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TOPICS IN ESOPHAGEAL DISEASES
Audio-Digest Internal Medicine
Volume 60, Issue 05
February 7, 2013

Refractory Gastroesophageal Reflux Disease – Robert C. Lowe, MD
Eosinophilic Esophagitis – Kevin M. McGrath, MD

  
Digital Media $24.99
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The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Internal Medicine Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Topics in Esophageal Diseases

Educational Objectives

The goal of this program is to improve the management of refractory gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EE). After hearing and assimilating this program, the clinician will be better able to:

1. Ensure patients with refractory GERD take proton pump inhibitors properly for optimal effect.

2. Determine whether symptoms are due to persistent acidic or nonacidic reflux.

3. Prescribe appropriate medical therapy for residual symptoms of GERD.

4. Establish a diagnosis of EE.

5. Implement multimodality therapy for the management of EE.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and the planning committee reported nothing to disclose. In his lecture, Dr. Lowe presents information that is related to the off-label or investigational use of a therapy, product, or device.

Refractory Gastroesophageal Reflux Disease

Robert C. Lowe, MD, Assistant Professor of Medicine, Boston University School of Medicine, and Education Director, Section of Gastroenterology, Boston Medical Center, Boston, MA

Efficacy of proton pump inhibitors (PPIs) for symptoms of gastroesophageal reflux disease (GERD): survey study of >1000 patients found 38% had residual symptoms; ≈50% of patients still take over-the-counter medications; patients with erosive GERD have better response to treatment, but majority of patients evaluated for GERD have nonerosive disease

Refractory GERD: defined as continued symptoms on PPI taken twice daily (dosing not approved by Food and Drug Administration [FDA]); studies show that, with once daily use of PPI, ≤30% of patients have continued production of acid; twice daily dosing commonly recommended and used (associated with abnormal production of acid in <10% of patients); few patients have resistant secretion of acid

Mechanism of PPIs: medication reaches parietal cells of stomach from basal side through bloodstream; PPIs subsequently excreted into lumen of stomach in which proton pumps located; PPIs protonated and activated in acidic environment (medication must be taken near mealtime, when acid present in stomach); once patient reaches steady state of PPI use, majority of pumps blocked; in general, all PPIs equally effective

GERD due to motility disorder: occurs at lower esophageal sphincter (consists of tonically contracted muscular center and diaphragmatic crura); frequency and duration of transient lower esophageal sphincter relaxations (TLESRs) increased; TLESR can be due to hiatal hernia

Visceral hypersensitivity: when bolus contacts wall of gastrointestinal tract, distention triggers motor and sensory signals; serotonergic neurons send signals to interneurons; above bolus, acetylcholine signal causes contraction of esophagus to push food down; inhibitory signals (eg, nitric oxide, vasoactive intestinal peptide [VIP]) go downstream of bolus to relax esophagus; serotonergic pathway sends signals to brain (cause sensations of pain, distension, difficulty swallowing, and/or globus); nerves possibly hypersensitive in patients with GERD

Management of refractory GERD

Compliance with medications: study by El-Serag et al (2009)  only 66% to 70% of prescriptions for PPIs filled; at 1 yr, compliance <50%; directions  take PPI before breakfast (first meal activates all proton pumps) for once-daily dosing; drug should not be taken before bedtime (medication does not work well in nonacidic stomach); patients using twice-daily dosing should take PPI before breakfast and dinner; correct timing of medication may be sufficient to resolve symptoms

Indications for endoscopy: generally not required for average person with GERD; appropriate if  GERD untreated >5 yr (screen for, eg, Barrett syndrome); reflux develops at >50 yr of age (risk for malignancy increased); warning signs (eg, dysphasia, bleeding) present; eosinophilic esophagitis (EE)  feline esophagus (ie, transient transverse esophageal folds) seen on endoscopy; incidence increasing; biopsy often performed on middle portion of esophagus; patients with EE respond well to immunosuppressive therapy (first line, 6 wk of swallowed fluticasone; recurrent or long-term therapy may be needed); presents with persistent reflux on PPIs and (often) some dysphagia; most common structural inflammatory disease seen in patients with reflux

pH testing: can identify persistent acid reflux; Bravo capsule pH monitoring system  affixes device to wall of esophagus; radio controls monitor pH activity for 48 hr; study often done with patient on PPI; results may show persistent acid reflux

Nonacidic reflux: may contribute to symptoms of gas and liquid from stomach (especially in hypersensitive patients), bile acids from duodenum, and reflux into mid- and upper esophagus; impedance testing  can identify nonacidic reflux; catheter placed down esophagus through nose; small amount of air precedes bolus of liquid; when air reaches catheter, impedance increases; when fluid bolus reaches catheter, impedance decreases markedly; when esophagus contracts, impedance increases again and returns to baseline; as bolus moves down, areas of impedance normally fall in stepwise fashion; in patients with reflux, impedance moves in opposite direction (low at bottom)

Practical tips for treatment: residual acid reflux  histamine blockers taken before bedtime (in addition to PPI taken before breakfast and dinner) may be helpful; studies variable but some show improvement in nocturnal symptoms; bile acid binders  eg, cholestyramine; can be used to treat nonalkaline reflux; no data on efficacy; promotility agents  metoclopramide effective in some patients with GERD but use restricted due to side effect profile; erythromycin only effective short term (tachyphylaxis develops after ≈3 days); TLESR inhibitors  g-aminobutyric acid (GABA) receptor agonists may decrease TLESRs (eg, baclofen appears to decrease reflux of gastric contents in placebo-controlled studies) but data limited

Functional heartburn: may be due to visceral hypersensitivity (diagnostic criteria from Rome Foundation); visceral pain modulators  effective in treatment of noncardiac chest pain; not proven for treatment of refractory GERD, but small studies show some benefit; drugs used include  amitriptyline (eg, Elavil, Endep, Vanatrip) dosed at 10 mg twice daily or 25 mg at bedtime; selective serotonin reuptake inhibitors (eg, paroxetine [Paxil, Pexeva], citalopram [Celexa])

Questions and Answers

Discontinuation of PPIs after GERD effectively controlled: studies show discontinuation produces rebound effect; only 20% to 25% of patients with proven GERD can stop medication (most patients [eg, almost 100% of those with erosive disease, 60%-75% of those with nonerosive disease] have recurrence of symptoms)

Risks of long-term use of PPIs: increased risk for osteoporosis (generally in patients with preexisting osteomalacia); associated with small increases in incidence of hospital-acquired pneumonia and Clostridium difficile infection; risks not high enough to contraindicate long-term use, but use only if indicated

Recommendations for travel to developing countries: no data available; Infectious Disease Society currently does not recommend discontinuation of PPIs

Eosinophilic Esophagitis

Kevin M. McGrath, MD, Associate Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA

Eosinophilic esophagitis: previously thought to be rare disorder; has emerged as one of most common causes of dysphagia and esophageal food impaction in adults; definition  chronic immune and/or antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction, and histologically by eosinophil-predominant inflammation

Epidemiology: paucity of studies due to inadequate recognition (in past, labeled small or narrow-caliber esophagus or esophagus with congenital esophageal rings) and lack of established diagnostic criteria; prevalence on rise due to increased recognition and incidence of allergic diseases

Etiology: unknown; may be allergic response or immune dysregulation driven by food allergy or aeroallergen; associated with atopic conditions; may be related to GERD; timing of onset unknown (ie, adult onset vs chronic condition beginning during childhood)

Atopic predisposition: IgE-mediated food allergy seen in significant number of patients (≤50% of adults test positive for ≥1 type of food [eg, peanuts, egg, soy, milk]); most patients have history of allergic rhinitis, asthma, or eczema; evaluation by immunologist recommended

Pathophysiology: chronic inflammatory condition (defined by dense eosinophilic infiltrate confined to esophageal mucosa); activation of eosinophils results in degranulation, upregulated cytokine production, chronic inflammation, and IgE production; recruitment and activation of eosinophils regulated by cytokines; net result potentially irreversible structural change to esophagus (eg, loss of mucosal elasticity, fibrosis in subepithelial layers [mostly submucosal], loss of wall compliance [lumen fixed]); role of GERD  unclear; evolving diagnostic criteria for EE include failure to respond to PPIs; EE and GERD not mutually exclusive (GERD may play secondary role in EE)

PPI-responsive EE: subset of patients  have typical presentation with chronic solid dysphasia; GERD excluded on basis of pH studies; demonstrate clinicopathologic response to high-dose PPIs; potential effects of PPIs  healing of disrupted epithelial barrier to prevent further immune regulation and activation; decreased eosinophil longevity; anti-inflammatory; pH studies  inaccurate for GERD

Diagnosis

Clinical presentation: adults  young adults; male predominance (3 men to 1 woman); atopic predisposition; long-standing solid dysphagia; recurrent food impactions; no response to PPI therapy; generally present with esophageal symptoms (eg, stricture); pediatric  typically present with abdominal pain, failure to thrive, nausea, and vomiting; signs  peripheral blood eosinophilia (in ≤50% of patients); increased serum IgE levels; positive skin prick and/or radioallergosorbent test (RAST); concerns  food allergies in childhood may not persist to adulthood; immediate hypersensitivity reactions often not apparent in adults; EE frequently occurs as isolated condition (ie, without other allergic manifestations)

Endoscopic features: mucosal rings (extremely common; can be corrugated and fixed or appear as feline esophagus); linear furrows; strictures; papules or exudates (eosinophilic microabscesses); significant overlap with findings associated with GERD (eg, hiatal hernia, Schatzki ring) possible

Radiographic features: barium swallow less sensitive in detecting narrowed esophagus and subtle endoscopic findings; endoscopy with biopsy gold standard for diagnosis (higher yield with histologic confirmation); radiologists may detect subtle narrowing (generally in proximal and mid-esophagus); depending on quality of barium study, rings or indentations (areas of fibrosis) may be seen

Histopathology: eosinophilic infiltration of esophageal mucosa  superficial layering of eosinophils; eosinophilic microabscesses; extracellular eosinophil granules; fibrosis of lamina propria; lack of consensus about  number of eosinophils/high-power field (HPF) required for definitive diagnosis (generally, bar set at 15 eosinophils/HPF); number and location of biopsies (usually, 4 from distal and 4 from proximal esophagus); in setting of GERD  eosinophilic infiltration generally seen in distal esophagus, but not in proximal esophagus

Genetic predisposition to EE: locus on chromosome 5 regulates thymic stromal lymphopoietin (TSLP; cytokine involved in T-helper cell determination); genetic variant in TSLP receptor gene on X chromosome linked to susceptibility for EE in males; genetic markers  may be available in future to aid in diagnosis and, potentially, prognostication

Treatment

Avoidance or removal of stimulation: elimination diet successfully treats EE (more so in pediatric population than in adults); compliance problematic (6-food elimination diet commonly used eliminates milk protein, soy, wheat, egg, peanut, and seafood); restriction based on allergen tests more acceptable to patients, but results variable

Structural disruption: esophageal dilation  must be performed cautiously with gentle intubation; speaker always does procedure with propofol-based sedation; choice of initial diameter can be estimated based on size of scope; begin with small bougies; after each passage of wire-guided bougie, esophagus reintubated; increase size of bougie 1 mm with each passage, until reintubation and reinspection of esophagus detects moderate mucosal tear; treatment effective for dysphagia but does not alter ongoing inflammatory process

Immune modulation

Corticosteroids: improve clinicopathologic features of EE in most patients; recurrence rates high upon discontinuation; swallowed fluticasone  most commonly used therapy; patient given inhaler and instructed to spray fluticasone 4 times to back of throat, then swallow; rinse and spit to prevent thrush; avoid eating or drinking for 30 min; generally done for 6 wk (repeated for recurrence); current trend for longer treatment; other options  daily budesonide (viscous suspension); systemic steroids or prednisone tapers recommended for severe or refractory cases

Montelukast: leukotriene receptor antagonist; small European study  dose titrated up to 100 mg/day; high dose associated with side effects (eg, nausea, myalgias); median length of treatment 14 mo; dysphagia eliminated in 7 of 8 patients, but recurred in 6 patients shortly after cessation of therapy; subsequent study  showed no benefit; current guidelines do not support use; however, speaker has had success using drug (10 mg) in combination therapy

Biologic agents: mepolizumab  humanized anti-interleukin (IL)-5 monoclonal antibody; decreases eosinophil infiltration but achieves no clinical improvement

Prognosis: 11-yr study concluded EE chronic but stable disease with no associated morbidity, mortality, or neoplastic change; patients have continued dysphagia and require periodic esophageal dilation

Future research: larger randomized controlled trials of treatment for EE needed; objective end points of trials need to be defined; speaker feels clinical end points should be primary, with histologic and immunologic improvement secondary end points

Questions and Answers

EE in patients with hypereosinophilia and other eosinophilic infiltrates: other than atopic predisposition (eg, asthma, allergic rhinitis, eczema), speaker has not seen EE with true eosinophilic gastroenteritis or colitis (extremely rare); atopic predisposition clear in majority of patients

Administration of fluticasone in patients already using for treatment of asthma: must be taken differently; inhaled medication does not contact esophageal mucosa; montelukast may help manage overlapping asthma

Suggested Reading

Abonia JP, Rothenberg ME: Eosinophilic esophagitis: rapidly advancing insights. Annu Rev Med 2012;63:421-34; Alexander JA et al: Swallowed fluticasone improves histologic but not symptomatic response of adults with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2012 Jul;10(7):742-749; El-Serag HB et al: The extent and determinants of prescribing and adherence with acid-reducing medications: a national claims database study. Am J Gastroenterol 2009 Sep;104(9):2161-7; Fass R: Therapeutic options for refractory gastroesophageal reflux disease. J Gastroenterol Hepatol 2012 Apr;27 Suppl 3:3-7; Filik L: Montelukast and maintenance of steroid-induced remission in eosinophilic esophagitis. Dig Dis Sci 2012 Jan;57(1):258-9; Gonsalves N et al: Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis. Gastrointest Endosc 2006 Sep;64(3):313-9; Hershcovici T, Fass R: An algorithm for diagnosis and treatment of refractory GERD. Best Pract Res Clin Gastroenterol 2010 Dec;24(6):923-36; Karamanolis G et al: Yield of combined impedance-pH monitoring for refractory reflux symptoms in clinical practice. J Neurogastroenterol Motil 2011 Apr;17(2):158-63; Liacouras CA et al: Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011 Jul;128(1):3-20; Liu JJ, Saltzman JR: Refractory gastro-oesophageal reflux disease: diagnosis and management. Drugs 2009 Oct 1;69(14):1935-44; Redd M, Schey R: Eosinophilic Esophagitis: Current Treatment. Dig Dis Sci 2012 Sep 22 [Epub ahead of print]; Roorda AK et al: Algorithmic approach to patients presenting with heartburn and epigastric pain refractory to empiric proton pump inhibitor therapy. Dig Dis Sci 2011 Oct;56(10):2871-8; Scarpignato C: Poor effectiveness of proton pump inhibitors in non-erosive reflux disease: the truth in the end! Neurogastroenterol Motil 2012 Aug;24(8):697-704; Schoepfer AM et al: Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation. Am J Gastroenterol 2010 May;105(5):1062-70; Sifrim D, Zerbib F: Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut 2012 Sep;61(9):1340-54; Straumann A: Treatment of eosinophilic esophagitis: diet, drugs, or dilation? Gastroenterology 2012 Jun;142(7):1409-11; Straumann A et al: Pediatric and adult eosinophilic esophagitis: similarities and differences. Allergy 2012 Apr;67(4):477-90; Yan BM, Shaffer EA: Eosinophilic esophagitis: a newly established cause of dysphagia. World J Gastroenterol 2006 Apr 21;12(15):2328-34; Zaninotto G, Attwood SE: Surgical management of refractory gastro-oesophageal reflux. Br J Surg 2010 Feb;97(2):139-40; Zerbib F et al: Functional heartburn: definition and management strategies. Curr Gastroenterol Rep 2012 Jun;14(3):181-8; Zur E: Eosinophilic esophagitis: treatment with oral viscous budesonide. Int J Pharm Compd 2012 Jul-Aug;16(4):288-93.


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