GASTROENTEROLOGY FOR THE INTERNIST
From the University of California, San Francisco, School of Medicine’s 34th Annual Advances in Internal Medicine
| UPDATE ON IRRITABLE BOWEL DISEASE—Richard A. Weisiger, MD, PhD, Professor of Medicine and Chief of
Gastroenterology Faculty Practice, University of California, San Francisco, School of Medicine
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| Irritable bowel syndrome (IBS): definition—group of functional disorders in which abdominal pain or discomfort
associated with altered defecation or change in bowel habit; prevalence—several North American surveys suggest 15%
to 20% incidence in adults at any given time; ≈30% of adults will have it at one point in lifetime; second most common
reason for missing work; seen more often in women than men (although good data suggest equal frequency, men less
likely to seek medical care); most do not seek medical care; accounts for $2 billion in expenses
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| IBS in clinical care: most physicians do not look forward to dealing with patients with IBS; physician and patient frequently
find office visit unsatisfactory; expectations of patient from clinician—to diagnose problem and to provide
treatment; to perform further testing to find treatable diagnosis; reality—no tests that work for IBS in clinical setting;
most drugs used shown ineffective in clinical trials; result—patient frustrated because expectations not met; clinician
frustrated because he or she unlikely to meet patient’s expectations; leads to poor medical care (overdiagnosis of other
conditions, eg, diverticulitis, endometriosis, adhesions; danger of patient getting unnecessary surgery; overuse of medications);
typical IBS patient—has frequently seen other physicians and been told nothing wrong; regardless of cause, patient
needs help dealing with symptoms; patient worried about repeated testing; concerns of clinicians—yet another
IBS patient that he or she cannot help; unable to answer questions patient will ask; what has been done before and what
might have been missed; possibility that patient has significant disease; whether tests should be repeated; diagnosis likely
IBS, and no effective treatment to offer; end up with another unhappy patient who will keep calling for help
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| Diagnosis of IBS: old approach—diagnosis of exclusion; extensive work-up before diagnosis costly; reinforces patient’s
belief in undiagnosed problem; new approach—make positive diagnosis as soon as possible; diagnosis typically
based on presence of appropriate symptoms, often with compatible stress history, normal physical examination, and absence
of alarm signs (weight loss, unexplained anemia, markers of inflammation or infection, bleeding, fever, or frequent
nocturnal symptoms); patients who present after 40 yr of age likely do not have IBS (presents typically in teens and 20s);
good social history helps with diagnosis and treatment
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| Non-gastrointestinal (GI) diseases associated with IBS: fibromyalgia; chronic fatigue syndrome; “spastic bladder”;
frequent headaches; anxiety; panic disorder; depression
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| Common problems that present like IBS: carbohydrate malabsorption—presents with gas, bloating, pain, and
diarrhea; occurs with inability to digest lactose, sorbitol, or excessive soft drink intake (contain fructose); sugars ferment in
lower bowel, producing gas, bloating, and pain; hydrogen breath test for diagnosis; celiac sprue—usually thought of as
severe wasting disease, but can present in milder form; argued that every patient with diarrhea should have serologic test
(tissue transglutaminase [tTG] test more specific form of antiendomysial antibody test); giardiasis—if patient exposed to
water from, eg, mountain stream; thyroid dysfunction—causes constipation, diarrhea, and inflammatory bowel disease
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| Management of IBS: necessary to make connection with patient; thorough physical examination important; full assessment
of psychologic and social factors; speaker always includes open-ended questions (eg, “what’s your life like right
now?”); once red flags excluded, make positive diagnosis early on; reassure patient that IBD does not shorten life or require
surgery, and that disease incurable but relapsing; with correct background, patient more willing to accept diagnosis;
nondrug options—stress reduction (exercise), healthy diet (look for food triggers), and counseling (including therapy)
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| Drugs for IBS: several, but none works particularly well; symptomatic treatment of diarrhea and constipation—first
exclude infectious and hormonal causes; fiber effective for diarrhea and constipation; many forms of fiber fermented by
gut bacteria and produce gas; antispasmodics—eg, dicyclomine, hyoscyamine; widely used but none shown effective in
double-blind trials; sedatives—make patient feel better, particularly those with anxiety component, but not effective
long-term solution; should treat depression; tricyclic antidepressants (TCAs)—have role, even if patient not clinically
depressed; antinociceptive mechanism not well understood; in meta-analysis of TCAs, odds ratio for improvement of abdominal
pain 4.2; limited studies for newer drugs; selective serotonin reuptake inhibitors (SSRIs)—weak data; high
rate of side effects (eg, constipation, dry eyes, dry mouth), but effective for IBS at much lower doses than used for depression;
speaker often starts patients on 10 mg of nortriptyline or amitriptyline at bedtime and increases by 10 to 15 mg every
2 mo; newer approaches—probiotics; Lactobacillus species shown to reduce bloating by improving digestion of lactose;
Bifidobacterium seems effective for pain; melatonin—over-the-counter hormone; safe; improves symptoms of
IBS, possibly by promoting better sleep; school of thought suggests bacterial overgrowth in bowel due to motility problems
possible cause for bloating and pain in IBS (broad-spectrum antibiotic possibly effective)
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| Tegaserod (Zelnorm): initially approved for short-term treatment in women with constipation-predominant IBS; also
approved for chronic idiopathic constipation; moderately expensive and quite effective; promotility agent; may work for
nausea and gastroparesis, but not yet clinically approved; clinical trials show that it helps with constipation; dosage 2 to 6
mg bid before meals; increases serotonin in gut; side effects include diarrhea
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| Alosetron (Lotronex): previously withdrawn, but now available on limited prescribing protocol; indicated for women
with severe diarrhea-predominant IBS; blocks action of serotonin in gut (5-hydroxytryptamine 3 [5-HT3 ] antagonist);
when initially released, not emphasized to physicians that drug should not be used for patients with constipation (led to
inappropriate use, causing patients to require surgery for ischemic colon; presently, only prescribed after patient signs
consent to stop drug if he or she has constipation; special sticker required on prescription)
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| Pathophysiology: IBS may have multiple causes and may not be single disease; early proposed mechanisms involve
motility (“spastic colon”), colonic inflammation (“spastic colitis”), excess secretion of mucus or electrolytes (“mucus
colitis”), or psychosomatic causes; at level of brain, persistent stress response causes release of stress hormones that bring
about altered brain processing; recent data suggest increased inflammation in gut, and that histamine increasing sensitivity
of nerves in gut to pain; also, decreased inhibition of pain at level of spinal cord may result in visceral hypersensitivity;
excess gas in gut due to bacterial overgrowth may cause pain; IBS mechanisms—more common in patients with
anxiety and depression; altered pain sensation, particularly increased sensitivity to abdominal pain (visceral hypersensitivity;
also may underlie fibromyalgia and spastic bladder) and decreased responsiveness to somatic pain; overlap with
other functional syndromes; symptoms correlate with recent life stress (if severe stressor present, patient unlikely to improve
unless stressor removed); intestinal motility changes (eg, constipation, diarrhea) and increased mucosal secretion;
often follows childhood abuse or neglect
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| Inflammation and IBS: postinfectious IBS—follows infection with enteric pathogen (most commonly Campylobacter
); follows 7% to 30% of bacterial dysentery cases (infection resolves but symptoms persist); accounts for up to 25%
of all IBS cases; indistinguishable from other forms of IBS; low level of inflammation present in IBS; biopsy of colon
shows increased cell counts, despite normal endoscopic findings; histamine known to cause motility problems (eg,
spasms); possible causes—failure to downregulate inflammatory response, food allergies, changes in bacterial flora, and
direct response to stress; stimulation of autonomic nervous system can produce inflammation in gut; inflammation potentially
causes patient to have increased gut sensitivity to pain; mast cells that release histamine and other factors close to enteric
nerves may degranulate when under stress, causing visceral hyperalgesia
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| Stress: normal response to danger; when under stress, brain releases stress hormones (eg, corticotropin-releasing factor
[CRF]); stress response not designed to deal with present-day stress, so not inconceivable that disease process side effect of
inappropriately activated stress pathway; CRF, in animal studies, causes decrease in small intestinal transit (gas and bloating),
increase in defecation (diarrhea) and stool water, and decrease in gastric emptying (nausea and vomiting); several
mechanisms in stress response found at lower brain levels; cingulate gyrus important for processing pain and danger; left
side of brain (thinking area) feels pain; in IBS patients—more diffuse activation in brain; in cingulate gyrus area, right side
of brain (involved in emotional thinking) activated; hypothesis that pain triggers painful memories; emotional component
makes treatment difficult; studies show that if patient feeling better about life, gut reverts to normal pattern; speaker thinks
IBS fairly normal condition brought about by abnormal environment
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| Summary: IBS is syndrome, not disease; may be related to stress hormones that cause secondary changes, including motor
abnormalities, mast cell degranulation, inflammation, and abnormal brain and spinal cord processing of pain; drugs in development
that block central stress pathways; whether IBS normal response to stress not proven; stress responses evolved in
humans and other animals to enhance survival in ancestral environment; responses may not be appropriate in modern society
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| A PRACTICAL GUIDE TO MANAGING GERD—John Inadomi, MD, Dean M. Craig Endowed Chair in Gastrointestinal
Medicine, Director, GI Outcomes and Health Services Research, University of California, San Francisco, and Chief,
Clinical Gastroenterology, San Francisco General Hospital
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| Two types of reflux disease: erosive esophagitis—diagnosed by endoscopy or radiographic studies; nonerosive
esophagitis—symptomatic reflux or nonerosive reflux disease
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| Clinical presentation of gastroesophageal reflux disease (GERD): atypical manifestations—in ear, nose,
and throat, include chronic cough, hoarseness, laryngitis, sinusitis, and, possibly, vocal cord cancer; pulmonary manifestations
include asthma, bronchitis, and idiopathic fibrosis; also dental erosion, halitosis, and noncardiac chest pain (most
common extraesophageal manifestation)
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| Los Angeles classification system for esophagitis: grade A (minor) to grade D (severe); endoscopically, evidence
of erosions; grade D has erosions involving >75% of circumference of esophagus; symptoms do not predict what is happening
in esophagus; only about one-third of people with reflux symptoms have erosions; regardless of whether erosions
present, distribution of symptom severity similar (disconnect between endoscopic findings and symptoms)
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| Treatment goals: resolution of symptoms and healing of erosive esophagitis; achieved through reduction of gastric acid
secretion; primary problem with reflux not hyperacidity, but motility problem involving lower esophageal sphincter
(LES); transient relaxation of LES induces reflux in most pathologic cases, yet most drugs do not act on it; several promotility
drugs available, but all have side effects; proton pump inhibitors (PPIs)—mainstay of therapy in healing
esophagitis; even without medication, ≈28% of patients with esophagitis heal in 12 wk; with histamine2- receptor antagonists
(H2 RAs), ≈50% of patients heal at 12 wk (84% with PPIs); most patients on PPIs do not experience complete resolution
and need additional therapy (eg, antacids)
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| When empiric therapy appropriate: classic reflux symptoms (eg, heartburn, regurgitation) have positive predictive
value of >80% for GERD; American College of Gastroenterology guidelines—state that if history typical of uncomplicated
GERD, empiric trial of therapy appropriate in absence of warning signs; argument for empiric therapy—
regardless of endoscopic findings, most patients with typical symptoms treated with PPI; endoscopy reserved for patients
with warning signs and symptoms refractory to empiric therapy, and for screening for Barrett’s esophagus (patient >50 yr
of age with longstanding heartburn); warning signs—include dysphagia, odynophagia, persistent vomiting, anorexia,
unintentional weight loss, anemia, fever, and GI bleeding (occult or overt); look for upper GI malignancies or complications
of reflux disease; on-demand therapy—take dose when symptoms occur and stop when symptoms abate; symptomatic
attacks of reflux self-limited and further shortened by starting treatment early; symptomatic reflux not
progressive disorder, but spectrum; easy and user-friendly; gives patient empowerment over disease; focuses on symptom
control; most cost-effective regimen for mild to moderate uncomplicated GERD; study—on-demand esomeprazole
therapy in symptomatic reflux; 36% of participants discontinued therapy because of symptom recurrence (primary outcome);
>90% of patients satisfied with taking medication on demand
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| Nocturnal GERD: majority of patients with chronic GERD suffer from nocturnal symptoms; difficult to treat; majority
of patients with nocturnal GERD require long-term or lifelong continuous therapy with PPI; study—combined therapy
of PPIs with H2 blockers; without therapy, should have 100% of patients with abnormal esophageal acid exposure; when
put on omeprazole 20 mg bid, ≈40% have abnormal acid exposure; if nighttime dose of ranitidine (300 mg) added, nighttime
acid exposure almost eliminated in all participants; however, tachyphylaxis noted and, after 1 mo, 30% of patients had
abnormal acid exposure
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| Nonmedical therapy: surgery—consists of open or laparoscopic fundoplication and some endoscopic therapies (Stretta
and EndoCinch); most follow-up from open fundoplication (few studies show long-term follow-up for laparoscopic procedure);
long-term follow-up ≤10 yr; after 4 to 5 yr, ≈50% of patients back on antisecretory drugs; poor response to medical
therapy is predictor of poor outcome; Stretta procedure—radiofrequency energy delivered to gastroesophageal (GE)
junction; decreases compliance of esophagus in area of GE junction and decreases transient LES relaxation; study—
randomized controlled trial (Stretta vs sham endoscopic procedure); blinded to patient and observer; participants with
chronic heartburn and acid regurgitation with evidence of pathologic esophageal acid exposure by pH study; after 1 yr,
Stretta procedure improved symptoms and quality of life, and decreased esophageal acid exposures; however, PPIs still required
for symptom relief in ≈30% of patients; complication rate ≈8.6% (eg, fever, mucosal injury, chest pain, dysphagia)
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Suggested Reading
American College of Gastroenterology Functional Gastrointestinal Disorders Task Force: Evidence-based position
statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol 97:S1, 2002; Cappell
MS: Clinical presentation, diagnosis, and management of gastroesophageal reflux disease. Med Clin North Am
89:243, 2005; Chandra A et al: A review of the atypical manifestations of gastroesophageal reflux disease. Int J
Clin Pract 58:41, 2004; Corazziari E et al: Clinical trial guidelines for pharmacological treatment of irritable
bowel syndrome. Aliment Pharmacol Ther 18:569, 2003; Der G: An overview of proton pump inhibitors. Gastroenterol
Nurs 26:182, 2003; Drossman DA et al: Alterations of brain activity associated with resolution of emotional
distress and pain in a case of severe irritable bowel syndrome. Gastroenterology 124:754, 2003; Fass R: Epidemiology
and pathophysiology of symptomatic gastroesophageal reflux disease. Am J Gastroenterol 98:S2, 2003; Greenwood-Van
Meerveld B et al: Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic
hypersensitivity in rats. Neurogastroenterol Motil 17:415, 2005; Guimaraes EV et al: Treatment of gastroesophageal
reflux disease. J Pediatr (Rio J) 82:S133, 2006; Mertz HR: Irritable bowel syndrome. N Engl J Med
349:2136, 2003; O'Mahony L et al: Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses
and relationship to cytokine profiles. Gastroenterology 128:541, 2005; Palsson OS et al: Psychiatric and
psychological dysfunction in irritable bowel syndrome and the role of psychological treatments. Gastroenterol Clin
North Am 34:281, 2005; Palsson OS: Should we incorporate psychological care into the management of IBS? Nat
Clin Pract Gastroenterol Hepatol 3:474, 2006; Schoenfeld P: Efficacy of current drug therapies in irritable bowel
syndrome: what works and does not work. Gastroenterol Clin North Am 34:319, 2005; Shaker R: Nighttime
GERD: clinical implications and therapeutic challenges. Best Pract Res Clin Gastroenterol 18 Suppl:31, 2004; Soll
AH et al: Gastroesophageal reflux disease: presentation and assessment of a common, challenging disorder. Clin
Cornerstone 5:2, 2003; Spiller R: Probiotics: an ideal anti-inflammatory treatment for IBS? Gastroenterology
128:783, 2005; Talley NJ et al: Irritable bowel syndrome: a little understood organic bowel disease? Lancet
360:555, 2002; Whitehead WE et al: Utility of red flag symptom exclusions in the diagnosis of irritable bowel
syndrome. Aliment Pharmacol Ther 24:137, 2006
Educational Objectives
| The goal of this program is to improve the management of irritable bowel syndrome (IBS) and gastroesophageal reflux
disease (GERD). After hearing and assimilating this program, the clinician will be better able to:
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 | Diagnose IBS based on history and symptoms and distinguish it from other diseases with similar presentation.
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| Prescribe appropriate drugs for IBS.
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| Recognize the impact of stress on the development of IBS.
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| Recognize when empiric therapy is appropriate for the treatment of GERD.
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| Diagnose and manage nocturnal GERD.
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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. Inadomi is a consultant
for AstraZeneca, Novartis, and Given Imaging, is on the Speakers’ Bureau of Wyeth, and has received grant
support from BÂRRX.
Acknowledgements
Drs. Weisiger and Inadomi were recorded at the 34th Annual Advances in Internal Medicine, held June 19-23, 2006,
in San Francisco, CA, and sponsored by the University of California, San Francisco, School of Medicine. The Audio-
Digest Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.
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