The GI Summit - onlne CME activity

Cosponsored by This activity is supported by an educational grant from

Sucampo Pharmaceuticals, Inc. and Takeda Pharmaceuticals North America, Inc.

Release Date: December 1, 2009 Expiration Date: December 1, 2010

Estimated time to complete: 3.0 hours

FacultyWilliam D. Chey, MD, AGAF, FACG, FACPProfessor of Internal MedicineUniversity of Michigan Health SystemAnn Arbor, MI

Prateek Sharma, MDProfessor of MedicineUniversity of Kansas School of MedicineKansas City, KS

* There is no fee to participate in this activity.

A C O N T I N U I N G M E D I C A L E D U C A T I O N M O N O G R A P H

9002G_Monograph.indd 1 11/12/09 4:19:43 PM

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IntroductionGastroenterologists and other gastrointestinal health care providers must understand the clinical implications of diagnostic innovations and new treatment agents for managing lower and upper gastrointestinal disorders so that they offer the best possible care for their patients. A host of breakthroughs and advances have been introduced in recent international meetings, which serve as forums for academicians, clinicians, researchers, trainees, and other gastrointestinal health professionals to share their discoveries with colleagues. The data presented at these meetings represent the collective knowledge of the world’s thought leaders on the best ways to manage gastrointestinal disorders, such as irritable bowel syndrome (IBS), chronic constipation, gastroesophageal reflux disease (GERD), and Barrett’s esophagus. This monograph recaps this cutting-edge information, and interprets how these data will affect clinicians’ ability to provide optimal care for patients with these syndromes.

Target AudienceThis program is designed for physicians, physician assistants, nurse practitioners, and pharmacists.

Method of Participation Read the objectives and other CME information, then proceed to read the monograph. To receive CME/CPE/CE Credit, please visit www.totalmeded.com/links/9002monograph to complete the post-test, evaluation form and print your certificate immediately. A score of 70% or above is required on the post-test to receive the CME/CPE/CE credit. This credit is available through December 1, 2010. No credit will be given after this time.

Learning ObjectivesUpon completion of this activity, participants will be able to:• Identify and implement the diagnostic and management recommendations of the latest US national guidelines on IBS • Assess the latest evidence on diagnosis and management of chronic constipation • Utilize the recommendations of the recent AGA Institute medical position statement on GERD to formulate strategies to diagnose and treat challenging patients • Analyze the challenges surrounding the management of Barrett’s esophagus and extraesophageal manifestations of GERD

Accreditation and DesignationPhysiciansThe AGA Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education to physicians.

The AGA Institute designates this educational activity for a maximum of 3.00 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

In accordance with the ACCME’s Standards for Commercial Support of Continuing Medical Education, all faculty and planning partners must disclose any financial relationship(s) or other relationship(s) held within the past 12 months. The AGA Institute implements a mechanism to identify and resolve all conflicts of interest prior to delivering the educational activity to learners.

Physician AssistantsAAPA accepts AMA PRA Category 1 Credit from organizations accredited by the ACCME.

Nurse PractitionersAANP accepts AMA PRA Category 1 Credit from organizations accredited by the ACCME.

PharmacistsPurdue University School of Pharmacy and Pharmaceutical Sciences is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This

is a knowledge based, continuing education activity of Purdue University, an equal access/equal opportunity institution Universal Activity Number (UAN): 0018-9999-09-238-H01-P 3.0 contact hours (.30 CEU). Release date: December 1, 2009. Expiration date: December 1, 2010.

FacultyWilliam D. Chey, MD, AGAF, FACG, FACPProfessor of Internal MedicineUniversity of Michigan Health SystemAnn Arbor, MI

Prateek Sharma, MDProfessor of MedicineUniversity of Kansas School of MedicineKansas City, KS

DisclosuresDr. Chey reported that he is a consultant to and speaker for Axcan Pharma; Prometheus; Salix Pharmaceuticals, Inc.; and Takeda Pharmaceuticals North America, Inc. He also reported that he is a consultant to AGI Therapeutics plc; Ironwood Pharmaceuticals, Inc.; Procter & Gamble; and SmartPill Corporation.

Dr. Sharma reported that he receives research support from BÂRRX Medical, Inc.; Olympus America Inc.; and Takeda Pharmaceuticals North America, Inc. He also reported that he is a consultant to Santarus, Inc. and Takeda Pharmaceuticals North America, Inc.

Jason Jenkins, medical writer at TCL Institute, LLC, has nothing to disclose.

The AGA Institute, TCL Institute, LLC and Purdue University School of Pharmacy and Pharmaceutical Sciences staff that were involved in the development of this activity have no financial relationships with any commercial interests that are relevant to this activity.

To resolve identified conflicts of interest, the educational content was fully peer-reviewed by a physician member of the AGA Institute Clinical Content Review Committee, who has nothing to disclose.

Disclosure of Unlabeled or Investigational DrugsThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the educational activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Further, attendees/participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this program.

DisclaimerThe content and views presented in this educational activity are those of the authors and do not necessarily reflect those of the AGA Institute; Takeda Pharmaceuticals North America, Inc.; Purdue University School of Pharmacy and Pharmaceutical Sciences; or TCL Institute, LLC. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, health care professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.

Provider Contact Information

TCL Institute, LLC I 104 Towerview Court I Cary, NC 27513Phone: (919) 467-0006, ext. 233 I Fax: (215) 243-7273

© Copyright 2009 TCL Institute, LLC


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InTrODUCTIOnGastroesophageal reflux disease (GERD), chronic constipation, and irritable bowel syndrome (IBS) were the first, second, and sixth most common digestive disorders in the United States in 2004, present in 18.3, 6.3, and 3.0 million ambulatory care patients, respectively, in recently released figures.1 Because of their prevalence, it is vitally important that clinicians stay up to date on the latest and most clinically relevant information about these gastrointestinal disorders.

This monograph reviews recent publications – including abstracts presented at Digestive Disease Week (DDW) 2009 – affecting clinicians’ strategies on the diagnosis and management of IBS, constipation, and acid-related disorders. (Note to readers: data presented in abstracts is considered to be preliminary until it is published in a peer-reviewed journal.)

IBSIBS presents a substantial burden to the health care system. Prevalence of IBS in North America ranges from 5% to 10%, and IBS patients made 3.0 million ambulatory care visits in the United States in 2004.1,2 The direct and indirect costs of caring for IBS patients in the United States were estimated to be more than $1 billion in 2004, with the costs for ambulatory care and prescription drugs responsible for the lion’s share.1 In addition, IBS patients use disproportionately more health care resources – > 50% more, in one estimate – than matched controls without IBS.2

Much of this cost is due to diagnostic tests, invasive procedures, and abdominal operations.2 Of the approximately 540,000 colonoscopies performed in the United States from 2001 to 2005, IBS symptoms were cited as the indication for 18.2%.1

IBS: DIAGnOSISThe functional bowel disorders, including IBS, are identified largely on the basis of characteristic symptoms. The most commonly used symptom-based diagnostic criteria for IBS, the Rome III criteria, define IBS as “recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of3:• Improvement with defecation• Onset associated with a change in frequency of stool• Onset associated with a change in form (appearance) of stool” The most recent US guidelines advocate a simpler definition: “abdominal pain or discomfort that occurs in association with altered bowel habits over a period of at least 3 months.”2

At present, IBS has no reliable biomarkers and no tests can positively diagnose IBS. Therefore, the question for clinicians when encountering patients with symptoms of IBS is whether to order diagnostic test(s) to rule out organic diseases whose symptoms overlap with IBS.

Case Study: AnnabelleAnnabelle, a 34-year-old female, reports

abdominal pain accompanied by diarrhea for the past 1.0-1.5 years. In your interview

with her, you learn that she has no other symptoms. She comes in today because a friend told her recently that these symptoms might be due to cancer. (There is no history of colorectal cancer or inflammatory bowel disease [IBD] in her family.) Her physical examination, including a complete digital rectal examination (DRE), is unremarkable. A

pregnancy test is negative. How would you proceed to make a diagnosis?

Which Diagnostic Tests Are Appropriate for IBS in

2009?Using Standard Laboratory Tests for IBS

Several standard laboratory tests are commonly ordered for IBS patients, but there is little evidence to support their use.

Sanders and colleagues studied 300 patients who met the Rome II criteria for IBS via a battery of standard hematological and biochemical tests.4 They found that 1 (0.3%) had an abnormal complete blood count (CBC); 2 (0.7%) had abnormal liver function test results due to excess alcohol intake; 2 (0.7%) had elevated serum C reactive protein; and 1 (0.3%) had an elevated erythrocyte sedimentation rate. Other studies have confirmed these results, similarly showing low rates of abnormal results on CBC, serum chemistries, and stool ova and parasites among IBS patients.5-7

The reason many clinicians order diagnostic tests on IBS patients is to hopefully identify an organic disease whose symptoms overlap with IBS. But studies have shown that patients with suspected IBS are no more likely than those in the general population to have IBD, colorectal cancer, or thyroid dysfunction (Table 1).2 Rates for celiac disease and lactose malabsorption are, however, higher in IBS patients than in the general population. Table 1. Pretest Probability of Various Organic Gastrointestinal Diseases in IBS Patients Versus General Population Prevalence2

Testing IBS Patients for Celiac DiseaseCeliac disease, which most commonly presents with diarrhea and abdominal pain, is often misdiagnosed as IBS.8,9 As Table 1 illustrates, the pretest probability of celiac disease among patients with IBS is estimated to be 4 times greater than the prevalence of celiac disease in the general population.2 A meta-analysis of 5 studies found that

Organic Gastrointestinal IBS Patients General PopulationDisease Pretest Probability (%) Prevalence (%)

Colitis/IBD 0.51-0.98 0.3-1.2

Colorectal Cancer 0-0.51 0-6

Thyroid Dysfunction 4.2 5-9

Gastrointestinal Infection 0-1.5 Not applicable

Celiac Sprue 3.6 0.7

Lactose Malabsorption 38 26


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34 (3.6%) of 952 IBS patients had both serologic and small bowel biopsy evidence of celiac disease compared to 12 (0.7%) of 1798 controls (odds ratio [OR] 4.34 [95% CI, 1.78-10.58]).10

The prevalence of celiac disease among IBS patients seems to be lower in the United States. In a 2008 case-control study comparing 566 IBS patients diagnosed by a physician to 555 healthy controls, Saito-Loftus and colleagues found that 1.0% of IBS patients had positive serology for celiac disease compared with 0.5% of controls (P > 0.05).11 A 2008 prospective study comparing 492 nonconstipated IBS patients (diagnosed by the Rome II criteria) to 458 controls showed that 1.2% of IBS patients and 0.4% of controls had biopsy-proven celiac disease (P = 0.28).7

Although these studies differ in design and diagnostic criteria for IBS and celiac disease, and lack statistical power due to their small size, they suggest that the prevalence of celiac disease among IBS patients in the United States is approximately 1%.7,11 Decision analytic models have demonstrated that mass screening for celiac disease among IBS patients is cost-effective if the prevalence of disease is > 0.5%-1.0%.12-14 Accordingly, the most recent US national guidelines on the diagnosis of IBS recommend routine serologic screening for celiac disease in patients with IBS with diarrhea (IBS-D) and IBS-mixed (IBS-M).2

Serologic screening tests for celiac disease include 3 immunoglobulin A (IgA)-based tests15:• Tissue transglutaminase antibodies (tTGA)• Antiendomysial antibodies (EMA)• Antigliadin antibodies IgA-tTGA was recommended by the AGA Institute as the most efficient single serologic test to detect celiac disease due to its high sensitivity and specificity.15

Specificity and sensitivity levels for each test are shown in Table 2.15 Table 2. Accuracy of IgA-Based Tests for Celiac Disease15

Clinicians should remember that IgA deficiency is 10-15 times more common in individuals with celiac disease than in the general population.15 But because the prevalence of IgA deficiency among individuals with celiac disease is low (1.7%-3.0%), the AGA Institute does not recommend routinely measuring serum IgA levels along with tTGA or EMA, except when IgA deficiency is strongly suspected. Instead, in patients with a negative tTGA or EMA in whom celiac disease is still suspected, the AGA Institute recommends measuring serum IgA levels as a reasonable next step. Alternatively, clinicians can avoid this issue by ordering IgG versions of these antibody tests.

Small intestinal mucosal biopsy demonstrating characteristic histologic changes in intestinal mucosa remains the gold standard for diagnosing celiac disease.15 Because histologic findings and serologic results can resolve when gluten is removed from the diet, these diagnostic tests should be performed prior to gluten restriction.

Testing IBS Patients for Lactose MaldigestionAs Table 1 illustrates, lactose maldigestion may also be more common in IBS patients than in the general population.2 A recently performed meta-analysis of 3 case-control studies demonstrated greater prevalence of lactose intolerance in IBS patients than in controls (38% vs 26%; OR 2.57 [95% CI, 1.27-5.22]).

The question of whether lactose maldigestion is more prevalent among IBS patients – or if the symptoms of lactose maldigestion are more bothersome to IBS patients – remains unanswered. In patients with lactose maldigestion, undigested lactose that passes into the colon is fermented to produce osmotically short-chain fatty acids, producing a laxative effect.16 Studies have suggested that IBS patients have underlying abnormalities in intestinal and/or colonic motility and visceral sensation, so perhaps IBS patients feel the effects of lactose maldigestion more than normal controls.2

The most recent US national guidelines recommend clinicians question IBS patients about a possible link between lactose ingestion and IBS symptoms, using a food diary to identify such an association if necessary.2 These guidelines also recommend clinicians consider performing lactose hydrogen breath testing when questions about lactose maldigestion remain despite attempts at dietary restriction.

Colonic Imaging for IBS PatientsStudies of colonic imaging demonstrate a low probability of structural disease in patients with IBS symptoms and no alarm features.2 A recent systematic review of 3 studies including 636 IBS patients found that colonic imaging via colonoscopy or barium enema with or without flexible sigmoidoscopy identified organic or structural disease in 1.3% (95% CI, 0.06%-2.30%).

Similarly, interim analysis of a prospective multicenter US study of 216 IBS-D or IBS-M patients and 416 healthy controls who underwent colonoscopy for colorectal cancer screening found no difference in the prevalence of colorectal cancer (IBS group: 0%; control group: 0.2%) or IBD (IBS group: 0.46%; control group: 0%) between the groups.17 In fact, the prevalence of adenomatous polyps and diverticulosis was lower in the IBS cohort than in healthy controls, a result that may be due to the younger age and greater proportion of women in the IBS cohort.

Based on this evidence, the most recent US national guidelines for IBS only recommend routine colonoscopy in those aged < 50 years who have alarm features (eg, anemia, weight loss, nocturnal diarrhea, or a family history of colorectal cancer or IBD).2 Of course, all individuals aged ≥ 50 years and African Americans aged ≥ 45 years should undergo colonic imaging, according to the most recent guidelines on colorectal cancer screening.18-20

Colonic Biopsy in IBS-D Patients for Microscopic ColitisIn a recent prospective trial, in which 216 patients with IBS-D and IBS-M underwent colonoscopy with colonic mucosal biopsies, microscopic colitis was detected in 5 patients (2.3%).17 All 5 of these patients met criteria for IBS. In a study of patients with histologically confirmed microscopic colitis, retrospective analysis of their medical records revealed that approximately half met diagnostic criteria (Rome I, Rome II, or Manning) for IBS.21

Serologic Test Specificity Sensitivity

IgA tTGA > 95% 90%-96%

IgA EMA 99.6% 75%-98%

IgA Antigliadin Antibodies ≈ 90% 85%-90%


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Based upon these results, the most recent US national guidelines on IBS recommend that if a patient with IBS-D has a colonoscopy, the clinician should consider performing random colonic mucosal biopsies to rule out microscopic colitis.2

Testing IBS Patients for SIBOLargely predicated upon results of studies using lactulose or glucose hydrogen breath testing as a surrogate for small intestinal bacterial overgrowth (SIBO), it has been conjectured that SIBO may be at the root of symptoms in some IBS sufferers.22 Unfortunately, the accuracy of breath testing in diagnosing SIBO has been questioned.23

This controversy is borne out by a recent review of studies on diagnostic testing for SIBO in IBS patients.24 Of the studies that used lactulose, glucose, or sucrose breath tests to diagnose SIBO, the prevalence of a positive breath test among IBS patients ranged from 28% to 61% (Table 3). But when jejunal aspirate and culture (the gold standard for diagnosing SIBO) was used, only 4% of IBS patients were diagnosed with SIBO.

Due to these disparate results, the most recent US guidelines concluded that insufficient evidence exists to recommend breath testing for SIBO in IBS patients.2

Table 3. Studies on Prevalence of Positive Breath Tests for SIBO in IBS Patients24

Testing IBS Patients for Fructose MalabsorptionJust as lactose malabsorption has been proposed as a cause of symptoms in some IBS patients, so too has malabsorption of other carbohydrates, such as fructose or sucrose, been proposed to cause or exacerbate IBS symptoms.

In one small clinical study, 31 (39%) of 80 IBS patients (Rome II criteria) had a positive fructose breath test, indicating fructose intolerance.25 Among these patients, those who adhered to a fructose-restricted diet experienced symptom improvement, whereas those who were noncompliant did not. Another small study of 24 IBS patients with fructose intolerance demonstrated that a fructose- and fructans-enhanced diet led to exacerbation of IBS symptoms whereas a fructose- and fructans-restricted diet improved IBS symptoms.26 For these patients, SIBO may be a confounding factor. In one clinical study, the number of positive results on lactose, fructose, and sorbitol breath tests was significantly reduced after SIBO was eradicated.27

The New Blood Test for Ten Biomarkers of IBSA new blood test has recently been developed to aid in diagnosing IBS.28 A computer-aided search of the literature identified more than 600 pathways implicated in IBS, involving > 60,000 biomarkers. This list of biomarkers was then narrowed by identifying those that are common to several pathways, serum based, and measurable via commercially available assays. Of the resulting biomarkers, 16

were selected whose expression differed significantly between IBS patients and controls. Of this group of 16 biomarkers, a final group of 10 (shown in Table 4) was selected due to their greater relative combined accuracy in differentiating blood samples from IBS and non-IBS patients.

Table 4. Biomarkers for IBS28

The performance of this test was evaluated in a cohort of 516 individuals, half with IBS (Rome II or Rome III criteria) and half with healthy controls.28 The blood test had a sensitivity of 50% and a specificity of 88% for identifying IBS, with overall diagnostic accuracy (percentage of correct predictions) of 70%. As can be seen in Table 5, the positive predictive value (PPV) was highest when the pretest probability of IBS was high and the negative predictive value (NPV) was lowest when the pretest probability of IBS was low.

Table 5. Test for Ten Biomarkers of IBS: PPV and NPV28

Fecal Biomarkers to Differentiate IBS From IBDSeveral leukocyte-derived proteins, including calprotectin, lactoferrin, and polymorphonuclear (PMN)-elastase, have been studied for their utility in distinguishing IBD from IBS.29 The theory is that mucosal inflammation leads to greater sloughing of leukocytes and their contents into the feces where they can be measured.

Consistent with this theory, a few studies have demonstrated that fecal levels of selected inflammatory markers are higher in patients with IBD than in those with IBS.30-32 Kane and colleagues showed that fecal lactoferrin concentration was significantly elevated in patients with IBD (with either inactive or active disease) compared with IBS patients and healthy controls.30 Two groups subsequently demonstrated that fecal lactoferrin, calprotectin, and PMN-elastase were significantly elevated in IBD patients compared with IBS patients.31,32 Several centers now routinely use fecal calprotectin or lactoferrin to differentiate IBS from IBD.31

Test Used to Number IBS Prevalence of Diagnose SIBO of Studies Patients Positive Test (%) 95% CI

Lactulose Breath Test 5 964 61 49-73

Glucose Breath Test 3 494 28 8-54

Sucrose Breath Test 1 158 33 26-41

Jejunal Aspirate 1 162 4 2-9 and Culture

Biomarker Description

Interleukin-1β Proinflammatory cytokine

Growth-related oncogene-α Chemokine involved in neutrophil migration

Brain-derived neurotrophic factor Involved in regulating neuronal transmission

Anti–Saccharomyces cerevisiae Associated with Crohn’s disease antibody IgA

Anti–CBir1 antibody Recognizes bacterial flagellin

Antihuman tTGA Recognizes the major autoantigen in celiac disease

Tumor necrosis factor–like weak Cytokine involved in multiple inducer of apoptosis processes

Antineutrophil cytoplasmic antibody Associated with ulcerative colitis

Tissue inhibitor of metalloproteinase-1 Inhibits metalloproteinases that break down extracellular matrix proteins

Neutrophil gelatinase-associated Modulates various cellular responses lipocalin

Pretest Probability of IBS 15% 25% 50% 75% 85%

PPV (%) 48 61 81 94 95

NPV (%) 93 85 64 38 23


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Fecal proteases are also under investigation for their utility in diagnosing IBS. In a pilot study, Róka and colleagues observed that fecal serine-protease activity was 4 times higher in IBS-D patients than in controls, IBS with constipation (IBS-C), or IBS-M patients.33 Follow-up studies from the same group revealed that the activity of a panel of fecal proteases – serine protease, matrix metalloproteases (MMPs), and PMN-elastase – in IBS-D patients differs from their activity in other diarrheic conditions (Table 6).34,35 A 2009 study demonstrated significantly lower expression of protease-activated receptor (PAR)-1 and a significantly lower ratio of PAR-1/PAR-2 expression in IBS-D patients compared with controls.36 These results all suggest that fecal proteases and/or protease receptors may prove useful for diagnosis of IBS-D in the future.

Table 6. Activity of Fecal Proteases in Various Diarrheic Conditions34,35

+++ significantly greater than control; - not significantly different than control

Future Diagnostic Testing for IBS: Genetic TestingBecause IBS has been reported to cluster in families, there has long been suspicion that IBS may have a genetic basis. But in the 5 twin studies conducted on IBS to date, the genetic liability was estimated at 0%-20%, based on concordance rates.37 In the 4 twin studies that also modeled correlations to determine whether phenotypic variance was due to genetic or environmental components, 3 found that the best-fit models included an additive genetic component as well as individual environmental exposure.

A noteworthy consideration in the single twin study that found little influence of genetic factors on IBS is that the patient population met Rome II criteria, whereas the definition of IBS was looser in the other 3 twin studies.38-41 When taken together, these studies suggest that there is a genetic basis for IBS, but the genetic effect is not strong.37

Several genes have been hypothesized to be involved in IBS.37 They include:• Serotonin transporter ([5-HTT LPR] SLC6A4) • 5-hydroxytryptamine type 2A (5-HT

2A) receptor

• Norepinephrine transporter (NET) • α

2A-adrenergic receptor (ADRA2A)

• α2C

-adrenergic receptor (ADRA2C)• Interleukin (IL)-10 • Transforming growth factor–β

1

• Tumor necrosis factor–α • β3 subunit of the G protein (GNβ3) • Sodium channel 1.5v (SCN5A) • Fatty acid amide hydrolase (FAAH)

Another recent study identified novel gene-environment interactions in IBS.42 After genotyping 312 IBS patients and 242 controls for the 5-HTT LPR and GNβ3 825C>T polymorphisms, Saito and colleagues did not identify an association between IBS and either variant. However, those with the GNβ3 825T allele who self-reported a previous gastrointestinal infection had significantly higher odds of having IBS (OR 3.9 [95% CI, 1.2-2.8]) than did those without a prior gastrointestinal infection (OR 0.82 [95% CI, 0.62-1.09]). Similarly, there was a significant interaction between infection and the 5-HTT LPR polymorphism. This study suggests that interaction between genetic polymorphisms and gastrointestinal infection may play a role in the pathogenesis of IBS.

Case Study: Annabelle Because Annabelle has symptoms of IBS and diarrhea, you order an IgA tTGA to test for celiac disease. The test result was negative. You make the diagnosis of IBS-D and provide Annabelle with educational information about IBS. How would you proceed to treat her?

IBS: MAnAGEMEnTManagement of IBS presents several challenges to clinicians. The appropriate management strategy for IBS should address abdominal pain, which is the hallmark of the syndrome, as well as the particular bowel symptoms relevant to an individual patient. This section reviews recently released US guidelines for IBS management, then examines the evidence on promising emerging therapies for IBS.

Current Evidence-Based recommendations for IBS ManagementThe latest US national guidelines for IBS management were issued in January 2009 (Table 7).2 Although tegaserod was given a strong recommendation in these guidelines, it will not be discussed because it is currently available only through an emergency investigational drug protocol.

Table 7. Summary of the Latest US National Recommendations for IBS Management2

Protease Healthy IBS-D Crohn’s Disease Ulcerative Infectious Controls Colitis Diarrhea

Fecal Serine Reference +++ Not reported +++ –Protease value

MMP-1 Reference – – – +++ value

MMP-2 Reference – – – +++ value

MMP-9 Undetectable Undetectable Not reported Present Present

PMN- Reference – – +++ +++Elastase value

Letter grades refer to strength of evidence: A = high quality; B = moderate quality; C = low or very low quality

Grade 1 (Strong) Grade 2 (Weak) Not Insufficient Recommendation Recommendation Recommended Evidence Tegaserod Alosetron (under emergency (under a prescribing investigational program) drug protocol) Female IBS-D patients: Female IBS-C patients: GRADE 2AGRADE 1A Male IBS-D patients:Female IBS-M patients: GRADE 2B GRADE 1B

Nonabsorbable antibiotics (no long-term safety or efficacy data)GRADE 1B

Alosetron Polyethylene glycol (under a prescribing 3350 program) (for constipation) Female patients with GRADE 2C severe IBS-D:GRADE 1B

Lubiprostone AntispasmodicsFemale IBS-C patients: (hyoscine,GRADE 1B peppermint oil) (limited safety data, no long-term efficacy data) GRADE 2C

Tricyclic antidepressants Loperamide and selective serotonin (for diarrhea) reuptake inhibitors GRADE 2C (limited data on safety and tolerability in IBS patients) GRADE 1B

Psychological therapiesGRADE 1B

Probiotics (Bifidobacteria)

GRADE 2C

Wheatand corn

bran

Psyllium(ispaghula husk)

GRADE 2C

Herbalmixtures andacupuncture

Food allergytesting andexclusion

diets


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RifaximinThree randomized controlled phase II trials of the nonabsorbable antibiotic rifaximin in IBS have been reported.43-45 In all 3, rifaximin demonstrated statistically significant improvement in global IBS symptoms and/or bloating.2

In the largest trial – a phase II multicenter, double-blind, placebo-controlled, randomized trial – Lembo and colleagues evaluated the short-term and sustained effectiveness of rifaximin in relieving IBS-D symptoms (as defined by Rome II criteria) compared with placebo.44 The primary comparison consisted of 2 groups of adult patients with IBS-D that received rifaximin 550 mg BID or placebo for 14 days, followed by an additional 14 days of placebo in both groups and a 12-week follow-up phase. Patients receiving rifaximin had significant improvement compared with those receiving placebo in both adequate relief of global IBS symptoms (52% vs 44%; P = 0.03) and relief of bloating (46% vs 40%; P = 0.04). In the 12-week follow-up, the percentage of patients reporting adequate relief of global symptoms and bloating with rifaximin increased to 62% and 59%, respectively (P < 0.05 for all figures compared to placebo).

Rifaximin is US Food and Drug Administration (FDA)-approved to treat traveler’s diarrhea at a dose of 200 mg TID for 3 days.46 However, in each of the trials on IBS patients, it was used at higher doses, from 400 mg BID for 10 days, 400 mg TID for 10 days, to 550 mg BID for 14 days.2 It was well-tolerated in each trial, with no greater incidence of adverse events compared with placebo.

Because rifaximin was primarily tested on IBS-D patients, the most recent national guidelines concluded that it is most likely to be effective in IBS-D patients or IBS patients with a predominant symptom of bloating at a dosage of 1200 mg for 10 to 14 days.2 Data from phase III trials and long-term safety and efficacy have not yet been reported.

AlosetronMost (95%) of the body’s serotonin is found in the gastrointestinal tract, and a number of serotonin receptors, including 5-HT

1, 5-HT

3,

and 5-HT4, are involved in gastrointestinal motor/secretory function

and visceral sensation.2 Several medications that target the serotonin system have shown efficacy in IBS, including the 5-HT

3 receptor

antagonist alosetron. A recent meta-analysis of the 8 randomized controlled trials (RCTs) conducted on alosetron in IBS from 1999 to 2007 concluded that the relative risk of symptoms persisting with alosetron was 0.79 (95% CI, 0.69-0.90), and the number needed to treat (NNT) was 8 (95% CI, 5-17).47

Alosetron was originally approved to treat women with IBS-D in February 2000, but because a small percentage of patients developed severe constipation and colonic ischemia, it was voluntarily withdrawn in November 2000.2 In June 2002, it was reintroduced in the United States, but only for female patients with chronic severe IBS-D unresponsive to conventional therapy and only if the prescriber was enrolled in the manufacturer’s prescribing program.

The new (postreintroduction) recommended starting dose of alosetron is 0.5 mg BID, half the dose used in early clinical trials.2 Retrospective analysis of adverse events published in the 5 years since alosetron’s reintroduction demonstrated that, of the

approximately 26,000 patients who received 160,000 prescriptions in that time, there were 15 confirmed cases of ischemic colitis and 5 of complications of constipation.48 None of these cases resulted in surgery, transfusion, or death.

LubiprostoneInitially FDA-approved for chronic idiopathic constipation, lubiprostone gained FDA approval for IBS-C in April 2008.49 In 2 phase III clinical trials of lubiprostone for IBS, which used a restrictive, multitiered responder definition designed to minimize placebo response rates, patients receiving lubiprostone achieved a higher response rate compared with those receiving placebo (17.9% vs 10.1%; P = 0.001).50 Because most of the participants in these trials were women, lubiprostone was FDA-approved for female patients aged ≥ 18 years with IBS-C.49

In a 36-week open-label extension of patients with > 70% compliance in the 12-week phase III trial, the monthly response rate of patients on lubiprostone improved from 15% (in the original 12-week trial) to 37% (on lubiprostone in both the 12-week trial and the 36-week extension).51 Post hoc analysis pooled data from the phase II and III trials revealed that patients with < 25% loose spontaneous bowel movements (SBMs) at baseline had a significantly better clinical response with lubiprostone.52

The dosage for lubiprostone for IBS-C is 8 μg BID.2 The most common adverse events of lubiprostone observed in phase II and III trials were nausea, diarrhea, and headache. Lubiprostone carries a pregnancy class C rating, and is contraindicated in patients with known mechanical gastrointestinal obstruction.

Tricyclic AntidepressantsA 2009 meta-analysis reviewed 9 RCTs conducted from 1978 to 2008 on tricyclic antidepressants (TCAs) in IBS.53 These trials, which included studies on desipramine, amitriptyline, imipramine, doxepin, and trimipramine for 4 to 12 weeks in a total of 575 IBS patients, were effective overall, with a relative risk of symptoms persisting of 0.68 (95% CI, 0.56-0.83) and an NNT of 4 (95% CI, 3-8). These studies were heterogeneous, so the NNT may be lower than that reported.

Adverse events of TCAs include the anticholinergic symptoms of constipation, dry mouth, and dizziness.54,55 Because of their constipating adverse events and because imipramine has been shown to prolong orocecal and whole gut transit times, TCAs may be more effective for IBS-D than IBS-C.53,56

SSRIsFive RCTs have been conducted on the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine, and citalopram in IBS.53 A recent meta-analysis of these studies, which included 230 IBS patients treated for 6 to 12 weeks, determined that SSRIs were effective overall, with a relative risk of symptoms persisting of 0.62 (95% CI, 0.45-0.87) and an NNT of 3.5 (95% CI, 2-14). Again, these studies were heterogeneous, so the NNT may be lower.

Adverse events of SSRIs include sexual dysfunction, headache, nausea, sedation, and insomnia.54 Because SSRIs may accelerate gastrointestinal transit – in one study, paroxetine decreased orocecal transit time in IBS patients and controls – SSRIs may be preferred for IBS-C rather than IBS-D.53,56


8

Psychological TherapiesA variety of psychological therapies, including cognitive behavioral therapy (CBT), relaxation therapy, hypnotherapy, multicomponent psychological therapy, dynamic psychotherapy, self-administered CBT, and stress management, have been tested on IBS patients.53 Based on a recent meta-analysis of 20 RCTs, the most recent US national guidelines on IBS strongly recommended 4 of them2,53:

• CBT (NNT 3.0 [95% CI, 2-7])• Hypnotherapy (NNT 2.0 [95% CI, 1.5-7.0])• Multicomponent psychological therapy (NNT 4.0 [95% CI, 3-8])• Dynamic psychotherapy (NNT 3.5 [95% CI, 2-25])

Several issues with these studies make it difficult to pool their findings. Adequate blinding is difficult, if not impossible; there was considerable heterogeneity between studies and 9 of the included studies were performed by the same investigators.2,53 Nevertheless, selected psychological therapies were consistently superior to usual care for global symptom improvement and were not associated with adverse events.2

Weakly Recommended IBS TherapiesA number of other therapies received a weak recommendation (ie, uncertainty in estimates of benefits and risks) by the latest US national guidelines on IBS management.2 These therapies include psyllium hydrophilic mucilloid (ispaghula husk), polyethylene glycol (PEG) 3350, antispasmodics, and loperamide.

Loperamide and PEG 3350 had no effect on abdominal pain or global symptoms, but loperamide effectively treated diarrhea and PEG 3350 improved constipation.2 Psyllium improved global IBS symptoms in 4 of 6 studies, with a relative risk of symptoms not improving on psyllium of 0.78 (95% CI, 0.63-0.96) and an NNT of 6.00 (95% CI, 3-50).

The antispasmodics hyoscyamine and dicyclomine are the most commonly prescribed medications for IBS in the United States, but there are little data to support their use.1,2 Many clinical trials have been performed on antispasmodics, but most of them studied medications not available in the United States or whose preparation differs from that available in the United States.2 Nevertheless, hyoscine and peppermint oil were weakly recommended in the latest US national guidelines.

The most common adverse events of antispasmodics are dry mouth, dizziness, and blurred vision.2 Long-term efficacy data on antispasmodics are not available and data on safety and tolerability are limited.

ProbioticsProbiotics were also weakly recommended in the latest US national guidelines on IBS.2 Since that report was prepared, however, 2 other reviews have been published on the use of probiotics in IBS.57,58 Bifidobacterium infantis 35624, the only probiotic evaluated in > 1 appropriately designed study, reduced mean symptom scores for abdominal pain/discomfort, abdominal bloating, straining, and overall IBS symptoms in 2 studies (P < 0.07 for bloating score; P < 0.05 for the other scores), with reported adverse events not different than those experienced with placebo.59,60

Case Study: Annabelle There are a number of options for treatment of IBS-D. To address her bowel symptoms, an antidiarrheal like loperamide would suffice. However, it does not address her abdominal pain. Other options include TCAs, rifaximin, or an antispasmodic, with nonpharmaceutical options such as psychological therapies or probiotics.

Emerging Therapies for IBSNew discoveries about the pathophysiology of IBS have revealed new targets for IBS therapy. As a result, a number of new therapies for IBS are in development and currently undergoing clinical trials (Table 8).2,61

Table 8. Emerging Therapies for IBS2,61

AsimadolineOpioid receptor ligands like asimadoline, a peripheral κ-opioid agonist, may be effective in IBS due to their effect on peripheral visceral afferent nerves.62 In a phase II RCT of 596 IBS patients (Rome II criteria), asimadoline compared with placebo relieved IBS pain and discomfort (46.7% vs 23.0%; P = 0.038) and increased the number of pain-free days (42.9% vs 18.0%; P = 0.001) in a subgroup of IBS-D patients with at least mild-to-moderate pain at baseline.63 It also improved scores for adequate relief of abdominal pain in patients with IBS-M, but no benefits were noted in IBS-C patients.64 Phase III trials on IBS-D and IBS-M are currently being planned.

Agent Mechanism of Action Targeted Clinical Disorder Status

AST-120 (Kremezin) Adsorbs bile acids IBS-D/IBS-M Phase II

Asimadoline κ-opioid agonist IBS Phase II

Dextofisopam 2,3-Benzodiazepine IBS Phase II agonist

Crofelemer CFTR inhibitor IBS-D Phase II

DDP225 Serotonin noradrenaline IBS-D Phase II reuptake inhibitor

Ramosetron 5-HT3 antagonist IBS-D Phase III

Pexacerfont CRF1-receptor IBS-D Phase II(BMS-562086) antagonist

GW876008 CRF1-receptor antagonist IBS Phase II

Solabegron β-3 receptor agonist IBS Phase II

R-verapamil Calcium channel blocker IBS-D Phase III*

Linaclotide Guanylate IBS-C Phase III cyclase-C agonist

Ibaconda 5-aminosalicylate/ IBS-C Phase II(Olsalazine/Colchicine) intestinal secretion

Tianeptine Enhances serotonin IBS Phase II reuptake

DDP733 Partial 5-HT3 agonist IBS-C Phase II

Traditional Chinese Herbal medicine IBS Phase IIMedicine

Gastrafate IB Sucrose sulfate-aluminum IBS Phase II/III(Sucralfate) salt: cytoprotection

VSL#3 Probiotic combination IBS-D Phase II

Flora-Q Probiotic IBS-D Phase II

Lactobacillus Probiotic IBS-D Phase IIfarciminis

Saccharomyces Probiotic IBS-D Phase IIIboulardii

AGN 203818 α2b agonist IBS pain Phase II

Mesalamine 5-Aminosalicylate Postinfectious Phase II IBS

* Failed to achieve end point in a phase III trial


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DextofisopamDextofisopam is a homophthalazine compound that binds to 2,3-benzodiazepine receptors in the subcortical and hypothalamic regions of the brain, which are known to modulate autonomic function including gastrointestinal motility and secretion.2 Unlike traditional benzodiazepines, dextofisopam has no addictive properties and is nonsedating.65

In a double-blind, placebo-controlled, phase II trial, dextofisopam-treated patients were adequate overall relief responders for significantly more months than placebo-treated patients (1.7 vs 1.3 months; P = 0.033).65 Dextofisopam also reduced stool frequency and improved stool consistency compared with placebo for all 3 months of treatment. A 12-week phase IIb RCT evaluating dextofisopam in female patients with IBS-D or IBS-M is currently ongoing.66

CrofelemerThe latex of the Croton lechleri plant in Western South America has been used medicinally by the indigenous people for centuries.67 Crofelemer, an extract from the latex, has demonstrated antisecretory properties in cells in vitro, an effect believed to be due to inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR).

In a 12-week double-blind RCT of 241 IBS-D patients, crofelemer had no effect on the primary end point of stool consistency, but at a dose of 500 mg it did increase the proportion of pain- and discomfort-free days among female IBS-D patients (26.1% vs 10.6%; P = 0.0076).67 Crofelemer is also being studied for human immunodeficiency virus–associated diarrhea.68

RamosetronDespite the safety issues associated with alosetron, the serotonergic pathway remains a tempting target for IBS therapy.2 The 5-HT

3

antagonist ramosetron is one of several serotonergic agents in development for IBS.

In a double-blind, parallel-group, comparative study of 539 IBS-D patients in Japan, ramosetron demonstrated statistically significant improvement in global IBS symptoms (47% of the 269 patients receiving ramosetron were monthly responders compared with 27% of the 270 patients receiving placebo; P < 0.001).69 Ramosetron-treated patients similarly had higher responder rates for relief of global IBS symptoms and abdominal pain compared with placebo in a European 12-week phase II trial of 691 IBS-D patients.2

DDP 225DDP 225, a selective norepinephrine reuptake inhibitor and 5-HT

3

antagonist, was recently studied in a phase II trial of 87 female IBS-D patients (Rome II criteria).70 In the trial, adequate response to DDP 225 was defined as at least 2 positive responses in the last 4 weeks of the study to the question, “In the last 7 days, have you had adequate relief of your IBS pain or discomfort?”

Among those who completed the study, significantly more of the 17 patients receiving DDP 225 1 mg/day (71% vs 25%; P = 0.009) and the 12 patients receiving DDP 225 3 mg/day (63% vs 25%; P = 0.03) achieved an adequate response compared with the 16 patients receiving placebo.70

PexacerfontCorticotropin-releasing factor (CRF) is one of the primary mediators of the hypothalamic-pituitary-adrenal axis and stress activation of CRF receptors has been shown to alter gastrointestinal function.2,71 CRF

1-receptor antagonists blocked stress-induced changes in

gastrointestinal function in animal models and also reduced anxiety while increasing sensation, and motility after electrical stimulation of the colon in a small cohort of IBS patients.72

A phase IIa dose-ranging RCT evaluating pexacerfont, a selective antagonist of the CRF

1 receptor, in 39 female IBS-D patients (Rome

II) was recently completed.71 Pexacerfont’s effects did not achieve statistical significance on gastric emptying, orocecal transit, ascending colon emptying, stool frequency, consistency, and ease of passage. Another CRF antagonist, GW876008, recently completed a phase II study in IBS.73

LinaclotideLinaclotide stimulates intestinal guanylate cyclase-C receptors to enhance chloride, bicarbonate, and fluid secretion from intestinal CFTR channels.2,62 It is currently being investigated as a treatment for both IBS-C and chronic constipation.

In a phase II dose-ranging RCT of 419 IBS-C patients (Rome II criteria), linaclotide compared with placebo significantly increased the number of complete SBMs per week (to 2.9, 2.5, 3.6, and 2.7 at doses of 75, 150, 300, and 600 μg, respectively, vs 1 μg; P < 0.05 throughout) and dose-dependently relieved abdominal pain (0.7-0.9 mean Likert scale change from baseline vs 0.5; P < 0.02 throughout).74 A long-term phase III safety study of linaclotide for IBS-C is currently underway.75

DDP733Another serotonergic agent, the partial 5-HT

3 agonist DDP733,

has also been demonstrated to increase intestinal motility.76 In a 4-week dose-ranging RCT of 91 IBS-C patients (Rome II), DDP733 significantly improved patients’ subjective assessment of their global IBS symptoms compared with placebo (53.8% vs 15.4%; P = 0.039).

IBS: SUMMArYClinical strategies for diagnosis and management of IBS continue to evolve based on a more thorough understanding of the disease. The recent recommendation that all individuals who meet symptomatic criteria for IBS-D and IBS-M be tested for celiac disease is a major change in the IBS diagnostic algorithm. Growing evidence about the lack of utility of most standard diagnostic tests and imaging studies also impacts this algorithm. Managing IBS has become more complex because currently available treatments have profoundly different mechanisms of action and target different sets of symptoms. Moreover, numerous emerging therapies for IBS are in development and nearing approval, which will offer clinicians a better arsenal of therapeutic options. Together, these changes offer greater diagnostic clarity and improved symptom control for patients with IBS.

CHrOnIC COnSTIPATIOnChronic constipation is the second most common digestive disorder in the United States, listed as the first diagnosis for 3.1 million ambulatory care visits or as any diagnosis in 6.3 million ambulatory care visits.1 It is most common in individuals aged < 15 years, even more common than in those aged > 65 years. The prevalence of


10

chronic constipation is rising, increasing more than 2-fold from 1992 to 2004, and associated costs are also rising. Direct and indirect costs for chronic constipation were estimated at $1.6 billion in 2004, largely from ambulatory care and hospital costs. The following section reviews the latest clinically relevant information on the diagnosis and treatment of chronic constipation.

Case Study: BelindaBelinda, a 62-year-old female, has experienced constipation for most of her adult life. Her symptoms began in her 30s and have gradually worsened in intensity as she has aged. Workups by her local gastroenterologist at a specialized academic center failed to identify anemia, thyroid dysfunction, pelvic floor dysfunction, or colorectal cancer. Today, she denies any hematochezia or weight loss and her family history is negative for colon cancer or IBD. She has osteoporosis and hypertension, for which she is taking a diuretic, calcium channel blocker, osteoporosis medication, and calcium supplement. She sees her physician regularly and has had 2 unremarkable colonoscopies (at age 50 and age 60). What test(s), if any, would you order in your diagnostic workup for Belinda?

CHrOnIC COnSTIPATIOn: DIAGnOSISLike IBS, chronic constipation is a symptom-based diagnosis. The Rome III criteria for functional constipation, updated in 2006, are the following (fulfilled for the last 3 months with symptom onset for ≥ 6 months)3: • 2 or more of the following: o Straining o Lumpy or hard stools o Sensation of incomplete evacuation o Sensation of anorectal obstruction/blockage o Manual maneuvers to facilitate defecation o Fewer than 3 defecations per week• Loose stools are rarely present without the use of laxatives• Insufficient criteria for IBS The presence of an alarm feature/red flag in a patient (including hematochezia, weight loss ≥ 10 pounds, family history of colon cancer or IBD, anemia, positive fecal occult blood tests, and the acute onset of constipation in elderly persons) signals that other diagnostic studies are needed.77 But when these alarm features are not present, clinicians face the question of whether to perform any diagnostic tests. The following section examines the evidence on the utility of diagnostic testing in patients with constipation.

The most important and underutilized aspect of the physical examination in a patient with complaints of constipation is the perianal and digital rectal examination. Careful inspection of the perianal area can disclose the presence of hemorrhoids and/or an anal fissure.78,79 In patients with constipation, lightly stimulating the perianal skin allows the simultaneous assessment of sensation and the “anal wink”, which collectively provide insight into local sensory innervation and reflex arcs. Asking the patient to simulate defecation in the resting position can uncover a nonrelaxing pelvic floor or rectal prolapse. On digital examination, the state of relaxation of the puborectalis sling, straightening of the anorectal angle, and relaxation of the anal sphincter with simulated defecation can provide invaluable insight into the presence or absence of dyssynergic defecation.79

Diagnostic Testing for Chronic ConstipationUsing Standard Laboratory Tests to Diagnose Chronic ConstipationShould standard hematological and biochemical tests be routinely ordered for patients who present with constipation? Unfortunately, no studies have examined the utility of these tests (eg, CBC, serum calcium, thyroid function) when evaluating patients with symptoms of chronic constipation.77,80

Because there is no evidence to support or reject the utility of screening blood tests, most recommendations from gastroenterological organizations are cautious. In its medical position statement, the American Gastroenterological Association recommended that clinicians consider a set of focused tests to exclude organic disorders that are treatable (ie, hypothyroidism) or important to diagnose early (ie, colon cancer).81 The American Society of Colon and Rectal Surgeons (ASCRS) does not support routine use of these tests in patients without alarm symptoms.82

The recommendation of the American College of Gastroenterology (ACG), based on expert opinion, was similar: ACG did not endorse routine diagnostic testing in patients with symptoms of chronic constipation without alarm signs or symptoms.77

Colonic Imaging to Diagnose Chronic ConstipationThere are a few studies on the use of colonoscopy to evaluate patients who present with constipation, but most of the studies are of modest quality.83 One widely cited study retrospectively examined the records of 563 patients with symptoms of chronic constipation who underwent colonoscopy or sigmoidoscopy.84 In this cohort, the prevalence of colon cancer was 1.4% and the prevalence of colonic adenomas was 14.0%. The rate of metaplasia in this cohort was comparable to that of asymptomatic patients undergoing colorectal cancer screening.

Therefore, several organizations, including the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, the ASCRS (2007), the ACG (2005), and the American Society for Gastrointestinal Endoscopy (2005), do not endorse the routine use of colonoscopy for patients aged < 50 years without alarm features or acute symptom onset.77,82,83,85 Colonoscopy as colorectal cancer screening is routinely recommended for all average-risk patients aged ≥ 50 years, and African American patients aged ≥ 45 years.18-20

Physiologic Testing to Identify Subtypes of Chronic ConstipationAt least 3 subtypes of constipation have been identified: slow transit constipation, dyssynergic defecation, and those with no discernable physiological abnormality to explain their constipation symptoms.86 Although the diagnosis of constipation is symptom-based, symptoms alone do not differentiate between these subtypes. In a study of 100 patients with refractory symptoms of difficult defecation for ≥ 1 year, most symptoms did not differentiate individuals with normal results on anorectal manometry from those with abnormal results (Table 9).87 Only the use of digital maneuvers to assist defecation was more likely among individuals with abnormal anorectal manometric patterns. Those individuals with constipation symptoms and significant abdominal pain/discomfort are classified as suffering from IBS-C.86

in at least 25% of

defecations


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Table 9. Prevalence of Constipation Symptoms Versus Pattern of Anorectal Manometry87

Subclassifying constipation has implications for the choice of therapy. In a study of 52 patients with delayed whole gut transit and refractory constipation, those with dyssynergic defecation significantly improved after 5 sessions of biofeedback training across a wide range of signs and symptoms (stool frequency, straining, bloating, laxative use, whole gut transit time, and balloon defecation) and through 24 months of follow-up.88 Biofeedback training did not benefit those who only had slow transit constipation. Therefore, it is important to differentiate between the subtypes of constipation to determine the most appropriate course of therapy.

Physiologic testing to identify the subtype of constipation is generally recommended for patients whose constipation is refractory to empiric treatment.81,82 However, the choice of physiologic test (colonic transit study, balloon expulsion test, defecography, or anorectal manometry) is difficult because of practical issues including availability, reimbursement, and local expertise. Even when such testing is available, the sensitivity, specificity, and predictive values of these tests have not yet been established.77

Colonic Transit StudyThe Rome III committee stated that retention of radiopaque markers in the proximal or transverse colon suggests colonic dysfunction, whereas retention in the rectosigmoid area suggests obstructed defecation.3 But a recent study of 196 patients with slow transit constipation (diagnosed by a radiopaque marker study) showed that colonic scintigraphy failed to discriminate between patients with only slow transit constipation and those with both slow transit constipation and rectal evacuatory disorder (diagnosed by proctography).89

In a study presented at DDW 2009, Rao and colleagues examined whether a wireless pH/pressure capsule can help identify the subtypes of chronic constipation.90 They found that individuals with slow transit constipation had significantly fewer contractions than those in the other 3 groups (dyssynergic defecation, normal transit constipation, or healthy control). In those 3 groups, the number of postprandial contractions was significantly greater than the number of preprandial contractions, whereas the difference was nonsignificant among individuals with slow transit constipation.

Anorectal Manometry and Balloon Expulsion TestsAnorectal manometry is routinely endorsed as a tool to assess defecation dynamics, but its utility in diagnosing dyssynergic defecation is still unclear.91 Balloon expulsion testing has an 89% specificity and a 97% negative predictive value for excluding pelvic

floor dyssynergia.92 Therefore, the authors concluded that balloon expulsion tests are a simpler and cheaper alternative to anorectal manometry.91 Case Study: Belinda A careful DRE revealed normal perianal sensation, no rectal prolapse, and normal relaxation of the puborectalis and anal sphincter with simulated defecation. You ask the patient to start a dietary fiber supplement with instructions to slowly titrate the dosage up over several weeks. She calls back in 2 weeks with no improvement in her constipation and problems with bloating. How would you proceed to treat her?

CHrOnIC COnSTIPATIOn: CUrrEnT MAnAGEMEnTFor many years, management of chronic constipation has been based on 3 important classes of therapy: bulking agents, stool softeners, and laxatives.77,93 Since the latest US national guidelines on constipation were published in 2005, 1 new type of medication has been approved for use in the United States and additional studies on other therapies have been published.

Dietary Fiber for Chronic Constipation: New EvidenceIn a study of 30 frail inhabitants (aged 57-98 years) of a long-term care facility who were all using laxatives, ingestion of up to 5.1 g of oat bran daily for 12 weeks reduced laxative use by 59% (P < 0.001) while maintaining body weight.94 In the control group, laxative use increased by 8% and body weight decreased significantly.

Two 2008 studies show that increased dietary fiber improves symptoms among those who met diagnostic criteria for chronic constipation.95,96 In a prospective RCT of 32 individuals with chronic constipation (Rome II criteria), those who ingested 20 g of supplemental fiber daily for 20 days in milk fortified with inulin and digestion-resistant maltodextrin improved in each of the Rome symptoms95: • Straining (92.9% of individuals at baseline to 35.7% after 20 days; P < 0.001)• Hard stools (85.7% to 21.4%; P < 0.001)• Sensation of incomplete evacuation (71.4% to 14.3%; P < 0.001)• Sensation of anal obstruction (71.4% to 14.3%; P < 0.001)• Use of manual maneuvers (21.4% to 0%; P = nonsignificant)• Having < 3 bowel movements per week (50.0% to 14.3%; P < 0.008)

A retrospective study of 179 patients with functional constipation (Rome II criteria), evaluated at a tertiary center in Brazil, showed that 38.5% improved with dietary and lifestyle changes (ingesting 30-40 g/day of supplemental wheat bran, 2 L/day of water, and regular walking and abdominal exercise) alone.96

No adverse events were reported in these trials.95,96

Probiotics for Chronic ConstipationAs mentioned earlier, probiotics are under investigation for treating IBS and have also been tested for their efficacy in relieving symptoms of chronic constipation.2,77

In a placebo-controlled crossover study of 266 women with chronic constipation (Rome II criteria), those who consumed yogurt containing fructooligosaccharide and Bifidobacterium animalis

Manometric Pattern During Attempted Defecation Normal Type I Type II Type IIISymptom (n = 30) (n = 32) (n = 24) (n = 14)

Straining 92% 96% 89% 83%Abdominal 80% 96% 89% 67%Fullness Incomplete 72% 96% 89% 100%EvacuationAbdominal 88% 81% 74% 75%DiscomfortDigital 28% 56% 47% 50%Maneuvers


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DN-173 010 x 108 UFC/g BID for 14 days had significantly increased stool frequency (6.1 ± 2.7 vs 5.0 ± 2.6 depositions/week), improved stool consistency, reduced straining, and reduced pain with defecation (P < 0.01).97 Another placebo-controlled RCT of 126 women with constipation demonstrated that those who drank fermented milk containing B. animalis DN-173 010 1.25 x 1010 CFU/pot, S. thermophilus, and L. bulgaricus daily for 14 days had increased stool frequency (4.1 ± 1.7 vs 2.6 ± 1.0 bowel movements/week; P < 0.01) and improved stool consistency (score of 0.6 ± 0.8 vs 1.3 ± 1.0; P < 0.01) compared to placebo.98

No adverse events were reported in these trials.97,98

Long-Term Data on PEG 3350 for Chronic ConstipationTwo reports of clinical trials on the osmotic laxative PEG 3350, which is now available over the counter (OTC), have been published since the most recent US national guidelines on constipation were released.99,100

In the first, a randomized open-label parallel study of 237 patients with chronic constipation (modified Rome criteria), 50% of the 120 PEG 3350-treated patients were responders (defined as success in > 50% of treatment weeks) compared with 30.8% of the 117 tegaserod-treated patients (tegaserod withdrawn from the US market in March 2007) (P = 0.003).2,99 In the second, a randomized, 12-month open-label, single-treatment study of 311 patients with chronic constipation (modified Rome criteria), approximately 80% of participants reported a successful response to treatment by month 2 and at each follow-up visit thereafter.100 Although all participants met Rome criteria for functional constipation at baseline, 85%-92% of study patients overall and 91%-95% of 117 elderly study patients no longer met Rome criteria over the course of the study.

Adverse events reported with PEG 3350 were primarily gastrointestinal (diarrhea, flatulence, nausea, abdominal pain, and bloating).99,100

Lubiprostone for Chronic ConstipationApproved by the FDA in January 2006 for chronic constipation, lubiprostone is a bicyclic fatty acid derivative of a metabolite of prostaglandin E1.101,102 In a recently published phase III trial of 224 patients with chronic constipation (defined as < 3 SBMs per week on average), 80% of the 120 patients receiving lubiprostone experienced an SBM within 48 hours of the first dose compared with 60.7% of the 122 patients receiving placebo (P = 0.0013).103 Across the 4 weeks of the study, those on lubiprostone experienced significant improvement in stool consistency, straining, and constipation severity compared with those on placebo.

Earlier studies demonstrated lubiprostone’s efficacy in relieving constipation, abdominal bloating, and abdominal discomfort over 48 weeks and in elderly patients (aged ≥ 65 years).104,105 The most common adverse events reported included nausea, headache, flatulence, dizziness, abdominal pain, and diarrhea. Nausea is a dose-dependent adverse event of lubiprostone that can be minimized through administration with food and water.46

It should be noted that lubiprostone is dosed at 24 μg BID for chronic constipation compared with 8 μg BID for IBS-C.101

It was previously believed that lubiprostone exerts its effects by activating chloride channel-2 channels on the apical side of intestinal epithelial cells, in a mechanism independent of the CFTR.106,107 But

a recent in vitro study demonstrated that lubiprostone induced a secretory response in the intestinal epithelium of controls but not of cystic fibrosis patients.108 Other experiments on cell lines and mouse epithelium led the authors to conclude that lubiprostone enhances intestinal chloride secretion via prostanoid-receptor signaling and subsequent activation of CFTR. Therefore, the mechanism of action of lubiprostone is still unclear.

Combination Therapy for Chronic ConstipationNo studies have examined combinations of different pharmacotherapies for chronic constipation.109 The Stepped Treatment of Older Adults on Laxatives trial was designed to investigate the efficacy of adding a second agent when the first therapy for constipation failed.110 The trial ended prematurely with only 19 participants because most patients preferred specific laxatives and did not want to be randomized to other treatments.

Switching Patterns After Tegaserod Was Withdrawn From the US MarketTegaserod, an agonist of the 5-HT

4 (serotonin) presynaptic receptor,

was FDA-approved for the treatment of chronic constipation in individuals aged < 65 years in July 2002.77,101 The US national guidelines on chronic constipation, published in 2005, strongly recommended tegaserod, citing its effectiveness at improving the frequency of complete SBMs, straining, stool frequency, and stool consistency in patients with chronic constipation.77

However, analysis in 2007 of 29 short-term RCTs including > 11,600 patients treated with tegaserod demonstrated that 13 tegaserod-treated patients had a confirmed cardiovascular ischemic event compared to 1 placebo-treated patient.111 Because the risk of serious cardiovascular events was higher with tegaserod than with placebo, the FDA asked tegaserod’s manufacturer to suspend US sales on March 30, 2007.112

Since tegaserod was removed from the US market, most of the 1056 patients formerly treated with tegaserod were either not switched to any prescription constipation drug (66.6%) or switched to lubiprostone (22.5%), PEG 3350 (10.2%), or lactulose (0.7%), according to a large US health care insurer database.113 When compared to those switched to PEG 3350, patients switched to lubiprostone were less likely to undergo inpatient hospitalization (hazard ratio [HR] 0.679 [95% CI, 0.519-0.890]) or have constipation-related complications (HR 0.314 [95% CI, 0.152-0.649]).

Emerging Therapies for Chronic ConstipationA number of treatments for chronic constipation have been tested in phase II and III clinical trials (Table 10).114,115

Table 10. New and Emerging Therapies for Chronic Constipation114,115

Agent Mechanism of Action Clinical Status

Neurotrophin-3 Neurotrophic factor Phase II

Linaclotide Guanylate cyclase-C Phase III receptor agonist

Prucalopride Selective 5-HT4 Phase III

receptor agonist

TD-5108 5-HT4 agonist Phase II

ATI-7505 5-HT4 agonist Phase II

Methylnaltrexone μ-opioid receptor Approved for opioid- Bromide antagonist induced constipation

Alvimopan μ-opioid receptor Under investigation to antagonist treat opioid-induced constipation


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Neurotrophin-3In pilot studies of neurotrophin-3 for neurologic disorders, neurotrophin-3 improved stool frequency and consistency in a dose-dependent manner.116 As a result, neurotrophin-3 was tested in a pilot study on constipated patients, which confirmed that neurotrophin-3 improved stool frequency, but did not significantly improve stool consistency, and ease of stool passage.117

In a subsequent double-blind, 4-week, dose-ranging, phase II RCT of 107 patients with functional constipation (Rome II), neurotrophin-3 at a dose of 9 mg TIW significantly increased total stool frequency per week compared with placebo (5.7 vs ≈ 1.8; P = 0.0003).116 Mean frequency of complete SBMs increased from 0.85 to 4.40 per week after 4 weeks (P = 0.0143) and the average number of days per week without a bowel movement with neurotrophin-3 was 1.6 compared with 3.2 with placebo (P = 0.0005).

LinaclotideLinaclotide, the guanylate cyclase-C agonist that enhances secretion from intestinal CFTR channels, has completed a phase II study for its use in IBS-C (described above) and is also being investigated for chronic constipation.114,115,118

In a 2009 2-week pilot study (phase IIa) of 42 individuals with chronic constipation (modified Rome criteria), linaclotide compared with placebo dose-dependently increased the weekly frequency of118:• Complete SBMs (2.2-3.2 mean change from baseline vs 1.3; P = nonsignificant)• Stool consistency score (2.58 mean change from baseline for linaclotide 1000 μg vs 0.43; P = 0.014)• Straining score (1.33 and 1.51 mean change from baseline for linaclotide 300 and 1000 μg, respectively, vs 0.36; P = nonsignificant)

Serotonergic Agents for Chronic ConstipationSerotonergic agents are under investigation in chronic constipation just as they are being investigated for IBS.114 Two 5-HT

4 receptor

partial agonists, cisapride and tegaserod, were previously available for chronic constipation, but have since been withdrawn from the US market. Cisapride was removed because of its association with rare dose-dependent cardiac events, including lengthening of the QT interval, syncope, and ventricular arrhythmia in patients with predisposing conditions. Tegaserod was removed for rare cardiovascular adverse events, including myocardial infarction, unstable angina, and stroke.

Other serotonergic agents currently under study for constipation include the selective 5-HT

4 receptor agonist prucalopride, the mixed

5-HT4 agonist and 5-HT

3 antagonist renzapride, and the 5-HT

4

agonists TD-5108 and AT1705.114

PrucaloprideThree identical 12-week phase III trials have recently been conducted on the use of prucalopride in chronic constipation.119-121 Analysis of combined data from the 3, including all 1924 patients with chronic constipation (defined as ≤ 2 spontaneous complete bowel movements [SCBMs] per week with straining, sensation of incomplete evacuation, or hard stools ≥ 25% of the time) studied, demonstrated that a greater percentage of patients receiving prucalopride (2 mg or 4 mg) compared with those receiving placebo had ≥ 3 SCBMs per week (23.6% and 24.7%, respectively, vs 11.3%; P < 0.001).122

In a long-term, open-label, follow-up study of 693 patients from these phase III trials allowed to continue treatment for up to 24 months (median study duration: 14 months), prucalopride was safe and well-tolerated.123 Abdominal pain, headache, diarrhea, nausea, flatulence, and dizziness were the most common adverse events.

TD-5108TD-5108, a highly selective agonist for the 5-HT

4 receptor, has been

tested in a 4-week, dose-ranging, phase II trial of 401 patients with chronic constipation (Rome III criteria, with < 3 SBMs/week during the 2-week baseline).124,125 For those on TD-5108 (15-50 mg), the number of SBMs per week increased by 3.3-3.6 on average over the 4-week period compared with 1.4 for those on placebo (P < 0.05). Straining, stool consistency, and laxative use were also significantly improved with TD-5108 compared with placebo.126 Adverse events noted in the trial were diarrhea and headache.125

Agents for Opioid-Induced Constipation: Methylnaltrexone Bromide and AlvimopanTwo peripheral μ-opioid receptor antagonists were FDA-approved in 2008 for opioid-induced constipation.127,128 Methylnaltrexone bromide was approved for opioid-induced constipation in patients with advanced illness receiving palliative care and unresponsive to laxatives.101 Alvimopan was approved for postoperative ileus following partial large or small bowel resection.

There was some hope that peripheral μ-opioid receptor antagonists may relieve chronic constipation, but in an RCT of 217 patients with chronic idiopathic constipation, alvimopan did not improve the frequency of complete SBMs, degree of straining, or stool consistency.129

Case Study: BelindaBelinda was asked to try an OTC PEG preparation at a dose of 17 g/day. When her symptoms persisted after 2 weeks, she was instructed to increase the PEG to twice-daily dosing. Several weeks later, she calls back with persistent complaints of constipation and intolerable complaints of abdominal fullness and flatulence. You suggest that probiotics might offer some benefit, and also prescribe lubiprostone 24 μg BID. You caution her to take it with food and water to reduce nausea. She returns 4 weeks later to report that her constipation has improved.

CHrOnIC COnSTIPATIOn: SUMMArYAs the second-most common digestive disorder in the United States, chronic constipation represents a substantial proportion of the caseload gastroenterology clinicians handle. Technological advances in diagnostic testing offer clinicians new options for differentiating the subtypes of chronic constipation. New and emerging therapies for chronic constipation are increasing the therapeutic options clinicians can offer their patients. These advances in diagnosis and management can assist clinicians to improve the care of their patients with chronic constipation.

GErDGERD was the most common digestive disease in the United States in 2004, resulting in 6.8 million ambulatory care visits and affecting roughly 6 of every 100 ambulatory care patients.1 The prevalence of GERD is increasing.130 GERD symptoms increased approximately 5% per year in North America and rates of ambulatory care visits for GERD increased almost 3-fold from 1992 to 2004 in the United States.1,130 A recent systematic review of population studies confirmed


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that the prevalence of GERD has increased over the past 2 decades in both North America and Europe, specifically in the United States, Singapore, and China.130

A number of factors are thought responsible for GERD’s increasing prevalence, as shown in Table 11.131-134

Table 11. Factors Responsible for Increased GERD Prevalence131-134

The increasing prevalence of GERD presents a burden to the health care system. Costs, both direct and indirect, of GERD in the United States were estimated at $12.6 billion in 2004, with $7.7 billion spent on an estimated 65 million prescriptions for GERD

medications.1 GERD is responsible for roughly half of all prescriptions for digestive disease in the United States. The top 5 medications prescribed for digestive disease, measured both by the number of prescriptions and their total cost, were all proton pump inhibitors (PPIs).

Emerging Theories on GErD Pathophysiology GERD is a motility disorder that results from excessive reflux events and poor esophageal acid clearance.135 GERD occurs when the antireflux mechanisms at the junction between the esophagus and the stomach are affected. Abnormalities include a defective antireflux barrier, prolonged esophageal acid clearance, altered esophageal mucosal resistance, and delayed gastric emptying.

The pathophysiology of GERD appears multifaceted, yet is poorly understood. While abnormal lower esophageal sphincter (LES) pressure and transient lower esophageal sphincter relaxation (TLESR) enables acid to rise in the esophagus, the etiology of abnormal LES pressure remains unknown.135

One emerging theory on an underlying cause of abnormal LES pressure centers on microbes. In 2009, Yang and colleagues published the results of a study in which they collected 34 biopsy samples of the distal esophagus and histologically classified them as normal, esophagitis, or Barrett’s esophagus (intestinal metaplasia).136 The researchers determined that esophageal microbiomes from the biopsy samples could be classified into 2 types: • Type I, in which the Streptococcus genus was dominant and concentrated into the normal samples• Type II, which had a much lower amount of Streptococcus but higher levels of Gram-negative anaerobes and microaerophiles (including pathogens such as Campylobacter). Type II was associated with the esophagitis samples (OR 15.4) and the Barrett’s esophagus samples (OR 16.5).

The authors speculated that the type II microbiome may act as a mechanism in provoking gastric reflux because lipopolysaccharides (produced by Gram-negative bacteria) induce abnormal relaxation of the LES by activating the inducible nitric oxide synthase pathway.136

GErD: DefinitionsUsing a modified Delphi process that extended over 2 years, an international consensus group developed a consensus definition of GERD and a classification scheme for its associated syndromes.137 They agreed upon the so-called “Montreal definition” of GERD: “GERD is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.”

The authors chose the word “troublesome” because it can be easily translated into other languages and it allows for variability in the impact of symptoms on individual patients. In addition, the “stomach contents” whose refluxate causes symptoms may, under this definition, be gaseous or weakly acidic.137

In the Montreal classification scheme (Figure 1), GERD is an umbrella term that includes symptomatic patients as well as asymptomatic patients with complications such as Barrett’s esophagus or reflux esophagitis.137

Factor Description/Evidence

Increasing Age • Independently associated with increased acid exposure • Retrospective study of 1307 patients with typical reflux symptoms referred for investigation, the percentage of time that ambulatory 24-hour esophageal pH was < 4 increased 1.1% (95% CI, 0.6%-1.4%) for each additional decade of life Increased • Suggested as being related to the Diabetes increased prevalence of GERD, Prevalence especially in diabetics with cardiovascular autonomic neuropathy or peripheral neuropathy Increased Use of • Medications thought to decrease LES Medications That pressure include theophylline, Decrease Lower anticholinergics, and calcium channel Esophageal Sphincter blockers (LES) Pressure Obesity • Obesity shown to increase intra- abdominal pressure, impair gastric emptying, decrease LES pressure, and increase the frequency of transient LES relaxation • Meta-analysis of 8 studies found that pooled weighted odds ratio for GERD symptoms was: o 1.43 (95% CI, 1.158-1.774) among overweight individuals (body mass index [BMI] 25-30 kg/m2) o 1.94 (95% CI, 1.468-2.566) among obese individuals (BMI > 30 kg/m2) Easy Access to • Because individuals can self-treat their Proton Pump heartburn, patients presenting to health Inhibitors (PPIs) care providers are often those who had an incomplete response to PPI therapy, or whose symptom recurrence had exceeded the recommended dosing schedule on the OTC PPI label


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Figure 1. Montreal Classification of GERD and Its Related Syndromes137

Symptomatic Esophageal SyndromesIndividuals who experience esophageal symptoms, whether defined by further diagnostic tests or not, are included in the 2 symptomatic esophageal syndromes: typical reflux syndrome and reflux chest pain syndrome.137

Typical reflux syndrome is characterized by the presence of heartburn (a burning sensation in the retrosternal area) and/or regurgitation (perception of flow of refluxed gastric content into the mouth or hypopharynx).137 Typical reflux syndrome, as defined by the Montreal Consensus Group, includes nonerosive reflux disease (NERD) and endoscopy-negative reflux disease. These 2 terms were excluded from the Montreal classification, because the consensus group preferred that its GERD definition and GERD’s associated syndromes not depend on any particular diagnostic test.

Although heartburn and regurgitation are the characteristic symptoms of typical reflux syndrome, other symptoms are frequently associated with GERD, including epigastric pain and sleep disturbance.137 Prevalence of sleep disturbance due to heartburn or regurgitation has been reported in 3806 (24.9%) of 15,314 respondents in the general population and in roughly 75% of individuals with GERD.138-140 Sleep disturbance can worsen GERD symptoms.141 In a study of 10 GERD patients and 10 healthy controls, acid infusion into the esophagus caused a statistically significant increase in intensity rating and acid perfusion sensitivity score among GERD patients but not healthy controls.

Gastroesophageal reflux can also cause reflux chest pain syndrome or episodes of chest pain that resemble ischemic cardiac pain, but without accompanying heartburn or regurgitation.142 Among individuals with noncardiac chest pain, GERD and esophageal motor disorders are responsible for an estimated 23%-80%, with GERD the most common cause in up to 60%.

Syndromes With Esophageal InjuryReflux esophagitis, defined endoscopically by visible breaks in the distal esophageal mucosa, is the most common manifestation of esophageal injury.137 The Los Angeles classification system, which grades the severity of esophagitis by the length of mucosal break, extension between the tops of mucosal folds, and/or extent of circumferential involvement, is the generally accepted standard.137,143

A major question surrounding reflux esophagitis is whether endoscopic findings and grade of esophagitis are stable over time. The ProGERD study, comprised of 3507 patients with NERD or reflux esophagitis (Los Angeles Grade A/B or C/D) who received follow-up endoscopy 2 years later, demonstrated both progression and regression of disease, with considerable movement between the 3 categories (Figure 2).144 Figure 2. Changes in Endoscopic Findings Among GERD Patients Over 2 Years144

Severe unchecked reflux disease can lead to reflux stricture, the narrowing of the esophageal lumen so that passage of food is impaired.137 Reflux stricture is much less common than reflux esophagitis, observed in < 5% of patients with erosive esophagitis.145 The classic symptom of patients with reflux stricture is persistent troublesome dysphagia, the perceived impairment of the passage of food from the mouth to the stomach.137 Nontroublesome dysphagia is also common in GERD.146 In a study of 11,495 patients with erosive esophagitis, 4449 (37%) reported some level of dysphagia at baseline; dysphagia resolved in most patients (3599 [83%]) after 4 weeks once-daily PPI therapy.

Extraesophageal Syndromes: Established AssociationsGERD symptoms often overlap with extraesophageal symptoms, leading to overdiagnosis and overtreatment.147 Primary care practitioners and gastroenterologists do not always distinguish between symptoms associated with GERD and other conditions (eg, functional dyspepsia).148 Extraesophageal disorders occur frequently in individuals with typical reflux syndrome.149 A study of 6215 individuals with typical reflux syndrome revealed that 2036 (32.8%) experienced extraesophageal syndromes, with cough present in 810 (13%), laryngitis in 645 (10.4%), and asthma in 296 (4.8%).

Several extraesophageal syndromes have been associated with GERD, including reflux cough, reflux laryngitis, and reflux asthma syndromes.137 Whether GERD is a causative agent is unclear. What is known is that these syndromes are rarely present without a concomitant esophageal syndrome and that they are multifactorial, with GERD as one of several potential aggravating cofactors.

GERD could potentially result in extraesophageal syndromes via direct (microaspiration of gastric contents) or indirect (vagally mediated) mechanisms.137 Animal studies have shown that when acid is directly applied to the larynx or airway, laryngeal ulceration and bronchospasm result. Further supporting the association


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between GERD and laryngitis is an RCT showing that only patients with both reflux disease and laryngitis benefited from PPI therapy, and that PPIs conferred no benefit over placebo in treating laryngitis when those with frequent heartburn were excluded.

Similarly, of asthmatics treated with twice-daily PPI therapy, only the group with both nocturnal respiratory and GERD symptoms responded better to the PPI than to placebo.137 However, clinical trials aimed at treating presumed reflux cough, reflux laryngitis, and reflux asthma syndromes by targeting GERD have inconsistent results. Therefore, it is still unclear whether the link between these syndromes and GERD is due to association or causation.

Extraesophageal Syndromes: Proposed AssociationsA number of other syndromes, including sinusitis, pulmonary fibrosis, pharyngitis, and recurrent otitis media, are putatively linked to GERD.137 The studies relating these syndromes to GERD are generally low quality and uncontrolled. For example, in an epidemiological study, US military veterans with reflux esophagitis had increased risk for sinusitis (OR 1.60 [95% CI, 1.51-1.70]) and idiopathic pulmonary fibrosis (OR 1.36 [95% CI, 1.25-1.48]).137,150 The evidence linking pharyngitis and recurrent otitis media is similarly weak.137

GErD: DIAGnOSIS The latest guidelines on the diagnosis of GERD were issued by the AGA Institute in 2008.151 Using the Montreal definition and classification of GERD discussed above, these guidelines outlined a diagnostic algorithm for GERD based on the latest evidence (Figure 3).

Figure 3. 2008 AGA Institute–Recommended Diagnostic Algorithm for GERD151

The current consensus is that clinicians initiate empiric treatment in patients with uncomplicated heartburn.151 For patients with esophageal GERD syndromes, the AGA Institute strongly recommends PPI therapy.

A recent Cochrane review of 134 trials on 35,978 patients with esophagitis concluded that PPIs are more effective than histamine

2-

receptor antagonists (H2RAs), which are more effective than

placebo.152 Most of the efficacy data on these medications is based on once-daily dosing.151 However, expert opinion overwhelmingly recommends twice-daily dosing of PPIs for patients with an esophageal GERD syndrome with inadequate symptom response to once-daily PPI therapy. A recent mail survey of 617 US patients with GERD or erosive esophagitis on PPIs confirmed a substantial percentage (22.2%) was taking them twice daily.153

Case Study: ThomasThomas, a 56-year-old male, presents with burning retrosternal chest pain that wakes him up at night 3-4 times per week. A visit to the emergency room 1 month ago ruled out underlying cardiovascular disease. Thomas tried lansoprazole 30 mg BID for 8 weeks, but experienced only modest improvement. An endoscopy performed 2 years ago revealed no hiatal hernia and no macroscopic signs of esophagitis. What test(s) would you choose to do next?

For symptoms that have not responded to twice-daily therapy, endoscopy is usually the first diagnostic test performed.151 Diagnostic testing is also recommended to avoid misdiagnosing one of several diseases that can mimic GERD: coronary artery disease, gall bladder disease, gastric or esophageal malignancy, peptic ulcer disease, and eosinophilic, infectious, or caustic esophagitis.

Alarm features can identify those patients who may have an alternative diagnosis or complications of GERD.154 A recent meta-analysis determined that weight loss, dysphagia, and epigastric mass on examination are the alarm features with the most utility for diagnosing upper gastrointestinal malignancy. Dysphagia may indicate a stricture or malignancy, but in one study it was reported by 37% of 11,945 patients with esophagitis without stricture or Barrett’s esophagus and resolved in 83% with PPI therapy. Therefore the AGA Institute recommendation is that only “troublesome” dysphagia (ie, not resolving with twice-daily PPI therapy) warrants endoscopy.

For those whose endoscopic evaluation is normal, the next diagnostic test performed is esophageal manometry.151 Manometry evaluates esophageal motor pattern, contraction amplitude, and LES pressure and function.155 Manometry can evaluate peristaltic function preoperatively and diagnose subtle presentations of the major motor disorders, achalasia, and distal esophageal spasm.151

For patients whose endoscopic and manometric tests are normal, pH monitoring or pH-impedance monitoring represents the next step in the diagnostic algorithm.151 Whether these monitoring techniques should be used when the patient is on or off PPI therapy is under debate, although the AGA Institute recommends they be performed while patients discontinue PPI therapy for 7 days.

In a 2008 study, 30 patients with symptoms of heartburn, chest pain, and/or regurgitation despite twice-daily PPI therapy underwent ambulatory pH-impedance monitoring twice: once on PPI therapy and once after ceasing PPI therapy for 7 days.156 They found that PPI therapy did not change the number or proximal extent of reflux episodes. However, 8 patients without a positive symptom association probability (SAP) on PPI therapy had a positive SAP off PPI therapy, whereas 4 patients with a positive SAP on PPIs did not have a positive SAP off PPIs (P = 0.118). These results led the authors to recommend pH-impedance testing be conducted with patients off PPI therapy.

Emerging Diagnostic Tests for GErDThe monitoring techniques previously described have certain limitations: • They offer no data if the patient is asymptomatic during the recording period• They measure intermittent symptoms, not permanent manifestations• The symptom event must be accurately defined and detected


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To address these limitations, a number of diagnostic modalities have emerged: wireless, capsule-based pH monitoring, pharyngeal probes, narrow band imaging (NBI), and confocal endomicroscopy.

Prolonged Wireless Capsule-Based pH MonitoringWireless capsule-based pH monitoring involves temporarily attaching a radiotelemetric capsule to the esophageal mucosa for 24-48 hours.157 This technique offers several advantages over traditional catheter pH recording: it is better tolerated, interferes less in daily activities, and has a higher satisfaction rate. However, it is also more invasive for the esophageal mucosa, more costly, and may carry an age limitation.

Because it allows the patient’s pH data to be recorded for a longer time than a traditional catheter, it can more accurately detect GERD. In a study of 62 patients with noncardiac chest pain on a wireless pH monitor, information suggesting a reflux diagnosis was obtained in 12 patients (19.4%) (95% CI, 11.5%-30.9%) by extending wireless pH monitoring to a second day.158

NBINBI, a novel imaging technique that uses shorter-wavelength light to characterize superficial tissue structures such as capillaries and mucosal pattern without using dyes, has demonstrated utility in diagnosing head and neck cancers, Barrett’s esophagus, and early esophageal, gastric, and colon cancer.159

A 2007 study examined NBI’s accuracy in diagnosing GERD by comparing NBI results in 50 GERD patients and 30 healthy controls.159 Significantly higher proportions of GERD patients had increased:

• Number of intrapapillary capillary loops (IPCLs) (OR 12.6 [95% CI, 3.8-42.0])• Tortuosity of IPCLs (OR 6.9 [95% CI, 2.5-19.0])• Dilatation of IPCLs (OR 20.0 [95% CI, 6.1-65.3])• Number of microerosions (52% vs 0%; P < 0.0001)

Interoberserver agreement for these 4 NBI findings ranged from 0.48 (moderate) to 0.88 (almost perfect), whereas intraobserver agreement values ranged from 0.39 to 0.52.159

Case Study: ThomasRecall that Thomas, a 56-year-old male, presented with burning retrosternal chest pain only moderately responsive to lansoprazole 30 mg BID for 8 weeks. Following the AGA Institute algorithm for diagnosis of GERD, you perform an endoscopy with biopsy. No macroscopic abnormalities were visible on endoscopy and biopsies were negative for inflammation, eosinophilic or otherwise. Following the AGA Institute algorithm, you proceed with esophageal manometry, which shows normal esophageal peristalsis and normal LES resting pressure and relaxation. Subsequent pH monitoring demonstrates esophageal acid exposure in the normal range (time with pH < 4: upright 3.2%, supine 0%, total 2.3%). During the 24-hour recording, Thomas experienced 6 symptom episodes; none of these was temporally associated with the onset of a reflux, acidic or nonacidic. Therefore, you diagnose Thomas with functional heartburn. After advising him about possible adverse events (ie, constipation), you start him on imipramine 50 mg at bedtime and discontinue his PPI therapy. You ask him to keep a diary to determine whether particular foods, activities, or situations provoke his symptoms. Finally, you request that Thomas follow-up in several months.

GErD: MAnAGEMEnTLong-term management of GERD depends on the manifestation of the disease.151 For patients with erosive esophagitis, numerous studies have shown that recurrence of erosive disease is dramatically reduced with daily PPI treatment.

A recent meta-analysis of 10 RCTs that evaluated the use of PPIs at maintenance doses (generally half the healing dose) for 26-52 weeks in maintaining healed esophagitis determined that 36.1% of those taking PPIs relapsed compared with 75.4% of those on placebo.160 For patients taking a maintenance dose of a PPI, the relative risk of relapse was 0.46 (95% CI, 0.38-0.57) and the NNT was 2.4 (95% CI, 2.1-2.9). The data were even stronger for those taking a healing dose: 21.7% of those taking a healing dose of a PPI relapsed compared with 78.8% of those on placebo, based on combined data from 9 RCTs, with a relative risk of relapse of 0.26 (95% CI, 0.19-0.36) and an NNT of 1.7 (95% CI, 1.6-1.8).

For patients with nonerosive disease, symptom recurrence is similarly reduced with maintenance PPI therapy.154 But for this patient population, on-demand PPI dosing (ie, daily therapy until symptoms resolve) appears effective.161 A review of 17 studies concluded that on-demand dosing of PPIs was effective in nonerosive disease or uninvestigated GERD, but not in erosive esophagitis.

Therefore, the AGA Institute recommended on-demand therapy for patients with an esophageal GERD syndrome without esophagitis.151 For patients with healed erosive esophagitis, on-demand therapy is not recommended. In a study of 470 patients with healed erosive esophagitis, the relapse rate after 6 months was 42% with on-demand PPI therapy and 19% with daily PPI therapy (P ≤ 0.0001).162

Maintenance PPI Therapy: Safety Issues

Case Study: JudyJudy, a 61-year-old executive, presents with chronic GERD symptoms that are partially relieved with once-daily PPI therapy. She is concerned about the recent news linking PPI use to osteoporosis and pneumonia, and she also wants better symptom control. Because of her busy schedule, she often forgets to take her PPIs 30 minutes before meals. She heard about other options for GERD, including new PPIs and surgical intervention, on the radio, so she presents to you today to find out what other options are available to her.

Simultaneous Use of PPIs and ClopidogrelSeveral recent studies have reported increased cardiovascular morbidity and mortality in patients taking clopidogrel and PPIs simultaneously.163-165 When initiating clopidogrel after myocardial infarction or stent placement, PPIs are often prescribed prophylactically to guard against gastrointestinal bleeding.164 However, certain PPIs inhibit the cytochrome P450 2C19 enzyme, which is involved in the bioactivation of clopidogrel.163-165

In a study of 8205 veterans hospitalized for acute coronary syndrome, death or rehospitalization occurred in 615 (20.8%) patients prescribed clopidogrel without PPI, but in 1561 (29.8%) of patients prescribed clopidogrel with a PPI.164 Furthermore, using clopidogrel with a PPI at any time was associated with increased risk of death or rehospitalization compared with using clopidogrel without a PPI (adjusted OR [AOR] 1.25 [95% CI, 1.11-1.41]).


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Other studies also suggest that clinicians exercise caution when prescribing PPIs with clopidogrel:• A large retrospective study of stent patients who were ≥ 80% compliant on clopidogrel for a year found that the incidence of a cardiovascular event within 1 year was greater in the 4521 patients taking clopidogrel with PPIs than in the 9862 patients taking clopidogrel alone (32.5% vs 21.2%; AOR 1.79 [95% CI, 1.62-1.97]).165 • A retrospective study conducted by Juurlink and colleagues of 13,636 patients who initiated clopidogrel following hospital discharge for an acute myocardial infarction determined that PPI use within 30 days was associated with reinfarction (AOR 1.27 [95% CI, 1.03-1.57]).163

It should be noted that use of the PPI pantoprazole, which does not inhibit cytochrome P450 2C19, was not associated with reinfarction in the study conducted by Juurlink and colleagues (OR 1.02 [95% CI, 0.70-1.47]) and another trial demonstrated that pantoprazole and esomeprazole were not associated with impaired response to clopidogrel.166

The FDA has launched an investigation to characterize the effects of genetic factors and other drugs (including PPIs) on the effectiveness of clopidogrel.167 Until the investigation is complete, it recommends that health care providers reevaluate the need to start or continue treatment with a PPI, including OTC omeprazole, in patients receiving clopidogrel. However, the American College of Cardiology, American Heart Association, and the ACG issued a joint statement in 2008 stating that, because the interaction between PPIs and clopidogrel has not been studied in large numbers of patients, there is no definitive evidence that using PPIs keeps clopidogrel from working to prevent cardiac events and patients who are currently taking these medications should not change their medication regimen unless advised by their clinician.168

PPI Use and Fracture RiskBecause acid suppression may inhibit calcium absorption, and PPIs may decrease bone resorption, there is some concern that PPI therapy may adversely affect calcium metabolism.169

Two recent population studies have demonstrated an association between PPI use and hip fracture.169,170 The first, a case-control study of 13,556 hip fractures and 135,386 controls, demonstrated an increased risk for hip fracture among individuals receiving PPIs for > 1 year (AOR 1.44 [95% CI, 1.30-1.59]), especially among those receiving high-dose PPI therapy (AOR 2.65 [95% CI, 1.80-3.90]; P < 0.001) or longer-term PPI therapy (AOR for PPI use for 4 years 1.59 [95% CI, 1.39-1.80]; P < 0.001).169 The second, a retrospective matched cohort study, determined that risk of hip fracture rose with increasing duration of PPI therapy, with an OR of 1.62 for exposure for ≥ 5 years (95% CI, 1.02-2.58; P = 0.04) and an OR of 4.55 for exposure for ≥ 7 years (95% CI, 1.68-12.29; P = 0.002).170

A case-control study presented at DDW 2009 similarly found increased risk of hip fracture with PPI therapy.171 Of 33,752 hip fracture diagnoses and 130,471 matched controls, patients with hip fractures were more likely to have taken PPIs for ≥ 2 years (OR 1.30 [95% CI, 1.21-1.39]) and those who took higher dosages for longer duration had increased risk.

PPI Use and InfectionNormal gastric juice, which has a pH < 4, rapidly kills ingested pathogens.172 Effective management of upper gastrointestinal symptoms, however, requires that gastric pH be maintained above 4 for ≥ 18 hours. Therefore, there is some concern that maintenance therapy with PPIs may increase the load of ingested pathogens and the risk for infection.

A systematic review found that acid suppression via H2RAs or

PPIs increased the risk of Clostridium difficile infection (OR 1.95 [95% CI, 1.48-2.58]) with a slightly higher risk among those taking PPIs (OR 2.05 [95% CI, 1.47-2.85]).173 Acid suppression with PPIs also increased the risk of enteric infection due to Salmonella, Shigella, Campylobacter, or Escherichia coli (OR 3.33 [95% CI, 1.84-6.02]).

Other studies have associated acid suppression with infection outside the gastrointestinal tract. In a large survey of 364,683 general practice patients, PPI use increased the risk for community-acquired pneumonia (CAP) (AOR 1.73 [95% CI, 1.33-2.25]) in a dose-dependent manner.172 The AOR for CAP was:

• 1.23 (95% CI, 0.78-1.93) for individuals receiving < 1 defined daily dose (DDD)• 1.94 (95% CI, 1.41-2.68) for those receiving 1 DDD• 2.28 (95% CI, 1.26-4.10) for those receiving > 1 DDD

A 2009 prospective pharmacoepidemiologic study of 63,878 patients hospitalized in an urban medical center showed an increased risk of hospital-acquired pneumonia among individuals on PPI therapy (AOR 1.3 [95% CI, 1.1-1.4]).174

PPI Overuse and RAHSAs PPI use increases due to reduced cost, increased availability, fewer concerns about adverse events, the paucity of viable alternatives, and its endorsement by most US and international consensus guidelines, issues surrounding PPI overuse and potential dependence are now a hot topic of debate.175

There is epidemiologic evidence of PPI overuse.176 One-quarter of patients without an indication for maintenance PPI therapy took PPIs continuously for > 6 months, according to a large population study in the Netherlands. Some critics charge that unnecessary PPI use may create the disease PPIs are designed to treat.175 They contend that patients free of their previous acid-related symptoms nevertheless continue to take PPIs despite having no current indication for the therapy. They argue that unnecessary PPI use induces the return of acid-related symptoms, forcing patients with no previous need for PPIs to continue taking them to treat their newly returned symptoms, resulting in PPI dependence.

Rebound acid hypersecretion (RAHS) – defined as an increase in gastric acid secretion above pretreatment levels following antisecretory therapy – may be what these critics had in mind.177 A randomized, double-blind, placebo-controlled trial published in July 2009 sought to determine if long-term PPI treatment followed by withdrawal induces RAHS, thus creating PPI dependency. Healthy participants were randomized to receive placebo for 12 weeks (n = 59) or esomeprazole 40 mg daily for 8 weeks followed by placebo for 4 weeks (n = 59). Patients filled out the Gastrointestinal Symptom Rating Scale (GSRS) weekly. A score of > 2 on any of the


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questions regarding heartburn, acid regurgitation, or dyspepsia was defined as a clinically relevant acid-related symptom. GSRS scores for acid-related symptoms were notably higher in the patients receiving esomeprazole after 12 weeks (1.3 ± 1.2) than in those receiving placebo (1.0 ± 0.3) (P = 0.001). Furthermore, 26 (44%) of those receiving the PPI reported ≥ 1 clinically relevant acid-related symptom in the last 3 weeks of the study compared with 9 (15%) of those receiving placebo (P < 0.001).

The results led the authors to conclude that RAHS caused the clinically relevant acid-related symptoms in previously healthy patients and hypothesize that RAHS could lead to PPI dependency.177

Future Approaches to Improve Acid Inhibition With PPIsAlthough PPIs are highly effective at acid suppression, they have limitations.178,179 They must be taken 30 minutes before meals to maximize efficacy because the amount of H+/K+-ATPase (the proton pump) in the parietal cell is at a maximum after a prolonged fast. Also, the elimination half-life for some PPIs is short, around 1-2 hours.180 For once-daily dosing, this means that only a negligible concentration of PPI remains in the circulation at the end of the dosing interval.

Various strategies address these limitations:• Twice-daily dosing of PPIs increases the area under the plasma concentration time curve and the duration of acid suppression181,182 • Utilizing an enantiomer of an older PPI can improve pharmacokinetic and clinical efficacy, which is also true of esomeprazole, the S-isomer of omeprazole, and dexrabeprazole, the R-isomer of rabeprazole183,184 • Removing the enteric coating from PPIs can hasten their release and absorption.179 An immediate-release formulation of omeprazole, buffered with sodium bicarbonate without an enteric coating, has been shown to rapidly neutralize gastric acid and maintain gastric pH > 4 for > 18 hours. • Combining PPI therapy with other acid suppression therapies, such as adding an H

2RA or TLESR inhibitor to ongoing PPI therapy,

may also improve efficacy185

Modified-Release PPI FormulationsModified-release formulations of PPIs may improve acid control. A dual delayed release (DDR) formulation of dexlansoprazole, in which initial drug release in the proximal small intestine is followed by release in the distal small intestine several hours later, was recently approved by the FDA.101,186 Once-daily dexlansoprazole is approved for the healing of all grades of erosive esophagitis for up to 8 weeks (60 mg), maintaining healing of erosive esophagitis for up to 6 months (30 mg once daily), and treating heartburn associated with NERD for 4 weeks (30 mg once daily).

Since not all pumps are inhibited by a single PPI dose and pumps regenerate during the day, significant acid secretory capacity can return by night with once-daily dosing of conventional PPIs.187 Dexlansoprazole represents an attempt to prolong the duration of PPI pharmacokinetic effect. The agent has 2 types of enteric-coated granules, which dissolve and release the drug at 2 different pHs, resulting in a concentration-time profile with 2 distinct peaks.101,188 The first peak occurs 1-2 hours after taking the drug, followed by a second

peak within 4-5 hours.188 Wu and colleagues demonstrated how dexlansoprazole’s 2 distinct peaks maintained active concentrations longer than a conventional PPI, as illustrated in Figure 4.189

Figure 4. DDR Dexlansoprazole Prolongs Active Concentration of Drug Compared With Conventional PPIs189

In 2 identical 8-week RCTs of a total of 4092 patients with erosive esophagitis, modified-release dexlansoprazole (60 mg and 90 mg) demonstrated noninferiority to lansoprazole 30 mg once daily in healing erosive esophagitis.186 In a post hoc analysis, dexlansoprazole 90 mg modified release was significantly more effective in healing moderate-to-severe erosive esophagitis (Los Angeles Grades C/D) than lansoprazole 30 mg once daily. A dose-finding study of esomeprazole modified release showed that the mean percentage time with intragastric pH > 4 was significantly greater with esomeprazole at the optimal dose of 60 mg modified release than when dosed at 20 mg BID (87.9% vs 78.9%; P < 0.05).190

Imidazopyridine-Based PPI: TenatoprazoleChanges to the chemical structure of PPIs can also improve their efficacy. Conventional PPIs, such as omeprazole, pantoprazole, lansoprazole, and rabeprazole, all have a benzimidazole-based structure and an elimination half-life of around 1-2 hours.180 Tenatoprazole, by contrast, has an imidazopyridine ring in place of the benzimidazole moiety, and a 7-hour half-life.

A randomized crossover study of 30 Helicobacter pylori–negative volunteers compared 7-day treatment with tenatoprazole to 7-day treatment with esomeprazole, with a 4-week washout between.181 Nocturnal mean pH on day 7 was significantly higher with tenatoprazole (4.64 ± 0.67 vs 3.61 ± 0.90; P < 0.0001), as was the percentage of time with pH > 4 (72.45% ± 14.89% vs 62.24% ± 13.55%; P < 0.0001). Tenatoprazole compared with esomeprazole continued to exert an effect 3-5 days after treatment withdrawal due to its long half-life (9.28 ± 6.41 hours vs 1.44 ± 0.29 hours).

Emerging GERD TherapiesLike PPIs, potassium-competitive acid blockers (P-CABs) bind to the H+/K+-ATPase (proton pump), but they do so at the extracellular surface where they compete with potassium.179 Clinical trial data on the P-CABs soraprazan and revaprazan have shown that they work quickly, with full efficacy from the first dose.

In a clinical trial, revaprazan had greater efficacy than omeprazole in controlling acid secretion.179 Another P-CAB, AZD0865, showed


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efficacy for healing erosive esophagitis similar to that of esomeprazole in a study of 1521 individuals with erosive esophagitis.191 The healing rate at 4 weeks was 81.1% with AZD8065 75 mg and 81.9% with esomeprazole 40 mg. AZD8065 also yielded a significantly greater acid control than esomeprazole in a study of 1459 NERD patients (intragastric pH > 4 approximately 78% of the time with AZD8065 75 mg vs approximately 60% with esomeprazole 20 mg; P = 0.033).192

A novel γ-aminobutyric acid type B receptor agonist, AZD3355, is being tested as add-on therapy for patients with GERD symptoms despite PPI therapy. In a study of 232 patients with continued GERD symptoms despite ≥ 6 weeks of PPI therapy, the proportion of responders (those with at most 1 24-hour period with heartburn or regurgitation of not more than mild intensity during the last week of treatment) was significantly greater with AZD3355 than with placebo (16% vs 8%; one-sided P = 0.026).193 In another study of 25 patients with GERD symptoms despite PPI therapy, AZD3355 reduced the mean total number of reflux events over 24 hours by approximately 35% compared with placebo (41.0 vs 62.7; mean difference 22 [95% CI, 15-23]).194 AZD3355 also reduced the geometric mean number of TLESRs by 25% and increased geometric mean LES pressure by 28% compared with placebo.

ADX10059, a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5) represents another approach to treatment.195 By its ability to inhibit mGluR5 signaling, ADX10059 reduced TLESRs and increased LES tone in animal models.

In a randomized, double-blind, placebo-controlled study of 24 healthy male patients presented at DDW 2009, Zerbib and Keywood randomized patients to receive placebo (n = 2) or ADX10059 at doses of 50 mg BID, 125 mg BID, and 250 mg BID (n = 6 for all 3 treatment groups) for 6 days.196 All 3 doses were well-tolerated, and a significant treatment effect was noted for total acid exposure percentage (P = 0.048) and number of weakly acidic reflux episodes (P = 0.0411). In particular, the 125 mg BID cohort had significant differences with ADX10059 in various reflux measures (median total reflux episodes, median total acid reflux episodes, and median total weakly acidic reflux episodes), leading the authors to conclude that ADX10059 dose-dependently decreased reflux events in healthy patients.

Antireflux SurgeryIn addition to these medical options for GERD therapy is the surgical option of antireflux surgery.154 However, the indications for and efficacy of antireflux surgery for GERD management are highly controversial. Because GERD has low morbidity and mortality, GERD therapies must be very safe to meet an acceptable risk/benefit ratio. As a result, the AGA Institute recommendations for surgery are generally cautious.

For patients with esophageal GERD syndromes in whom antireflux surgery and PPI therapy would offer similar efficacy, the AGA Institute recommends PPIs as initial therapy, reserving antireflux surgery as an option for patients intolerant of acid suppressive therapy (Grade

A recommendation).151 The AGA Institute recommends antireflux surgery (Grade B recommendation) for patients with an esophageal GERD syndrome with persistent troublesome symptoms despite PPI therapy, but warns that the potential risks of surgery should be carefully weighed. It also recommends against surgery for patients who are symptomatically well-controlled on medical therapy.

Case Study: JudyTo respond to Judy’s concerns about the link between PPI use and osteoporosis and pneumonia, you educate her on the most recent data on PPI safety. In addition, you switch her to a new PPI (dexlansoprazole delayed release 30 mg once daily) to control her symptoms. She reports improved compliance and symptom control, but still experiences occasional nighttime regurgitation episodes.

GErD: SUMMArYRecent data on safety issues with PPIs are now changing the gastroenterology clinician’s treatment algorithm for GERD. Emerging diagnostic techniques, ongoing refinements in the pharmacokinetics and delivery of PPI therapy, and novel acid reflux medications offer promise in improving both the diagnosis and management of GERD. These advances increase the options available to clinicians so they can optimize and individualize management of patients with this very common disease.

BArrETT’S ESOPHAGUSAppropriate GERD management is important because chronic reflux symptoms substantially increase the risk of esophageal adenocarcinoma.197 In a large prospective case-control study of approximately 85% of Swedish patients newly diagnosed with esophageal adenocarcinoma between 1994 and 1997, patients with reflux symptoms at least once per week (OR 7.7 [95% CI, 5.3-11.4]) and those with nocturnal reflux weekly (OR 10.8 [95% CI, 7.0-16.7]) were at a higher risk of esophageal adenocarcinoma. For individuals with ≥ 20 years of severe symptoms, the risk of esophageal adenocarcinoma was substantially higher (OR 43.5 [95% CI, 18.3-103.5]).

This very strong association between reflux symptoms and esophageal adenocarcinoma has been corroborated by epidemiologic data.198 The incidence of esophageal adenocarcinoma has risen 6-fold from 1973 to 2001, along with the rising prevalence of GERD. In fact, the rate of increase in the incidence of esophageal adenocarcinoma has now surpassed that of melanoma, prostate cancer, breast cancer, lung cancer, and colorectal cancer.

recently Updated Guidelines on ManagementThe diagnosis and treatment of Barrett’s esophagus continues to be controversial, and there is much debate regarding its proper management. Because of major advancements in the diagnosis and treatment of Barrett’s esophagus in the first decade of the 21st century, the ACG revised its guidelines on the management of the disease in 2008.199 The primary ACG recommendations are listed in Table 12.


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Table 12. ACG Recommendations on Barrett’s Esophagus Management199

In 2009, the Society of Thoracic Surgeons (STS) issued its own set of management guidelines for Barrett’s esophagus.200 The STS recommendations focus on one of the statements issued by the ACG in its guidelines (“Esophagectomy is no longer the necessary treatment response to high grade dysplasia”), stating that “We believed that it was important to have a balanced guideline from our society addressing the role of esophageal resection, as well as these other approaches that are becoming increasingly adopted in clinical practice.” Regarding esophagectomy, the STS recommendations state:• It is reasonable to use esophagectomy to eliminate high-grade dysplasia (HGD) and any associated cancer. The majority of cancers found incidentally in patients with HGD are cured by esophagectomy. (Level B Evidence)• Esophagectomy for Barrett’s esophagus with HGD is reasonable and can be performed safely, with an operative mortality approaching 1% (Level B Evidence)• It is beneficial to perform esophagectomies for HGD in high- volume centers and by surgical teams with specific expertise in these procedures (Level B Evidence)• Vagal-sparing or minimally invasive esophagectomy may be considered for patients with HGD because quality of life and the adjustment period may be improved by these approaches (Level B Evidence)

Terminology to Describe Barrett’s EsophagusOne area of debate is terminology. Although the term “Barrett’s esophagus” is widely used, there is little consensus about its meaning.137 Clinicians agree that Barrett’s esophagus involves the partial replacement – from the gastroesophageal junction proximally – of esophageal squamous epithelium with metaplastic columnar epithelium (Figure 5). Disagreement exists, however, on whether the term “Barrett’s esophagus” should be based on endoscopy and/or histology.

Figure 5. Endoscopic and Histologic Views of Barrett’s Esophagus

Photos courtesy of Byron Cryer, MD.

The Montreal Group proposed new terminology to address the linguistic confusion over endoscopically versus histologically defined metaplasia.137 For endoscopic findings consistent with Barrett’s esophagus that have not yet been histologically evaluated, they used the term “endoscopically suspected esophageal metaplasia” (ESEM). Then, in the most controversial topic of the entire Montreal process, the group agreed that the term “Barrett’s esophagus” be reserved for ESEM with biopsy evidence of any type of columnar epithelium and the type of metaplasia specified, “Barrett’s esophagus, GM+” for Barrett’s esophagus with gastric metaplasia, and “Barrett’s esophagus, SIM+” for Barrett’s esophagus with specialized intestinal metaplasia.

• Barrett’s esophagus is a “change in the distal esophageal epithelium of any length that can be recognized as columnar type mucosa at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus”• Screening for Barrett’s esophagus remains controversial because of the lack of documented impact on mortality from esophageal adenocarcinoma• The highest yield for Barrett’s is in older (aged ≥ 50 years) Caucasian males with longstanding heartburn• The grade of dysplasia determines the appropriate surveillance interval• Any grade of dysplasia by histology should be confirmed by an expert pathologist• Low-grade dysplasia requires expert pathologist confirmation and more frequent endoscopy and biopsy• High-grade dysplasia (HGD) requires confirmation by an expert pathologist and represents a threshold for intervention• A more intensive biopsy protocol is necessary to exclude the presence of concomitant adenocarcinoma• Any mucosal irregularity (eg, nodularity or ulcer) is best assessed with endoscopic resection for a more extensive histologic evaluation and exclusion of cancer• Management of patients with HGD is dependent on local expertise (both endoscopic and surgical) and the patient’s age, comorbidity, and preferences• Esophagectomy is no longer the necessary treatment response to HGD• Although promising, no sufficient evidence exists to recommend use of the following imaging systems on a routine clinical basis: o Narrow band imaging o FICE o Autofluorescence imaging o Chromoendoscopy o Optimal coherence tomography o Laser confocal microscopy o Spectroscopic devices o Reflectance o Fluorescence o Light scattering• Currently, validated biomarkers or panels that can be performed on a clinical basis for widespread laboratory use are not available• Promising biomarkers to predict cancer include nuclear DNA content abnormalities (ie, aneuploidy and tetraploidy in biopsy specimens), as well as loss of heterozygosity of specific genes such as P16 and P53• Recent studies demonstrate that methylation of P16, RUNX3, and HPP1, as well as demographic characteristics of the patients and Barrett’s esophagus length are indicators of cancer risk• Chemoprevention in premalignant state of esophageal adenocarcinoma represents a promising future strategy, but sufficient prospective evidence that any treatment prevents cancer is lacking• For Barrett’s esophagus patients, the goal of pharmacologic acid suppression with PPIs is to control reflux symptoms• In the short term, nonendoscopic methods that identify Barrett’s mucosa based on high resolution, spectroscopic, or colorimetric means may become available• A multicenter RCT of surveillance endoscopy is needed to determine its validity• One or more of the following technologies will become clinically available: o Fluorescence o Light scattering o Reflectance o Raman spectroscopy o Laser confocal microscopy o Endomicroscopy o Optical coherence tomography• A prospective definition of risk of diffuse compared with focal dysplasia • Advances in technologies of endoscopic ablation therapy (ie, radiofrequency ablation, cryotherapy, photodynamic therapy)• Documentation of frequency and duration of the surveillance protocol after endoscopic ablation therapy requires careful study• Validation of a biomarker panel to risk stratify Barrett’s esophagus patients

Definition

Screening

Surveillance

Dysplasia Management

Imaging

Biomarkers

Chemoprevention

Reflux Control

Anticipated Developments


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The US and UK definitions of Barrett’s esophagus differ from the Montreal standard, most notably on the question of histologic evidence of intestinal metaplasia.201,202

The consensus UK opinion is that diagnosis of Barrett’s esophagus requires visible endoscopic evidence of columnar metaplasia above the gastroesophageal junction (GEJ) with histologic confirmation.201 Because, in UK pathologic opinion, “intestinal metaplasia can always be identified in endoscopically-visible columnar metaplasia providing a sufficient number of biopsies are taken over an adequate time-scale,” they do not require histologic evidence of intestinal metaplasia.

The US definition requires evidence of intestinal-type metaplasia on biopsy: “Barrett’s esophagus is a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus and excludes intestinal metaplasia of the cardia.”202 It should be noted, however, that although this has been the US definition since 1998, in a 2004 survey, only 80% of practicing US gastroenterologists agreed that intestinal metaplasia was a prerequisite for the diagnosis of Barrett’s esophagus, and only 72% of a panel of US experts on Barrett’s esophagus at the 2003 AGA Barrett’s Esophagus Workshop agreed.203,204

Endoscopically Grading Barrett’s EsophagusBecause the extent of esophageal columnar metaplasia influences the risk of esophageal adenocarcinoma, the Montreal group recommended that ESEM be described with a standardized measure of endoscopic extent.137 At the time of publication, there was little research into the best approach. Since 2006, an international working group developed and validated standardized criteria to describe the extent of esophageal columnar metaplasia.205,206

Dubbed the Prague Circumferential and Maximal (C&M) criteria because they were first presented at the 2004 United European Gastroenterology Week in Prague, they establish criteria for endoscopically recognizing the GEJ and measuring the circumferential and maximal extents of Barrett’s esophagus segments above the GEJ in centimeters (Figure 6).206 Validation studies of endoscopy video clips determined (after outlying data from assessors who did not understand the classification were removed) overall reliability coefficients of 0.94 for “C” (internal and external) and 0.88 and 0.93 for “M” (internal and external, respectively), which correlate to “almost perfect” reliability. Figure 6. Prague C&M Standardized Grading of Barrett’s Esophagus*206

* With a classification of C3M5

Emerging Imaging Modalities to Diagnose Barrett’s EsophagusGiven the sampling error inherent in esophageal biopsy, new imaging techniques have been developed to enhance imaging of Barrett’s esophagus and improve detection of dysplasia.207,208 One of these is NBI, which changes the optical features of the current sequential lighting videoendoscopes to spectral narrow-band filters.207 Using high-intensity blue light with these spectral filters allows imaging of superficial tissue structures, including capillary and mucosal patterns. In a prospective cohort study of 51 patients with known or suspected Barrett’s esophagus, the ridge/villous mucosal pattern seen on NBI had 93.5% sensitivity and 86.7% specificity for identifying the 28 cases of intestinal metaplasia without dysplasia, whereas the irregular/distorted mucosal pattern on NBI had 100% sensitivity and 98.7% specificity for identifying the 7 HGD cases (Figure 7).207

Figure 7. NBI Images of Mucosal Patterns207

A. Ridge/villous mucosal pattern. B. Irregular/distorted mucosal pattern. Images provided by Prateek Sharma, MD.

The utility of this new imaging technique is under investigation.209

A simplified classification system that evaluated mucosal and vascular patterns visible with NBI was recently tested in a group of international observers. Although there was moderate-to-substantial intraobserver agreement and moderate interobserver agreement, only 71% of the images of high-grade intraepithelial neoplasia/early cancer were correctly identified. Therefore, the authors questioned whether NBI could replace histologic sampling.

Another imaging technique tested on Barrett’s esophagus is confocal laser endomicroscopy (CLE), which allows subsurface analysis of the intestinal mucosa and in vivo histology during ongoing endoscopy.208 In a study of 63 patients with Barrett’s esophagus (20 with long-standing reflux symptoms, 30 with known Barrett’s esophagus, and 13 with suspected Barrett’s-associated neoplasia), CLE had a sensitivity of 98% and specificity of 94% to detect Barrett’s esophagus and a sensitivity of 93% and specificity of 98% to detect neoplasia. The mean κ value for interobserver agreement was 0.843.

Case Study: LarryLarry, a 61-year-old male with a body mass index of 30.2 kg/m2, presents with persistent GERD symptoms that are well-controlled with once-daily PPI therapy. Endoscopy reveals C2M4 Barrett’s esophagus, but no dysplasia. Is Larry a candidate for ablation of metaplastic epithelium?


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Managing risk Factors in Barrett’s EsophagusAppropriate management of Barrett’s esophagus begins with modulating predisposing risk factors. Risk factors include obesity, particularly visceral adiposity, tobacco and alcohol use, Caucasian race, male gender, and middle age.210-212 Other risk factors relate to the duration and severity of GERD: development of GERD symptoms at an early age, > 5-10 years of GERD symptoms, nocturnal GERD symptoms, and GERD complications (eg, ulceration, strictures, bleeding, and esophagitis).

The main concern with Barrett’s esophagus is that it may progress to esophageal adenocarcinoma, which has a 5-year survival rate of < 15%.213 The greatest risk of progression seems to be in those cases in which intestinal metaplasia develops more abnormal features, from low-grade dysplasia (LGD) to HGD.214 For Barrett’s esophagus patients with nondysplastic intestinal metaplasia, some evidence suggests PPI therapy reduces the incidence of dysplasia.215 Retrospective analysis of a prospectively characterized cohort of 236 veterans with Barrett’s esophagus followed by a single experienced endoscopist demonstrated that the cumulative incidence of dysplasia was significantly lower among those who received PPI therapy than among those who received an H

2RA or no antisecretory

therapy after diagnosis (P < 0.0001 for log rank test on Kaplan-Meier survival analysis) (Figure 8).

Figure 8. Incidence of Dysplasia Among Patients With Barrett’s Esophagus215

radiofrequency Ablation for Barrett’s EsophagusOne controversial, yet promising area of research is the use of radiofrequency ablation (RFA) to eradicate Barrett’s esophagus. Several studies have now examined RFA.214,216,217

In a multicenter RCT of 127 patients with dysplastic Barrett’s esophagus ≤ 8 cm in length, RFA performed up to 4 times during the study was compared to a sham procedure.214 At assessment 12 months from baseline, RFA completely eradicated dysplasia in significantly more patients with LGD (90.5% vs 22.7%; P < 0.001), HGD (81.0% vs 19.0%; P < 0.001), or any grade of dysplasia (77.4% vs 2.3%; P < 0.001). The RFA-treated group had significantly greater chest pain on day 1 after the initial circumferential RFA compared with the sham-treated group (median 23 vs 0 on a 0-100 point Visual Analogue Scale; P < 0.001), but median day 1 chest pain scores were 0 after subsequent focal RFA. Esophageal stricture developed in 5 patients (6%) in the ablation group.

A similar study examined the safety and efficacy of RFA every 2-4 months in patients with Barrett’s esophagus in a community practice setting.216 Among the 137 patients with follow-up biopsy > 1 year after RFA who received 2 RFA procedures, RFA completely eradicated dysplasia in all 27 patients with evidence of dysplasia at baseline and 77% of the 105 patients with intestinal metaplasia at baseline. Of the 429 patients (788 RFA procedures) who comprised the safety cohort, there were 9 strictures, 4 with mild bleeding during RFA, 1 with mucosal injury during RFA, 1 with fever, and 1 with hematemesis.

Finally, a 2009 study examined the safety and efficacy of RFA for very long segments (≥ 10 cm) of Barrett’s esophagus.217 Of the 26 patients in the study, with a Barrett’s esophagus with a median length of 11 cm (range, 10-20 cm), those with visible lesions underwent focal endoscopic resection, then all received initial circumferential and subsequent focal RFA every 2-3 months. A total of 14 patients achieved complete remission after circumferential RFA with a median of 2 (interquartile range 1-3) focal RFA sessions. Notably, 12% of these patients with long-segment Barrett’s esophagus showed poor healing after RFA, which the authors believed reflected the severity of the underlying reflux disease.

Management of Barrett’s esophagus was excluded from the 2008 AGA Institute medical position statement on the management of GERD; it will be the subject of an upcoming AGA medical position statement.151

Case Study: LarryIs Larry, the 61-year-old male with C2M4 Barrett’s esophagus but no dysplasia, a candidate for ablation of metaplastic epithelium? Because the risk of cancer in nondysplastic Barrett’s esophagus is very low, endoscopic ablation is not recommended. Instead, Larry should continue with once-daily PPI therapy to control his persistent GERD symptoms.

BArrETT’S ESOPHAGUS: SUMMArYRecent updates in the terminology for and grading of Barrett’s esophagus, as well as advances in imaging and therapy, are rapidly changing clinicians’ options for diagnosis and therapy of Barrett’s esophagus. The science underlying these changes is still in development, and consensus has not yet been reached about where they fit in diagnostic and therapeutic algorithms for Barrett’s esophagus. These new and emerging options nevertheless offer options to clinicians who treat patients with Barrett’s esophagus.

COnCLUSIOnStaying abreast of the technological breakthroughs and advances in diagnosis and treatment of the gastrointestinal disorders discussed in this monograph is crucial for gastroenterologists’ ability to optimally treat their patients. A host of breakthroughs and advances have been introduced in recent international meetings, which serve as forums for academicians, clinicians, researchers, trainees, and other gastrointestinal health professionals to share their discoveries with colleagues. The data presented in these meetings represent the collective knowledge of the world’s thought leaders on the best ways to manage these diseases. The application of this knowledge in everyday practice is necessary for gastroenterologists to provide the best possible care for their patients.

Thank you for participating in this activity. To take the posttest and evaluation and to receive credit, please go to: www.totalmeded.com/links/9002monograph


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rEFErEnCES


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Corley DA. Proton pump inhibitors, H171. 2 antagonists, and risk of hip frac-

ture: a large population-based study. Gastroenterology. 2009; 136(suppl 1):A-70. Abstract 414.Laheij RJ, Sturkenboom MC, Hassing RJ, et al. 172. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292:1955-1960.Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of 173. enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102:2047-2056. Herzig SJ, Howell MD, Ngo LH, et al. Acid-suppressive medication use 174. and the risk for hospital-acquired pneumonia. JAMA. 2009;301: 2120-2128.McColl KE, Gillen D. Evidence that proton-pump inhibitor therapy induces 175. the symptoms it is used to treat. Gastroenterology. 2009;137:20-22.Van Soest EM, Siersema PD, Dieleman JP, et al. 176. Persistence and adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ther. 2006;24:377-385.Reimer C, Søndergaard B, Hilsted L, et al. Proton-pump inhibitor therapy 177. induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009;137:80-87.Gunaratnam NT, Jessup TP, Inadomi J, et al. Sub-optimal proton pump 178. inhibitor dosing is prevalent in patients with poorly controlled gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2006;23: 1473-1477.Boparai V, Rajagopalan J, Triadafilopoulos G. Guide to the use of proton 179. pump inhibitors in adult patients. Drugs. 2008;68:925-947. Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacol-180. ogy of proton pump inhibitors. Aliment Pharmacol Ther. 2006; 23(suppl 2):2-8. Hunt RH, Armstrong D, James C, et al. Effect on intragastric pH of a PPI 181. with a prolonged plasma half-life: comparison between tenatoprazole and esomeprazole on the duration of acid suppression in healthy male volun-teers. Am J Gastroenterol. 2005;100:1949-1956.Charbel S, Khandwala F, Vaezi MF. The role of esophageal pH moni-182. toring in symptomatic patients on PPI therapy. Am J Gastroenterol. 2005;100:283-289.Lindberg P, Keeling D, Fryklund J, et al. Review article: esomeprazole 183. —enhanced bio-availability, specificity for the proton pump and inhibition of acid secretion. Aliment Pharmacol Ther. 2003;17:481-488.Pai V, Pai N. Randomized, double-blind, comparative study of dexrabe-184. prazole 10 mg versus rabeprazole 20 mg in the treatment of gastroesoph-ageal reflux disease. World J Gastroenterol. 2007;13:4100-4102.Fass R. Proton pump inhibitor failure—what are the therapeutic options? 185. Am J Gastroenterol. 2009;104(suppl):S33-S38.Sharma P, Shaheen NJ, Perez MC, et al. Clinical trials: healing of erosive 186. oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation – results from two randomized controlled studies. Aliment Pharmacol Ther. 2009;29:731-741.Sachs G. Physiology of the parietal cell and therapeutic implications. 187. Pharmacotherapy. 2003;23:68S-73S.Lee RD, Vakily M, Mulford D, et al. Clinical trial: the effect and timing of 188. food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel dual delayed release formulation of a proton pump inhibitor – evidence for dosing flexibility. Aliment Pharmacol Ther. 2009;29:824-833.Wu J, Vakily M, Witt G, et al. TAK-390MR vs. lansoprazole (LAN) for 189. maintenance of drug concentration above a threshold which corresponds to higher%-time pH > 4. Am J Gastroenterol. 2007;102(suppl 2):S124. Abstract 15.Rohss K, Wilder-Smith C, Sagar M, et al. Can acid control be improved 190. with a modified-release formulation of a proton pump inhibitor? Am J Gastroenterol. 2008;103(suppl 1):S19. Abstract 48.Kahrilas PJ, Dent J, Lauritsen K, et al. A randomized, comparative study 191. of three doses of AZD0865 and esomeprazole for healing of reflux esophagitis. Clin Gastroenterol Hepatol. 2007;5:1385-1391.Dent J, Kahrilas PJ, Hatlebakk JG, et al. A randomized, comparative 192. trial of a potassium-competitive acid blocker (AZD0865) and esomepra-zole for the treatment of patients with nonerosive reflux disease. Am J Gastroenterol. 2008;103:20-26.Boeckxstaens GE, Beaumont H, Hatlebakk JG, et al. Efficacy and tol-193. erability of the novel reflux inhibitor, AZD3355, as add-on treatment in GERD patients with symptoms despite proton pump inhibitor therapy. Gastroenterology. 2009;136(suppl 1):A-436. Abstract M1875.Boeckxstaens GE, Denison H, Ruth M, et al. Effect of AZD3355, a novel 194. GABA

B agonist, on reflux and lower esophageal sphincter function in

patients with GERD with symptoms despite proton pump inhibitor treat-ment. Gastroenterology. 2009;136(suppl 1):A-433. Abstract M1861.Keywood C, Tack JF. Effect of mGluR5 inhibition with ADX10059, on day 195. and night time reflux and clinical symptoms in patients with gastro-esoph-ageal reflux disease (GERD): a proof of concept study. Gastroenterology. 2009;136(suppl 1):A-121. Abstract 774.


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Zerbib F, Keywood C. Efficacy and tolerability of ADX10059, a negative 196. allosteric modulator of mGluR5, on gastro-esophageal reflux: a pH-impedance study in healthy subjects. Gastroenterology. 2009; 136(suppl 1):A-434. Abstract M1867.Lagergren J, Bergström R, Lindgren A, et al. Symptomatic gastroesopha-197. geal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340:825-831.Pohl H, Welch HG. The role of overdiagnosis and reclassification in 198. the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97:142-146.Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, 199. surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol. 2008;103:788-797.Fernando HC, Murthy SC, Hofstetter W, et al. The Society of Thoracic 200. Surgeons practice guideline series: guidelines for the management of Barrett’s esophagus with high-grade dysplasia. Ann Thorac Surg. 2009;87:1993-2002.Working Party of the British Society of Gastroenterology. Guidelines for 201. the diagnosis and management of Barrett’s columnar-lined oesopha-gus. British Society of Gastroenterology Web site. http://www.bsg.org.uk/pdf_word_docs/Barretts_Oes.pdf. Published August 2005. Accessed August 31, 2009.Sampliner RE. Updated guidelines for the diagnosis, surveillance, and 202. therapy of Barrett’s esophagus. Am J Gastroenterol. 2002;97:1888-1895.Howden CW, Metz DC, Chey WD, et al. Degree of conformity between 203. US gastroenterologists and experts concerning Barrett’s esophagus (BE). Gastroenterology. 2005;128(suppl 2):A148. Abstract 912.Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis 204. and management of Barrett’s esophagus: the AGA Chicago Workshop. Gastroenterology. 2004;127:310-330.Armstrong D. 205. Review article: towards consistency in the endoscopic diagnosis of Barrett’s oesophagus and columnar metaplasia. Aliment Pharmacol Ther. 2004;20(suppl 5):40-47.Sharma P, Dent J, Armstrong D, et al. The development and validation of 206. an endoscopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology. 2006;131:1392-1399. Sharma P, Bansal A, Mathur S, et al. The utility of a novel narrow 207. band imaging endoscopy system in patients with Barrett’s esophagus. Gastrointest Endosc. 2006;64:167-175.

Kiesslich R, Gossner L, Goetz M, et al. In vivo histology of Barrett’s 208. esophagus and associated neoplasia by confocal laser endomicroscopy. Clin Gastroenterol Hepatol. 2006;4:979-987.Herrero LA, Curvers WL, Bansal A, et al. Zooming in on Barrett oesopha-209. gus using narrow-band imaging: an international observer agreement study. Eur J Gastroenterol Hepatol. 2009;21:1068-1075.Falk GW. Barrett’s esophagus. 210. Gastroenterology. 2002;122:1569-1591.El-Serag HB, Kvapil P, Hacken-Bitar J, et al. Abdominal obesity and the 211. risk of Barrett’s esophagus. Am J Gastroenterol. 2005;100:2151-2156.Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett’s esopha-212. gus in the general population: an endoscopic study. Gastroenterology. 2005;129:1825-1831.Eloubeidi MA, Mason AC, Desmond RA, et al. Temporal trends (1973-213. 1997) in survival of patients with esophageal adenocarcinoma in the United States: a glimmer of hope? Am J Gastroenterol. 2003;98: 1627-1633.Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in 214. Barrett’s esophagus with dysplasia. N Engl J Med. 2009;360:2277-2288.El-Serag HB, Aguirre TV, Davis S, et al. Proton pump inhibitors are asso-215. ciated with reduced incidence of dysplasia in Barrett’s esophagus. Am J Gastroenterol. 2004;99:1877-1883.Lyday W, Corbett FS, Kuperman DA, et al. Endoscopic radiofrequency 216. ablation of Barrett’s esophagus: safety and efficacy outcomes in 429 patients treated in a multi-center community practice registry. Gastrointest Endosc. 2009;69:AB114. Abstract 520.Herrero LA, Pouw RE, Van Vilsteren FG, et al. What are the outcomes 217. of endoscopic radiofrequency ablation for very long segments of Barrett esophagus containing neoplasia? Gastrointest Endosc. 2009;69:AB116. Abstract 525.

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