet; response depended on level of adherence (60% of patients could
not adhere to diet); Chinese herbal therapy—placebo-controlled studies show herbal therapy more effective than placebo;
study found more prolonged posttreatment effect with individualized herbal preparation, compared to patients getting standard
preparation or placebo; need knowledge of mechanism of action, long-term study data, and potential drug interactions;
acupuncture—study measuring rectal sensation in IBS patients found no effect, compared to placebo; pilot study found transcutaneous
electrical acustimulation decreased rectal perception; another study found no difference in disease-specific quality
of life with acupuncture or sham acupuncture; probiotics—study found VSL#3 slowed colonic transit and improved flatulence;
consider use in patient with bloating and flatulence; study found patients taking probiotic mix had reduction in symptom
scores and decreased borborygmi; placebo-controlled trial found Bifidobacterium infantis significantly decreased IBS
symptom scores, compared to Lactobacillus salivarius and placebo; study found greater ratio of IL-12 to IL-10 in IBS patients,
compared to healthy volunteers; ratio normalized in patients who had symptom response to B infantis
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| Novel therapies for IBS: serotonin receptor agents—altered serotonin signaling may play role in IBS; serotonin involved
in GI secretions, motility, and sensation; altered serotonin signaling alters GI physiology and may result in clinical
symptoms of IBS; 5-hydroxytryptamine-3 (5-HT3 ) antagonists alosetron and cilansetron (not FDA-approved)
effective in patients with IBS-D; 5-hydroxytryptamine-4 (5-HT4 ) agonist tegaserod effective in patients with IBS-C;
tegaserod—more efficacious than placebo in relieving global IBS symptoms in women with IBS-C; stimulates 5-HT4
receptors and peristalsis, induces chloride secretion, draws water into lumen, aids stool formation, and may modulate visceral
sensitivity; new data show that intermittent retreatment with tegaserod relieves overall IBS-C symptoms and abdominal
pain and discomfort; Food and Drug Administration (FDA) approved for chronic constipation (without
predominant pain) in women and men <65 yr of age; alosetron—more efficacious than placebo in relieving global IBS
symptoms in women with IBS-D; central and peripheral mechanisms improve IBS symptoms; long-term efficacy trial
showed alosetron had significant effect over placebo for adequate relief of symptoms; study of alosetron in men with
IBS-D found alosetron effective in men, compared to placebo
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| Drugs in development for IBS-D: cilansetron—5-HT3 antagonist; dextofisopam (2,3 benzodiazepine)—achieved
overall relief of symptoms in IBS-D and IBS-A; improved stool consistency and frequency; corticotropin-releasing factor
(CRF) antagonist—nonselective CRF antagonist; study found it reduced increase in abdominal pain and anxiety
evoked by electrical stimulation of rectum but did not change pain threshold
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| Drugs in development for IBS-C: renzapride—combination 5-HT3 antagonist and 5-HT4 agonist; accelerates colonic
transit, improves stool consistency, and increases stool frequency, but no overall relief of abdominal pain and discomfort;
asimadoline—opioid agonist; reduced colonic perception of balloon distention; alvimopan and naltrexone—
opioid antagonists; effective in opioid-induced bowel dysfunction; lubiprostone—chloride channel activator; efficacious
for chronic constipation
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| Treatment guidelines for IBS: mild to moderate symptom severity—educate patient about diet, encourage lifestyle
changes, establish successful patient-physician relationship; consider single pharmacologic agent; consider more aggressive
treatment if patient experiences impaired functioning or quality of life; severe symptoms—require multidisciplinary
approach; consider combination of therapeutic agents; IBS-D—recommend loperamide (Imodium) as
prophylaxis, low dose tricyclic antidepressants (TCAs; eg, nortriptyline, amitriptyline); start with low dose and increase
to lowest most effective dose; consider clonidine; consider antibiotic therapy for small intestinal bacterial overgrowth;
use alosetron in women with severe IBS-D who fail conventional therapy; IBS-C—use fiber for mild cases; recommend
tegaserod 6 mg po bid; use osmotic laxative, eg, milk of magnesia, polyethylene glycol (PEG); consider herbal therapy; if
patient in significant pain, use laxative agent and add low-dose TCA (eg, desipramine); consider biofeedback for pelvic
floor dyssynergia; IBS-A—treatment depends on symptom characteristics; use constipation- and diarrhea-specific therapy
as needed; pain—use TCA, selective norepinephrine reuptake inhibitor (SNRI; eg, duloxetine); bloating—
prokinetic agent, probiotics, low-dose TCA, or antibiotic therapy for small bowel overgrowth; psychologic and stress-
related symptoms or poor coping—recommend SSRI, SNRI, psychologic or behavioral therapy
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| MANAGEMENT OF PEDIATRIC PAIN —Lonnie Zeltzer, MD, Professor of Pediatrics, Anesthesiology, Psychiatry, and
Biobehavioral Sciences; Director, Pediatric Pain Program, David Geffen School of Medicine at the University of California,
Los Angeles
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| Factors to consider: pain sensory perception—describes intensity and location of pain; affective aspects of pain—
bother, unpleasantness, and suffering part of pain localized to anterior cingulate cortex; patterns of brain activity that affect
pain sensory systems and pain affective systems seen on imaging; neuroenteric system—involved in functional abdominal
pain, GI system pain, pain associated with functional GI disorders; biopsychosocial model of pain—chronic
and functional abdominal pain both physical and psychologic and involves environment; pain perception—involves integration
and interpretation of sensory inputs that can be enhanced or dampened; influenced by emotions, beliefs, memories
of pain, genetics, and early life experiences; controllability of pain—perception of controllability important; child
needs to feel sense of mastery and control, even before sensory experience of pain changed; relevance or meaning of
pain—parent may believe child’s abdominal pain serious or potentially fatal; child may become anxious about pain, and
this may increase pain and suffering; coping ability—passive style (parent and child look to physician to cure pain) predictor
of continued pain and dysfunction; active style (child has pain but still functioning and more likely to engage in
coping strategies)
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| Clinical evaluation: get pain history; look for other physical symptoms (eg, headaches, fibromyalgia, or cluster of symptoms,
both somatic and visceral); assess physical, social, and academic or work and family functioning; assess emotional
and cognitive functioning; assess major life events; determine consequences of pain
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| Treatment modalities: education—explain reason for pain (dysregulation in neural signaling system);
pharmacologic—some children benefit from therapy with SSRI; ≈80% of children seen at pain clinic have anxiety disorder,
and ≈50% meet criteria for major depressive disorder; physical therapy—child may develop myofascial or musculoskeletal
pain because of posture assumed as result of pain; consider referring child to physical therapist; behavioral—set
up behavioral incentive plan to work through pain; psychologic—psychotherapy; family therapy; complementary/alternative
medicine—includes meditation, hypnotherapy, biofeedback, massage, and yoga
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Educational Objectives
| The goal of this activity is to provide the listener with an understanding of the genetics, traditional and novel therapies,
and pain management of functional gastrointestinal (GI) disorders. After hearing and assimilating this program,
the clinician will be better able to:
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| 1. Discuss the genetics of irritable bowel syndrome (IBS).
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| 2. Identify gene polymorphisms that are thought to play a role in IBS.
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| 3. Evaluate the efficacy of traditional therapies for IBS.
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| 4. Describe the emerging and novel therapies for IBS.
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| 5. Manage pain in a pediatric patient with a functional GI disorder.
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Discussed on This Program
Alosetron HCl [Lotronex]
Alvimopan (investigational)
Amitriptyline HCl [Elavil]
Asimadoline (investigational)
Cilansetron (investigational)
Clonidine HCl [Catapres, Duraclon]
Dextofisopam (investigational)
Duloxetine [Cymbalta]
Loperamide HCl [several trade names]
Lubiprostone [Amitiza]
Naltrexone HCl [ReVia]
Neomycin sulfate [Mycifradin, Neo-fradin, Neo-Tabs]
Nortriptyline HCl [Aventyl HCl, Aventyl HCl Pulvules, Pamelor]
Polyethylene glycol-electrolyte solution (PEG-ES) [CoLyte, GoLYTELY, NuLytely, OCL]
Renzapride (investigational)
Rifaximin [Normix, Xifaxan]
Tegaserod maleate [Zelnorm]
Suggested Reading
Ahn J et al: Emerging treatments for irritable bowel syndrome. Expert Opin Pharmacother. 3:9, 2002; Camilleri
M: Mechanisms in IBS: something old, something new, something borrowed... Neurogastroenterol Motil. 17:311,
2005; Crowell MD et al: New insights into the pathophysiology of irritable bowel syndrome: implications for future
treatments. Curr Gastroenterol Rep. 7:272, 2005; Hyman PE et al: Visceral pain-associated disability syndrome: a
descriptive analysis. J Pediatr Gastroenterol Nutr. 35:663, 2002; Mawe GM et al: Review article: intestinal serotonin
signaling in irritable bowel syndrome. Aliment Pharmacol Ther. 23:1067, 2006; Mohammed I et al: Genetic influences
in irritable bowel syndrome: a twin study. Am J Gastroenterol. 100:1340, 2005; Park MI et al: Genetics
and genotypes in irritable bowel syndrome: implications for diagnosis and treatment. Gastroenterol Clin North Am.
34:305, 2005; Sach JA et al: Irritable Bowel Syndrome. Curr Treat Options Gastroenterol. 5:267, 2002; Saito YA
et al: The genetics of irritable bowel syndrome. Clin Gastroenterol Hepatol. 3:1057, 2005; Tan S et al: Traditional
Chinese medicine based subgrouping of irritable bowel syndrome patients. Am J Chin Med. 33:365, 2005; van der
Veek PP et al: Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome.
Am J Gastroenterol. 100:2510, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the following has been disclosed: Dr. Lembo is a consultant for Novartis Pharmaceuticals and Takeda, Inc. Dr. Chang
is a consultant for Novartis Pharmaceuticals, GlaxoSmithKline, Vela Pharmaceuticals, and Solvay Pharmaceuticals.
Drs. Chang, Lembo, and Zeltzer were recorded January 21, 2006, in Los Angeles, CA, at Diagnosis and Management of
Functional GI Disorders: from Child to Adult, sponsored by the David Geffen School of Medicine at the University of
California, Los Angeles. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the production
of this program.
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