SLLABUS Esophageal Disorders…underlying esophageal disorder, or (4) have an inconsistent or...

CHAPTER 1

Esophageal DisordersSYLLABUS

1

IntroductionThe list of symptoms that strongly suggest the presence of an esophageal disorder is relatively small (Table 1.1). None of these typical symptoms are specific to a particular esophageal disorder. In addition, there are a variety of symptoms or signs that (1) are infrequent, atypical manifestations of esophageal disorders, (2) are more commonly seen with nonesophageal disorders, (3) represent extraesophageal complications of the underlying esophageal disorder, or (4) have an inconsistent or unproven relationship to esophageal disor-ders (Table 1.2). Symptoms may arise from disorders intrinsic to the esophagus or conditions that affect the esophagus secondarily.

Gastroesophageal Reflux DiseaseGastroesophageal reflux disease (GERD) is by far the most common esophageal disorder. Gastroesophageal reflux occurs in normal individuals, and there is some overlap in the amount of reflux seen in healthy subjects and those diagnosed with GERD. This overlap and the fact that otherwise healthy individuals may occasion-ally note some manifestations of reflux events are taken into account in the Montreal consensus definition of GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.”1

Benson T. Massey, MD, FACP and Reza Shaker, MD, MACP

EDUCATIONAL OBJECTIVES

AFTER COMPLETING THIS CHAPTER, THE LEARNER SHOULD BE ABLE TO:

1. Recognize the typical and atypical presentations of esophageal disorders.2. Review the pathophysiology of gastroesophageal reflux disease (GERD).3. List the risk factors associated with GERD.4. Identify the typical endoscopic and pathologic findings of eosinophilic esophagitis.5. Know the differential diagnosis for esophageal eosinophilia.6. Know the treatment options for eosinophilic esophagitis.7. Review the advantages and limitations of the different diagnostic tests available to diagnose esophageal disorders.8. Learn the natural history of esophageal disorders as patients move from pediatric to adult care, and the differences

in childhood and adult presentations.9. Know the appropriate use and limitations of proton pump inhibitors in treating different patient groups.

Digestive Diseases Self-Education Program® 2

Pathophysiology of GERD

The most common mechanism by which gastric con-tents reflux into the esophagus is the transient lower esophageal sphincter relaxation (TLESR). TLESRs are characterized by brief (<1 minute) inhibition of the tone of the lower esophageal sphincter (LES), cessation of the phasic respiratory contractions of the diaphragmatic crura, and reduction in the con-tractility of the circular muscle of the esophageal body.2–4 In addition, contraction of the esophageal

longitudinal muscle during a TLESR can be strong enough to pull the gastroesophageal junction into the thoracic cavity.5,6 These actions allow movement of gastric contents from a region of higher intralu-minal pressure in the abdomen to the lower intra-luminal pressure of the thoracic esophagus. TLESRs may be accompanied by relaxation or contraction of the upper esophageal sphincter (UES).7–9 Relaxation of the UES in the presence of gas reflux can result in belching, whereas liquid refluxates may be regurgi-tated into the pharynx. Reflexive contractions of the UES will block orad movement of esophageal con-tents into the upper aerodigestive tract.

TLESRs require an intact vagal innervation. Neurotransmission between the afferent and effer-ent limbs of the TLESR response are mediated or modulated by nitric oxide as well as cholecystokinin A, gamma-aminobutyric acid B, and metabotropic glutamate receptors.10–13 TLESRs are triggered by distension of the stomach; are more common in the awake, postprandial state; and are reduced in frequency during recumbency and deep sleep.2,14,15 TLESRs are a normal physiologic process that facil-itates the venting of swallowed air from the upper digestive tract. Some degree of liquid reflux occurs normally as part of this process.

TLESRs occur with similar frequency in healthy subjects and patients with GERD.16Where patients with GERD differ from healthy subjects is in the na-ture of the reflux events that accompany TLESRs, with GERD patients developing more acid reflux dur-ing TLESRs and more proximal migration of reflux-ate into the esophageal lumen.16, 17 While TLESRs are the dominant mechanism for reflux in patients with GERD, those who have lost tonic function of the LES or developed abnormalities in the normal valvular anatomy of the gastroesophageal junction exhibit additional processes for displacement of gastric contents into the esophageal lumen, including con-tinuously low LES pressure, reflux during abdomi-nal straining, and re-reflux of gastric contents.3,17–20 Pediatric patients show similar mechanisms for re-flux.21,22 Hiatal hernia is a risk factor for the presence of erosive esophagitis in both adult and pediatric patients with GERD.23–26 Although ingested food buf-fers gastric acidity, an “acid pocket” can persist in the

n Heartburn n Bland or sour regurgitation n Chest pain n Dysphagia (solid/liquid/mixed) n Odynophagia n Eructation/hiccup

n Dyspepsia (epigastric burning/fullness) n Nausea with or without vomiting n Hematemesis n Globus n Coughing n Throat clearing n Throat pain n Throat burning n Hoarseness n Wheezing/stridor n Dyspnea n Apnea n Movement disorder (Sandifer syndrome) n Halitosis n Sleep disturbance n Anorexia/weight loss/failure to thrive n Sudden infant death

Table 1.1

Cardinal Symptoms of Esophageal Disorders

Table 1.2

Atypical Symptoms of Esophageal Disorders

3 Chapter 1 — Esophageal Disorders

proximal stomach post-prandially. This acid pocket extends above the diaphragm and even up into the distal esophagus, particularly in GERD patients with hiatal hernia. In this situation TLESR events are more likely to be accompanied by acid reflux.27

Conditions that increase the pressure differen-tial between the abdominal and thoracic cavities or cause retention of gastric contents will promote reflux. Obese subjects, who have higher intra-ab-dominal pressures,28 have greater TLESR responses to gastric distension following a meal,29 more acid reflux events on ambulatory pH monitoring,30 and more proximal migration of refluxate into the esoph-agus31. Conversely, in patients with lung disease, such as cystic fibrosis, the lower inspiratory thoracic pres-sure induces more proximal reflux32. Some patients with GERD have delayed emptying of the proximal stomach.33 Consumption of high-fat meals, which empty more slowly from the stomach, are associated with GERD.34 Also, dietary patterns that result in in-creased colonic fermentation can increase TLESRs and symptomatic reflux.35

Symptom ManifestationClinical sequelae of reflux depend on the duration and distribution of esophageal exposure to the re-fluxate. Extension of the refluxate into the proximal esophagus is more likely to be symptomatic,36 and migration past the UES into the pharynx predisposes the patient to oral and upper airway injury from the refluxate. The duration of esophageal acid exposure recording during ambulatory pH monitoring cor-relates with the severity of esophagitis,37 and GERD patients with complicated reflux disease have signifi-cantly greater esophageal acid exposure times than those without these complications.38 The duration of acid exposure depends on the interplay between the factors previously discussed that promote acid reflux events and those factors serving to clear refluxed acid from the esophagus. Esophageal clearance of acid depends on intact motor function of the esopha-geal body, as the refluxed volume is cleared by prima-ry or secondary peristalsis. Patients with severe pep-tic esophagitis have a high incidence of esophageal peristaltic dysfunction.39 Restoration of the normal intraluminal esophageal pH also requires neutraliza-

tion of acid retained in the esophageal mucous layer by the bicarbonate in swallowed saliva.40 Esophageal acid exposure to the point of inducing heartburn stimulates saliva production (water brash). Condi-tions that impair salivary production predispose pa-tients to reflux esophagitis. Nocturnal reflux during transient awakenings often leads to prolonged epi-sodes of acid exposure because swallowing and sali-vation are inhibited following return to sleep.

The contents of the refluxate determine the se-verity of symptoms and esophageal mucosal injury. Only a minority of reflux events are symptomatical-ly perceived. Reflux events producing a lower value of intraluminal esophageal pH are more likely to re-sult in heartburn,36 and the healing of esophagitis by proton pump inhibitors (PPIs) is associated with a reduction in the number of acid reflux events which is greater than the reduction in the total number of reflux events.41 However, reflux events contain-ing gas in the refluxate are more likely to be per-ceived.42 Exposure to bile acids and pancreatic en-zymes induces esophageal mucosal injury in animal models,43 and the duration of esophageal exposure to the contents of duodenogastric reflux is higher in patients with erosive esophagitis and Barrett’s esophagus.44 Patients with GERD overall do not have abnormal levels of gastric acid secretion. However, patients with acid hypersecretory states such as Zollinger-Ellison Syndrome are at risk to develop reflux esophagitis.45

Patients infected with Helicobacter pylori (HP) have reduced risks for developing reflux esophagitis, Barrett’s esophagus, and esophageal adenocarcino-ma, an effect that may in part be mediated through gastric mucosal atrophy and the associated reduc-tion in acid secretion that result from long-standing infection.46 Men without HP infection actually show increasing gastric acid secretion with age.47 While the presence of HP infection is associated with an improved response to therapy for GERD,48,49 eradica-tion of HP does not seem to induce reflux symptoms in otherwise healthy subjects50 or increase the dose of acid suppression therapy needed to control symp-toms in patients with reflux esophagitis.51

Recent evidence suggests that the development of esophageal mucosal lesions in response to the


noxious component of refluxate is not simply a di-rect chemical injury to the mucosa. Animal studies indicate the initial response is induction of an in-flammatory cascade, involving both neurogenically mediated inflammation52 and the recruitment of inflammatory cytokines.53 Injury to the esophageal mucosa results in dilated intracellular spaces and increased mucosal permeability.54 These changes in mucosal permeability are associated with reduc-tions in esophageal intraluminal and mucosal elec-trical impedance.55-7

The development of symptoms such as heart-burn or chest pain requires activation of esopha-geal nociceptors, with transmission of afferent pain signals via spinal afferent pathways to brainstem and higher cortical centers. The receptive fields for esophageal sensation show considerable overlap among different thoracic dermatomes. This in part explains the difficulty in localizing esophageal symp-toms. Moreover, spinal afferent neurons can receive input from multiple thoracic structures, making it difficult at a cortical level to discriminate between esophageal and, for example, cardiac sources for pain. Esophageal pain pathways may develop both peripheral and central sensitization, wherein prior exposure to noxious stimuli lowers the threshold for subsequent noxious stimuli to initiate symptoms, as well as induce hyperalgesia and allodynia in adjacent structures.58 Thus a major determinant of whether any specific acid reflux event induces symptoms is the cumulative acid exposure during preceding time periods.36

The threshold for reflux events to produce symptoms is lowered by acute auditory stress,59 and the burden of chronic life stress events is a major predictor of the severity of ongoing reflux symptoms over longer time periods.60 Sleep deprivation low-ers the threshold for esophageal acid exposure to cause symptoms;61 this effect is likely compounded by the fact that GERD has a great effect on the qual-ity of sleep.62,63 On the other hand, loss of normal nociceptive pathways may predispose the esopha-gus to injury. Patients with Barrett’s esophagus have been shown to have reduced sensitivity to acid infu-sion64 and esophageal distension,65 and have reduced symptom responses to acid reflux.66

Epidemiology, Risk Factors, and Natural History

GERD is the most commonly diagnosed gastrointes-tinal disorder, accounting for nearly 9 million out-patient visits annually in the United States.67 GERD occurs among all age cohorts, from infancy to senes-cence. Typical reflux symptoms such as regurgita-tion occur in the majority of healthy infants, with the prevalence of such symptoms progressively decreas-ing over the first 1–2 years of life.68,69 GERD symp-toms are present in <10% of young children and adolescents.70,71 However, among infants diagnosed with reflux esophagitis, mucosal lesions persist over 1 year, even if symptoms resolve.72 A substantial frac-tion of children diagnosed with GERD have persis-tence of reflux symptoms and esophagitis into ado-lescence and early adulthood.73

The estimates on prevalence of GERD among adults vary among studies, depending on the criteria for ascertaining the diagnosis. Studies on the prev-alence of typical symptoms as an indirect marker for the presence of GERD indicate that about half of adults report such symptoms at some time, and about a fifth have symptoms at least weekly.74-76 Findings from population-based endoscopic screen-ing studies indicate a lower prevalence of esophagitis (12–16%) of whom about one-third report no reflux symptoms.75,76 GERD is present around the globe and the pre-valence appears to be increasing over time.77 While symptoms of GERD are seen frequently in both genders and ethnic groups, lower rates of complicat-

n Obesity n Hiatal hernia n Smoking n Nonsteroidal anti-inflammatory drugs (NSAIDs) n Chronic atrophic gastritis/Helicobacter pylori infection

(inverse association) n Aging n Irritable bowel syndrome n Anxiety/depression n Family history of GERD

Table 1.3

Risk Factors Associated with GERD


ed reflux disease are seen in women and Blacks.78-82 The prevalence of GERD symptoms and complicated disease tends to increase with age.81,83-85

Epidemiologic studies have identified several risk factors associated with the presence of GERD (Table 1.3). Obesity and presence of a hiatal hernia are the dominant anatomic findings associated with reflux symptoms and esophagitis in studies through-out the world. Both the presence of infection with HP and the subsequent development of chronic atrophic gastritis have been associated with a reduced risk for reflux esophagitis. Among lifestyle factors, smoking has the most consistently positive association with GERD, whereas the findings for alcohol, caffeine, and other dietary components show either inconsistent or no such associations.86 Among medications, non-steroidal anti-inflammatory agents and aspirin are associated with GERD symptoms, ulceration, and stricturing.87-90 The rate of co-occurrence of GERD and irritable bowel syndrome in the community is more than would be expected by chance.91 Both anxi-ety and depression are risk factors for the presence of GERD symptoms.92 Factors associated with the de-velopment of new GERD symptoms over time include older age, female sex, lower educational status, gain in BMI, and smoking.93 Family and twin studies have indicated a familial risk for GERD.94-96 The interplay between common environmental and genetic risks is not currently completely understood, although a re-cent genome-wide screening of patients with GERD implicates mutations involving the regulation of the gene for type III collagen in the development of hiatal hernias in men and GERD in both sexes.97

Longitudinal studies of patients with GERD in clinical care show that many either acquire or lose the finding of erosive esophagitis with time.98 Over-all, the incidence of new GERD symptoms exceeds the rate of loss, resulting in a net increase in GERD preva-lence of 30% over 11 years in one study.99 Follow-up endoscopy in patients with GERD with initially nor-mal mucosa shows a low (1-5%) likelihood for inter-val development of Barrett’s esophagus, whereas pa-tients with esophagitis at initial endoscopy have up to a 5-fold higher risk to develop Barrett’s esophagus after five years of follow-up.98,100,101

GERD-Related Syndromes

The Montreal Classification of GERD syndromes (Figure 1.1) incorporates research showing that for many patients the manifestations are symptomatic only, without evidence for overt damage to the esophagus or extraesophageal structures. It also takes into account those patients who have complications of GERD without manifesting typical GERD symptoms. Finally, it acknowledges the potential for extraesophageal complications of GERD, based on the strength of evidence for association and causality.

Complications of GERD Esophagitis and Ulceration

GERD-related mucosal erosions typically have their base on the squamocolumnar junction and extend proximally in a flame-shaped distribution, but can extend to involve nearly the entire esophageal muco-sa. The Los Angeles classification of erosive esopha-gitis has been demonstrated to have good intra- and interobserver agreement (Table 1.4). Validity of this classification scheme is demonstrated by the asso-ciation of higher grades with more esophageal acid exposure, greater reflux symptom severity, less fre-quent complete healing of esophagitis on therapy, and greater frequency of symptom relapse after a course of therapy.37

Table 1.4

Los Angeles Classification for Erosive Esophagitis

Grade A

One (or more) mucosal break, ≤5 mm long, that does not extend between the tops of two muco-sal folds

Grade B

One (or more) mucosal break, >5 mm long, that does not extend between the tops of two muco-sal folds

Grade C

One (or more) mucosal break that is continuous between the tops of two or more mucosal folds, but that involves <75% of the circumference

Grade D

One (or more) mucosal break that involves at least 75% of the esophageal circumference


Esophageal ulcers are more severe mucosal breaks, completely through the esophageal mucosa. The major complication from peptic esophagitis is bleeding. About one-fifth of patients undergoing en-doscopic evaluation for upper gastrointestinal hem-orrhage are found to have erosive esophagitis.102 In certain patient groups, such as the elderly and those with developmental abnormalities and/or cogni-tive impairment, reflux esophagitis may be the most common cause for upper gastrointestinal hemor-rhage.103,104 Reflux esophagitis is an etiology for iron deficiency anemia in all age groups.105,106

StricturesPeptic strictures may be ringlike or involve longer segments of the esophagus with diffuse narrowing.

Peptic strictures usually have a distal location near the squamocolumnar junction and are commonly accompanied by other mucosal changes from peptic injury, such as erosions, ulcerations, and Barrett’s mucosa. For strictures separated by more than a few centimeters from the squamocolumnar junction and intervening normal mucosa, other etiologies for the stricture must be considered, including pill injury, neoplasia, and eosinophilic esophagitis. The diameter of the narrowest part of the stricture determines the risk for dysphagia, and nearly all patients having strictures <12 mm in diameter report difficulties with solid foods. The severity of esophagitis accompanying the stricture also determines the degree of reported dysphagia.103 Additional symptoms associated with strictures are hiccups and retching.

EsophagealSyndromes ExtraesophagealSyndromes

SymptomaticSyndromes

SyndromeswithEsophagealInjury

Established

Associations

Proposed Associations

1. Typicalrefluxsyndrome

2. Refluxchestpainsyndrome

1. Refluxesophagitis

2. Refluxstricture 3. Barrett’s

esophagus 4. Esophageal

adenocarcinoma

1. Refluxcoughsyndrome

2. Refluxlaryngitissyndrome

3. Refluxasthmasyndrome

4. Refluxdentalerosionsyndrome

1. Pharyngitis 2. Sinusitis 3. Idiopathic

pulmonaryfibrosis

4. Recurrentotitismedia

GERDSyndromes

Figure 1.1

Montreal Classification of Syndromes Resulting from GERD

From Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101(8):1900–20.


Barrett’s esophagusBarrett’s esophagus is the term used for the replace-ment of the normal squamous epithelium lining the esophagus with a columnar epithelium characterized by intestinal metaplasia containing goblet cells. The presence of Barrett’s esophagus is suspected when the squamocolumnar junction is displaced proximal to the anatomic gastroesophageal junction. The sus-pected diagnosis requires pathologic confirmation from biopsies of the abnormal-appearing mucosa. Barrett’s mucosa may range in length from the ap-pearance of an irregular z-line to nearly complete replacement of the entire squamous mucosa in the esophageal body. The Prague C & M criteria for as-sessing the extent of the esophageal lumen involve-ment by Barrett’s epithelium have shown good in-terobserver agreement (Figure 1.2).108

Barrett’s esophagus can be seen at any age, but becomes more prevalent with increasing age. Endoscopic screening studies of adult populations have suggested an overall prevalence of 1–2%, with about half of subjects so identified not reporting typical GERD symptoms.75,109 The risk factors associated with Barrett’s esophagus are similar to those for uncomplicated GERD, but severe erosive esophagitis is an additional risk factor, as are male sex and white race. As observed in patients with erosive esophagitis, hiatal hernia, reduced LES pressure, and esophageal peristaltic dysfunction are commonly present and contribute to the excess esophageal acid exposure. Reflux of duodenal contents into the

esophagus is also common in patients with Barrett’s esophagus. The major clinical concern for patients with Barrett’s esophagus is their greater risk for developing adenocarcinoma of the esophagus. Screening and surveillance for adenocarcinoma are covered in Chapter 14, Gastrointestinal Cancer.

Extraesophageal ManifestationsGastroesophageal reflux can affect structures above the esophagus, either through the direct exposure of these structures to the noxious effects of the re-fluxate or via the activation of vago-vagal reflexes. The conditions for which extraesophageal reflux has been implicated are listed in Table 1.5. Structures lo-cated above the esophagus are not normally exposed to any acid reflux and do not have mechanisms avail-able for acid neutralization and clearance. Even brief episodes of relatively minor exposure to noxious re-fluxate could have major pathologic and symptom-atic consequences. Extraesophageal symptoms are present in about a third of patients with GERD.110

Several factors make it difficult to attribute any individual patient’s extraesophageal symptoms and findings to GERD. First, the association may not be one of cause-and-effect but reflect a high degree of co-occurrence of the two conditions by unclear mecha-nisms. Second, the patient’s symptoms and findings may just as plausibly result from another unrecog-nized disorder. For example, chronic cough could also result from unidentified reactive airways dis-ease, bronchiectasis, allergic laryngitis, or sinus dis-ease. Third, initial descriptions of the association of severe extra esophageal manifestations with severe

n Asthma n Aspiration pneumonitis/pulmonary fibrosis n Laryngitis/vocal cord lesions n Laryngeal cancer n Chronic cough n Dental erosions n Sinusitis n Otitis media

Figure 1.2

Prague Classification of Barrett’s EsophagusTable 1.5

Extraesophageal Manifestations

and Associations of GERD


reflux disease have not consistently been replicated with milder forms of these conditions. For example, the initial descriptions of severe ulcerative laryngitis and tracheal stenosis were seen as complications in patients with severe reflux disease, and brought to clinical awareness the concept of pathologic laryngo-pharyngeal reflux. However, attempts to ascribe less severe laryngeal findings and symptoms have been hampered by poor intra- and inter-observer agree-ment on the presence of laryngoscopic findings that are attributable to reflux.111 Furthermore, the major-ity of patients with these milder laryngeal findings have no evidence for esophagitis or hiatal hernia. Fi-nally, some degree of supra-esophageal reflux can be seen in normal subjects,112 as can the laryngoscopic findings attributed to reflux disease.113 The natural history of laryngeal symptoms in patients with GERD is that these tend to resolve with time, in a course independent of the severity of the underlying reflux disease or treatment.114

Therapy for GERD Lifestyle Modifications

Lifestyle modifications for GERD include avoid-ance triggers such as consuming large meals, eat-ing shortly before sleeping, and consuming foods and beverages that predictably cause symptoms. Patients with nighttime symptoms should elevate the head of the bed. Patients should be cautioned regarding the hazards of obesity, smoking, and use of nonsteroidal drugs, and encouraged to modify these risk factors. While the currently available evi-dence to support these suggested lifestyle changes is limited,115,116 their lack of expense and additional benefits to health make them reasonable interven-tions. However, these will be inadequate by them-selves for most patients with GERD.

Medical TherapyThe mainstay for medical treatment of GERD in the twenty-first century is proton pump inhibitor (PPI) therapy.117 Most patients with GERD respond ad-equately to a single daily PPI dose, taken before the first meal of the day. With dose escalation to twice daily before meals when needed, the vast majority

of patients with erosive reflux disease will heal and their symptoms will resolve on PPI therapy. There is no evidence to support more frequent dosing. The different available PPI agents are similar in their ef-ficacy, and in the United States, the choice of agent for any particular patient is increasingly driven by formulary decisions of the patient’s insurance plan. Maintenance therapy at the dose needed for healing has the highest chance of maintaining remission, but patients may be titrated down to the lowest daily dose that permits control of symptoms. Patients with nonerosive reflux disease [NERD] and abnor-mal results on ambulatory reflux testing respond equally well to PPI therapy.118 Many NERD patients can use short-course therapy for symptom recur-rence, rather than continuous daily PPI therapy. The current concerns for long-term PPI therapy include increased risk for bone fractures, infections such as Clostridium difficile, vitamin B12 deficiency, and re-duced efficacy of clopidogrel therapy; none of these concerns to date have been substantiated in a pro-spective, placebo-controlled trial.

For patients who have intolerance to or contra-indications for PPI therapy, the histamine2-receptor antagonists and sucralfate have some demonstrated efficacy above placebo, although the benefits are less than for PPI therapy. Agents combining alginate with an antacid can reduce esophageal acid exposure in the post-prandial period.119 Metoclopramide is not recommended as a primary or adjunct therapy for GERD. The efficacy for currently available anti-se-cretory therapies is greater for symptoms of heart-burn than for regurgitation,120 and many patients with GERD continue to report incomplete symptom control on PPI therapy.121 Risk factors for failure of typical symptoms to respond to PPI therapy include lack of esophagitis or obesity and the presence of functional dyspepsia or irritable bowel syndrome.122 Patients with lower acid exposure times on ambula-tory reflux testing are also less likely to have symp-tom improvement on PPI therapy.123

SurgeryLaparoscopic antireflux surgery also has efficacy similar to PPI therapy in long-term follow-up stud-ies.124 For surgery, a somewhat higher improvement


in primary GERD symptoms is offset by more symp-toms of dysphagia and gas-bloat.125 About half of pa-tients undergoing surgery require surgical revision or medical therapy over time. These factors, plus the risk of postoperative complications and the small risk of operative mortality, indicate that surgery should be reserved for those patients whose GERD-related symptoms and complications cannot be con-trolled adequately by medical therapy. For patients with medically-complicated obesity that warrants bariatric surgery, Roux-en-Y gastric bypass can be an effective antireflux procedure.126 However, ver-tical-banded gastroplasty is associated with a high rate of postoperative GERD. A variety of endoscopic approaches to create an antireflux barrier have been developed. None to date have demonstrated convincing durable efficacy and are not currently recommended.

Extraesophageal SyndromesPlacebo-controlled trials of acid suppressive therapy have not found significant benefit in the findings and symptoms of reflux laryngitis127 or in the treatment of asthmatics without reflux symptoms, even if abnor-mal esophageal acid exposure is present.128 Anti-reflux surgery is very unlikely to be helpful for extra-esoph-ageal symptoms in the patient without concomitant heartburn and excessive (>12%) esophageal acid ex-posure.129 When therapy controls the cardinal symp-toms of GERD, but atypical symptoms persist, the pa-tient should be investigated for the presence of other disorders that could cause the latter.

Peptic StrictureDilation of peptic strictures improves symptoms of dysphagia. However, there is no proven benefit of di-lating subtle, asymptomatic strictures that are found incidentally. If dysphagia is the dominant symptom and the stricture diameter is <12 mm diameter, then initial treatment with dilation will produce immedi-ate benefit. For more patent and less symptomatic strictures, the option exists for an initial trial of PPI therapy. Control of GERD with PPI therapy reduces the need for repeat stricture dilation.130 Yet, this therapy will need to be continued indefinitely. For newly diagnosed strictures, if there is concern about

the peptic etiology, obtaining mucosal biopsy speci-mens is prudent; repeat biopsy should also be con-sidered if a presumed peptic stricture fails to respond to intervention. Patients with strictures should be cautioned to avoid medications with a high risk for esophageal injury, such as non-steroidal anti-inflam-matory drugs and bisphosphonates.

Barrett’s EsophagusTherapy in patients with Barrett’s esophagus is to control the symptoms of GERD, since neither medical nor surgical treatment results in clinically meaning-ful regression of Barrett’s mucosa. The current con-sensus recommendation is to control symptoms, not normalize esophageal acid exposure. Ongoing PPI therapy may inhibit the development of dysplasia in Barrett’s esophagus.131 However, neither medical nor surgical treatment of GERD has yet been shown to reduce the incidence of adenocarcinoma in pa-tients with Barrett’s esophagus. Techniques for en-doscopic mucosal ablation are not currently recom-mended for Barrett’s mucosa without high-grade or low-grade dysplasia. Chemoprevention with agents such as COX-2 inhibitors, is not recommended solely to treat Barrett’s esophagus. Surveillance of Barrett’s esophagus and treatment of associated dysplasia and adenocarcinoma are reviewed in Chapter 14 on Gastrointestinal Cancer. Smoking cessation should be recommended to all patients with known Bar-rett’s esophagus.

n GERD n EoE n Eosinophilic gastritis/gastroenteritis/enteritis n Celiac disease n Inflammatory bowel disease n Drug reactions n Hypereosinophilic syndrome n Infections n Autoimmune disorders n Esophageal motor disorders n Graft-versus-host disease

Table 1.6

Conditions Associated with Esophageal Eosinophilia


Eosinophilic EsophagitisEosinophilic esophagitis (EoE) is a clinicopathologic dis-ease characterized by symptoms resulting from esophageal dysfunction accompanied by pathologic evidence of a pre-dominantly eosinophilic inflammatory response confined to the esophagus. By consensus, in untreated patients the accepted density of eosinophilic infiltration is 15/high-powered field.132 Other conditions can cause esophageal eosinophilia, and these need to be excluded (see Table 1.6) before a diagnosis of primary EoE can be established. The entity of proton pump inhibitor-responsive esophageal eo-sinophilia (PPI-REE) does not fit clearly into this diagnostic scheme. This entity may represent a constellation of con-ditions, including GERD, true EoE that responds to further reduction of normal levels of esophageal acid exposure (or anti-inflammatory effects of PPI therapy), or co-occurrence of GERD and EoE, where treatment of GERD secondarily im-proves the EoE. PPI-REE and EoE cannot be distinguished on the basis of clinical symptoms, endoscopic findings, or tissue markers of eosinophilic inflammation.133, 134

Pathophysiology A genetic basis for the disorder was first suggested by a high concordance for the disease among family members.135 Genome-wide analysis has identified the gene for the cy-tokine thymic stromal lymphopoetin (TSLP), involved in TH2 cell determination, is a susceptibility locus for EoE, as is a variant in the TSLP receptor gene (located on the X-chromosome) for male patients.136 A variant in the filaggrin gene (associated with atopic dermatitis) is more prevalent In EoE.137 Variants in the TGFB gene appear to determine response to topical steroid therapy.138 The esophageal mu-cosa in EoE shows over-expression of eotaxin-3139 and up-regulation of interleukin-13.140 The majority of pediatric and adult patients exhibit allergic responses to food and/or aeroallergens,141 and most patients have other atopic disor-ders. Taken together, these findings support the concept of EoE as an allergic disorder, driven by exposure to common allergens. Specific variants in the genetic control of the im-mune response to antigenic stimulation likely result in the characteristic inflammatory/fibrotic responses within the esophagus.

Epidemiology and Natural HistoryEpidemiologic studies suggest a population based preva-lence of <1 per 1000, while among unselected adult pa-

Figure 1.3

Endoscopic Findings in Eosinophilic Esophagitis

A. Food impaction B. Corrugated appearance and mucosal white spots. C. Corrugations and longitudinal creases D. “Felinization” from muscularis mucosae contraction.

Figure3A

Figure3B

Figure3C

Figure3D


tients undergoing clinical endoscopic evaluation, esopha-geal eosinophilia may be found in up to 6.5%.142 Studies of pathology databases suggest a true increase in the inci-dence and prevalence of EoE over the past few decades.143,144 In adults, the diagnosis is less frequently made in winter months. EoE is more prevalent in male and non-Hispanic white patients.145 EoE occurs in all age groups.

Clinical Presentation and EvaluationThe most common clinical presentation is solid food dys-phagia, and EoE has become the most common diagnosis in young patients presenting with food impactions. Pediatric patients are more likely to present with recurrent vomiting or food intolerance, but other esophageal symptoms, such as heartburn and chest pain, may be seen in all age groups. Pediatric patients may fall off the normal growth curve. No constellation of symptoms is pathognomonic for EoE. Most patients will have a history of other atopic (asthma, eczema, allergic rhinitis, food allergy) conditions.

The characteristic endoscopic features (Figure 1.3) of EoE are listed in Table 1.7, but it is important to recognize that some patients may have a normal endoscopic appear-ance.146 The presence of eosinophilic inflammation within esophageal mucosal biopsy specimens is required to make the diagnosis (Figure 1.4) By current consensus, eosinophil counts of ≥15 per high-powered field (HPF) are needed for the diagnosis.132,147 Diagnostic eosinophil counts may not be present during seasons with low levels of aeroallergens in some patients.148 Biopsies obtained when patients are treat-ed can produce false negative results. Additional pathologic findings include eosinophilic microabscesses, basal cell hy-perplasia, elongation of dermal pegs, superficial layering of eosinophils, extracellular eosinophil granules, and subepi-thelial fibrosis. The pathologic changes of EoE can be seen throughout the esophagus, but are often patchy in distribu-tion, requiring multiple biopsies from different levels of the esophagus for adequate diagnostic sensitivity.

EoE patients with comorbid atopic illnesses or history of food allergies should be evaluated by an allergist. How-ever, routine allergy testing for food and aeroallergens is not otherwise recommended.

Therapy for EoEThe first therapy needed for many patients with EoE is re-moval of food impactions; flexible endoscopy is safe in this setting and allows diagnosis of the underlying condition.149

n Corrugated mucosa n Longitudinal mucosal furrows n Mucosal white spots/plaques n Focal rings and strictures n Diffusely small-caliber esophageal lumen n Fragile (“crepe paper”) mucosa

Table 1.7

Endoscopic Findings in Eosinophilic Esophagitis

Figure 1.4

Photomicrographs of the Pathologic Changes Seen in Eosino-

philic Esophagitis

Top: Basal cell hyperplasia and elongation of the connective tissue papillae are present. Bottom: The stratified squamous epithelium of the esophagus has numerous (>15/HPF) eosinophils between epithelial cells (arrows). Also noted is basal cell hyperplasia (bracket). (Courtesy of Richard Komorowski, MD, Medical College of Wisconsin.)


Dilation of rings and strictures is safe and effective therapy for improving dysphagia, but the need for repeat dilations with time is common.150 The muco-sa in untreated EoE can tear easily, and dilation can produce deep rents into the mucosa that cause chest pain and odynophagia severe enough to require brief hospitalization for pain control and hydration. If care is taken to avoid excessive dilation in any one treat-ment session, risk of perforation is < 1%.132 The pas-sage of single large-caliber (54–60 French) bougies to treat a seemingly isolated distal ring in EoE can be hazardous because endoscopically unrecognized stenoses may coexist proximally; dilation with grad-uated balloon catheters may be safer in this instance. Dilation therapy does not alter the underlying in-flammatory process.151

Unless there is a dominant stricture that is like-ly driving dysphagia symptoms, the current trend in EoE management is to defer dilation until the re-sponse to dietary and/or medical therapy is known (See Table 1.8). PPI therapy is a reasonable first line medical therapy for patients with suspected EoE because (1) this may uncover a case of PPI-REE152 and (2) this can address concomitant GERD in pa-tients with EoE. Topical corticosteroid therapy, such as fluticasone or budesonide, has been shown to

eliminate the eosinophilic infiltrate and esophageal proliferative responses and inconsistently improve symptoms in both pediatric and adult patients.153-157

Chronic therapy carries some risk of (typically mild or asymptomatic) esophageal candidiasis. Mon-telukast at high doses may improve symptoms, but without resolution of the mucosal eosinophilic infiltrate.158 Cromolyn sodium has not been shown to be beneficial. In a limited trial the anti–interleu-kin-5 antibody mepolizumab was shown to reduce tissue eosinophil levels without significant symp-tom resolution.159

Elemental and elimination diets to reduce an-tigenic stimulation have been beneficial in chil-dren,160,161 while a six food elimination diet has been shown to improve symptoms and resolve eosinophil-ic inflammation in adults.161 In this as well as in a pediatric study,162,163 the results of food allergy (skin prick) testing have not been shown to be reliable in predicting the causative foods on rechallenge.

Cessation of therapy for EoE results in relapse of pathologic changes and symptoms,164 and the effect of therapy on the long-term need for stricture dilation frequency is unclear. Comorbid atopic con-ditions, such as allergic rhinitis and asthma, should also be treated.165

Table 1.8

Medical and Dietary Therapies for Eosinophilic Esophagitis

Modality Comments

Proton Pump Inhibitor 20-40 mg qd to bid

Consider as initial treatment to exclude PPI-REE. Use to treat coexistent GERD.

Systemic corticosteroids 2 mg/kg/d (60 mg/d maximum)

For severe symptoms; 4 week course, then taper off. Requires other therapy for maintenance.

Fluticasone 880-1760 mcg/dBudesonide 1-2 mg/d

Better esophageal coating with viscous liquid formulations. Resolution of eosinophilia > symptom improvement. Risk for candida esophagitis

Elemental dietMost effective therapy in pediatric population. Expensive. Poorly tolerated (most require feeding tube).

Six food elimination diet (wheat, milk, eggs, soy, peanuts/tree nuts, fish/shellfish).

Consultation with dietician to assure appropriate elimination/nutritional bal-ance. May be able to re-introduce some foods.

Targeted elimination diet based on allergy test findings

Current testing poorly predicts response in adults. Lower response than elemental diet in children. Added cost of testing.


Other Intrinsic Structural Disorders of the Esophagus Congenital Esophageal Stenosis, Atresia, and Tracheoesophageal Fistula

Abnormal embryonic development arising in the esophageal and tracheal anlagen can result in incom-plete separation of the esophagus from the trachea and incomplete development of the esophagus. The resulting defects range in severity from esophageal stenosis to tracheoesophageal fistula to esophageal atresia. Most of these present in the perinatal period with feeding difficulties, vomiting, cough produc-tive of feedings, and pneumonia. Patients with more subtle stenoses may not present with dysphagic symptoms until adulthood. The defects can often be bridged using a gastric tube reconstruction, but with the obligate absence of a lower esophageal sphincter and normal esophageal motility, these patients are at high risk for subsequent complications of GERD.166

Inlet Patch (Gastric Heterotopia)About 1–10% of individuals have an inlet patch of columnar mucosa located at or below the distal as-pect of the UES; the detection rate is higher when endoscopic examination is focused on identifying these lesions and narrow-band imaging is employed. Whether the origins are congenital or develop sec-ondarily is not clear, as reflux esophagitis and Bar-rett’s esophagus are common associated findings. Most inlet patches are asymptomatic, but some larger patches appear capable of secreting acid and may be complicated by symptoms of globus and dys-phagia. Complications include esophageal strictures, ulcers, and rare neoplastic degeneration.

Esophageal Manifestations of Systemic Disorders

Many systemic conditions can affect the esophagus secondarily. In some cases, esophageal complica-tions first bring the disorder to medical attention and can be the most problematic manifestation for some patients.

DiabetesSeveral factors predispose diabetic patients to de-velop GERD and its complications. Importantly, the majority of patients with type 2 diabetes are obese. Additionally, hyperglycemia increases the rate of TLESR response to gastric distension in healthy sub-jects,167 and diabetic patients with higher glycosyl-ated hemoglobin values are more likely report GERD symptoms.168,169 Many patients with diabetes have delayed gastric emptying, predisposing them to re-flux. Patients with diabetes may also be less sensitive to the presence of abnormal amounts of reflux170 and thus may not come to clinical attention until they de-velop more severe complications of peptic esophagi-tis. Reflux esophagitis is the most common finding in patients with diabetic ketoacidosis and upper gastro-intestinal hemorrhage.171 Diabetes is a risk factor for developing Candida esophagitis.

Connective Tissue DisordersIn patients with progressive systemic sclerosis or mixed connective tissue disease, the reduction in LES pres-sure and peristaltic function from atrophy of the smooth muscle predisposes these patients to severe reflux dis-ease, as does the delayed gastric emptying that is also frequently present in these patients. Uncontrolled reflux may be a risk factor for chronic aspiration and pulmonary fibrosis in these patients. Patients with Sjögren’s (sicca) syndrome have reduced ability to neutralize refluxed acid. The loss of the lubricating properties of saliva also causes dysphagia for solids. Patients with connective tissue disorders are at risk for iatrogenic complications from immunosuppression (infectious esophagitis) or pill injury (nonsteroidal anti-inflammatory drugs and bisphosphonates for arthritis and osteoporosis).

Table 1.9

Primary Dermatologic Disorders Affecting the Esophagus

n Epidermolysis bullosa n Bullous phemphigoid n Pemphigus vulgaris n Stevens-Johnson syndrome n Lichen planus


Dermatologic DisordersDue to its squamous epithelium, the esophagus is subject to several systemic diseases typically affect-ing the skin (Table 1.9). These immune-mediated disorders can manifest on endoscopy as blisters, a positive Nikolsky’s sign, erosions, plaques, ulcers, and strictures. The presence of skin and oral lesions usually provides clues to the diagnosis, although esophageal involvement is rarely the presenting manifestation. Immuno-fluorescent staining of bi-opsy specimens can confirm the diagnosis.

InfectionThe major clinical infections of the esophagus are Candida, herpes, and cytomegalovirus. The most common symptom of infectious esophagitis is ody-nophagia. Risk factors for all infections include pro-found suppression of the immune system, as can be seen in patients with acquired immunodeficiency syndrome or in patients on immunosuppressive therapy for transplants. Poorly controlled HIV infec-tion itself can be associated with large ulcers that are negative for other infectious agents. Additional risk factors for fungal infections include diabetes, recent antibiotic exposure, and swallowed topical cortico-steroid therapy.172 Candidal infections usually have an endoscopic appearance of a whitish exudate (“cot-tage cheese”), while viral infections typically cause esophageal ulceration.

Cardiovascular DisordersThe major clinical issue regarding cardiovascular dis-orders and the esophagus is the need to avoid ascrib-ing symptoms from cardiac disease to the esophagus. While GERD may cause chest pain in patients with known coronary artery disease,173 the obverse is also true. Patients with coronary artery disease may pres-ent with vague chest symptoms ascribed to heart-burn, or atypical gastrointestinal symptoms such as nausea or eructation, and there is some evidence in population studies that misdiagnosis of myocar-dial infarction as GERD is an important problem.174 Complicating matters further is that fact that GERD is a common comorbidity in patients with coronary artery disease,175 and esophageal acid exposure can

reduce coronary blood flow via a vagal reflex.176

Congenital or acquired abnormalities of the car-diovascular system can obstruct the esophagus via extrinsic compression (dysphagia lusoria). Dissec-tion of the thoracic aortic may cause acute esopha-geal necrosis. Rupture of an aortic aneurysm into the esophagus is usually a fatal event, presenting as massive hematemesis. Accidental and Latrogenic Esophageal Disorders Esophageal Pill Injury, Caustic Ingestion, and Foreign BodiesWell over 100 medications have been reported to cause pill-induced esophageal injury.177-179 The most common agents in clinical practice are listed in Table 1.10. Doxycycline is notorious for causing severe odynophagia, but this symptom is seen with many other agents, as well as symptoms of heartburn, chest pain, and dysphagia. Injury can range from erosions to deep ulcers to perforation, and the initial lesion may evolve into a refractory stricture. A clue to the etiology of these lesions is their common locations above the level of the lower esophageal sphincter and above the aortic arch, unlike lesions from GERD, which are usually based on or just above the squa-mocolumnar junction. A common history preceding such injury is that the patient swallowed the pill dry and/or while recumbent. Risk factors for pill injury are old age and sustained release preparations.

Table 1.10

Common Medications for Pill-Induced Esophageal Injury

n Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)

n Bisphosphonates n Potassium chloride n Doxycycline/tetracycline n Ascorbic acid n Ferrous sulfate


Extremely acid (pH <2) or alkaline (pH >12) solutions can cause severe esophageal injury. A full thickness injury may result in perforation acutely and chronic stricture formation, requiring repeat-ed courses of dilation. Some patients will require esophageal replacement. Early endoscopy (within 24 hours) is safe and warranted to assess the severity of injury in patients who have symptoms after reported ingestion. A lack of oral lesions does not exclude se-vere injury more distally in the esophagus.

Inadvertent or intentional ingestion of sharp or pointed foreign bodies, such as bones, pins, and ra-zor blades, places the patient at risk for esophageal laceration or perforation, with subsequent develop-ment of mediastinitis or fistula into the cardiovascu-lar system. Retained button batteries can produce a deep tissue injury. Retained esophageal foreign bod-ies constitute an endoscopic emergency.

Medication and Radiation EffectsMedications that inhibit smooth-muscle tone or con-tractility can theoretically place patients at higher risk for gastroesophageal reflux and delayed clearance of refluxate. Such agents include calcium channel block-ers, theophylline, and beta-agonists, the latter two being used frequently in asthmatics, who commonly have coexisting GERD. Agents with anticholinergic properties can also decrease salivary secretion, re-sulting in impaired neutralization of refluxed acid.

Ionizing radiation has both early and delayed ef-fects on the esophagus. Acutely, the inflammatory re-sponse may cause dysphagia and odynophagia severe enough to require alternate means of alimentation. More severe injury can lead to extensive transmural necrosis, with hemorrhage and perforation. Later ef-fects tend to be from stenosis, which may extend to complete luminal occlusion. Concurrent chemother-apy increases the risk of injury for any given course of radiation therapy. Patients with radiation-induced xerostomia have a higher frequency of abnormal esophageal acid exposure and reflux esophagitis.180

Consequences of Instrumental and Surgical ProceduresPassage of instrumentation into the esophageal lu-men carries a small risk of abrasion, laceration, hema-

toma, or frank perforation of the esophagus. This risk becomes much greater in the presence of structural disorders, such as rings and strictures, particularly since subtle strictures may not be easily recognized at the time of endoscopy. Perforation is the dreaded complication of stricture dilation; the time-honored dictum is to pass no more than three successively larger dilators, once resistance to dilator passage is present, in any one session. Treatments to eradicate abnormal mucosa and vessels in the esophagus may produce strictures.

Immediate iatrogenic injuries from esophageal surgery include mucosal tears, frank perforations, intramural hematomas, ischemic necrosis, and anastomotic strictures and leaks. Patients under-going antireflux surgery may have immediate or delayed symptoms from overly tight or long wraps, slipped wraps, or development of a paraesopha-geal hernia. About half of patients following a my-otomy for achalasia develop symptoms or findings of GERD.

Patients undergoing radiofrequency ablation for cardiac arrhythmias are at risk to develop ther-mal injury to the adjacent esophagus. Such lesions are not always symptomatic, but the concern is for the rare development of fatal cardioesophageal fis-tula formation following such transmural esopha-geal injury.

Motor, Neoplastic, and Portal Hypertensive Disorders of the Esophagus

These topics are covered in separate chapters. The clinician must remain aware that these can coexist with other esophageal disorders. For example, pa-tients with esophageal achalasia may suffer from pill injury, Candida esophagitis, reflux disease (following surgical myotomy), or esophageal cancer. Patients with GERD and Barrett’s esophagus may develop adenocarcinoma of the esophagus. Patients may de-velop esophageal strictures from efforts to eradicate varices. Patients with motor disorders can develop Zenker’s and other pulsion diverticula.


Heartburn/ Regurgitation

PPI trial GERD

EGD +/- biopsy DX

Chest Pain Syndrome

CAD?

PPI trial GERD

DX

EGD +/- biopsy DX

Atypical/Alarm Symptoms

EGD +/- biopsy DX

PPI trial GERD

INITIAL DIAGNOSTIC APPROACH FOR SUSPECTED ESOPHAGEAL DISORDER

+ +

+ +

+

+

+ -

-

-

-

-

-

-

APPROACH AFTER PPI TRIAL & EGD ARE NEGATIVE

Solid dysphagia only

Esophagram with solid bolus

Esophageal manometry

Ambulatory reflux testing off therapy

Functional disorder

Non-esophageal disorder

Prior testing falsely negative

DX DX

DX

+

+

+ +

-

-

- -

Figure 1.5

Flow Charts for the Evaluation of the Patient with Symptoms Suggesting the Presence of an Esophageal Disorder.

Figure 1.5 shows the initial approach to a suspected esophageal disorder, depending on the nature of the presenting symptoms and the additional work-up to perform if the patient fails to respond to a PPI trial and/or EGD testing is nondiagnostic. DX, diagnosis made; CAD, coronary artery disease; PPI, proton pump inhibitor therapy; EGD, upper endoscopy.


Approach to the Patient with Suspected Esophageal Disorders

The patient history remains the cornerstone of evaluation when esophageal disorders are suspected, with emphasis on the presence, severity, time course, and associations of cardinal and atypical symptoms. History-taking should also address the presence of conditions that secondarily affect the esophagus, as should the physical examination (which is typically normal for primary esophageal disorders). Additional testing is usually necessary to obtain an accurate diagnosis of esophageal disorders, with the sequence of testing being guided by findings from the history and physical examination findings in conjunction with knowledge regarding the background prevalence and clinical associations of the different esophageal disorders.

Diagnostic Strategies and Options for TestingRational and cost-effective testing and treatment in the twenty-first century are based on the knowledge that the most prevalent esophageal disorder by far is GERD. Even patients presenting with atypical symp-toms are more likely to have GERD than another esophageal disorder. This high prior probability of GERD drives the diagnostic algorithm outlined in Figure 1.5.

For patients presenting with the classical symp-toms of heartburn (typically postprandial substernal burning with upward radiation) and sour regurgita-tion, the likelihood that they have GERD as the etiol-ogy is so great that a trial of PPI therapy can be both diagnostic and therapeutic. If the patient responds appropriately, no other testing is necessary to con-firm the diagnosis. The utility of evaluating such pa-tients for asymptomatic complications of GERD, such as Barrett’s esophagus, is controversial. Any such testing should be guided by the presence of known risk factors for Barrett’s esophagus.

On the other hand, patients who have other car-dinal symptoms, such as odynophagia and trouble-some dysphagia (not mild, brief, and infrequent bo-lus hesitancy or sticking sensations) should undergo early endoscopic evaluation, because of the greater

likelihood of GERD complications or the presence of another serious esophageal disorder. Endoscopic evaluation of dysphagia should include random bi-opsies from the proximal and distal esophagus (if no other explanation for dysphagia is seen), to identify otherwise unsuspected EoE. Early endoscopy should also be performed in patients with additional alarm symptoms, such as weight loss, failure to thrive, re-petitive vomiting, or hematemesis. Patients with a combination of cardinal and atypical symptoms are also candidates for early endoscopy, as are patients over age 55 with dyspeptic symptoms.

Careful consideration has to be given to the pa-tient presenting only with chest discomfort atypical for GERD. The concern is that the patient has undiag-nosed coronary artery disease (CAD). CAD and GERD share many of the same risk factors and commonly occur together. Such patients warrant rigorous evalu-ation to exclude a cardiac source of pain before eval-uation of possible esophageal sources. For patients with these atypical coronary syndromes, resting EKG and routine exercise stress testing alone may not be adequately sensitive.

Following a negative cardiac evaluation for pa-tients with only chest pain, and a negative endoscopy in patients with other cardinal esophageal symp-toms, the next reasonable step is a diagnostic/ther-apeutic trial of PPI therapy (once daily, followed by twice daily if no response, each for at least 8 weeks), since in this setting the most likely remaining diag-nosis is still GERD. Patients who fail a PPI trial should proceed to endoscopy, if this has not already been done, as the chances for finding other esophageal disorders or complications of GERD on such testing become greater in this setting.

After a negative endoscopy, if the patient’s domi-nant symptom is solid food dysphagia, the next test should be a barium pharyngoesophagram that incor-porates a solid bolus challenge, to assess for previ-ously missed subtle rings, webs, and stenoses. Oth-erwise (and if the esophagram is negative), the next test should be an esophageal manometry to detect the presence of an esophageal motor disorder, such as achalasia or distal esophageal spasm.

At this point, the patient in whom preceding test-ing was non-diagnostic and whose cardinal symp-


toms failed to respond to a PPI trial should undergo ambulatory esophageal pH testing. This can be com-bined with impedance for assessing nonacid reflux, to determine whether the patient may have nonero-sive reflux disease (NERD) that failed to respond to therapy and is temporally associated with the pa-tient’s symptoms. The preceding manometric evalu-ation will also aid in probe placement. Ambulatory reflux testing should be performed off of therapy, since the goal at this point is to confirm that GERD is indeed present. For patients with GERD documented previously but poor response to therapy, a case can be made for ambulatory reflux testing on twice daily PPI therapy to document failure of such therapy, but with an expected yield of less than one in ten.181

In patients whose diagnostic evaluation remains inconclusive after the above sequence, the most like-ly etiology for symptoms is a sensory disturbance, such as functional heartburn, which may not neces-sarily have its origin in the esophagus. Alternatively, the chances are greater at this point that the symp-toms come from a nonesophageal disorder. Finally, a careful review of prior testing should be undertaken, to assess for test quality concerns and other reasons for false-negative testing.

For some patients without cardinal esophageal symptoms, the issue is whether their atypical symp-toms might be from an esophageal disorder. In these cases, the prior probability of an underlying esopha-geal disorder is so low that the patient would be best served by evaluation first for other disorders that are more likely to be the source of symptoms. Once other causes are excluded, evaluation can proceed along the lines described for patients with cardinal esoph-ageal symptoms, with the proviso that patients with candidate supraesophageal symptoms are unlikely to respond to PPI trials when typical GERD symp-toms are absent.

Unfortunately, a common clinical scenario is the patient whose test results support the diagnosis of GERD but who fails to respond to GERD-directed therapy. The most plausible reasons for this failure are in Table 1.11. Compliance has become a greater issue, as expensive PPI agents have become avail-able over the counter and are no longer covered by insurance. Patients are often not instructed as to the

appropriate timing of PPI therapy, which should be taken before meals. Unrecognized conditions that could be impairing the response to therapy at this point include celiac disease, surreptitious nonste-roidal anti-inflammatory drug (NSAID) use/abuse, and systemic sclerosis. The most common causes for false-positive endoscopic diagnoses of GERD are erosions from pill injury and strictures from EoE. Repeat ambulatory pH/impedance testing should be performed on therapy in this setting, as it may help identify those patients whose therapy is not controlling their reflux.182

For the patient who fails to respond to antire-flux surgery, or relapses after initial success, endos-copy is the first test, the goal being to assess integ-rity of the surgical repair and such complications as the development of a paraesophageal hernia.183 Endoscopy can also detect whether the patient has a new, or previously missed, esophageal disorder. If endoscopy is unrevealing, the next test should be esophageal manometry, especially if this was not performed preoperatively. If these tests are nega-tive and the patient fails a PPI test, ambulatory pH monitoring is likely to be normal. Such patients are likely to have functional disorders as the cause of their symptoms.

The capabilities and caveats for the major tests to evaluate esophageal disorders are described be-low. The lack of perfect sensitivity and specific-ity of these tests must be considered when they are used to evaluate patients with a low pretest likeli-hood of an esophageal disorder, such as those with only atypical symptoms. In this setting, negative test results are often the most helpful, because the post-test probability is sufficiently low that esophageal etiologies can be removed from further consideration.

Proton Pump Inhibitor TestThe virtue of the PPI test for GERD, which is simply assessing whether the patient’s symptoms respond to a short course of PPI therapy, is its simplicity and low expense. However, the specific agent, dosage, and duration are not standardized, and a meta-analysis of trials of the PPI test indicate a sensitivity of 78% but a specificity of only 54%.184 Thus the test is useful only in cases where the pretest probability of GERD


is already large (typical GERD symptoms only, or pri-or testing excludes other candidate disorders). The recent recognition of the entitity of PPI-responsive esophageal eosinophilia has further complicated the interpretation of the PPI test. An additional concern regarding the PPI test is the risk of development of symptoms from rebound acid hypersecretion upon PPI withdrawal.185

EndoscopyEndoscopy allows the visual identification of mucosal and structural abnormalities in the esophagus and affords the opportunity to obtain diagnostic mucosal biopsies. Treatment of some disorders (stricture di-lation, control of bleeding) can also be performed at the time of testing. False-positive results from endos-copy are usually related to misinterpretation of iden-tified lesions (mistaking white spots of EoE for candi-diasis, or ulcers from viruses or pill injury for GERD, or EoE strictures for peptic stictures). Preventable causes for false-negative endoscopies include fail-ure to (1) examine the esophageal inlet carefully for webs and inlet patches, (2) recognize the character-istic features of EoE, (3) obtain mucosal biopsy spec-imens to diagnose EoE and (4) recognize abnormal post-operative anatomy.186 However, despite careful technique, subtle webs and stenoses may remain undetected. In addition, nearly half of patients with GERD do not have detectable endoscopic abnormali-ties, especially in an era when many patients are al-ready on a PPI at the time of endoscopy.

RadiologyBarium fluoroscopic studies are insensitive to flat mucosal lesions, and the findings of reflux events during these studies do not reliably predict the pres-ence of GERD.187 These studies can be useful for iden-tifying subtle webs, rings, and stenoses that are not detectable by endoscopy, but this requires the ad-ditional use of an adequate-sized solid bolus chal-lenge. Barium studies can also assess the detail of strictures too tight to allow endoscope passage and identify esophageal fistulas. Computed tomography (CT) imaging can detect pathologic thickening of the esophageal wall and extrinsic pathologic processes that compress or invade the esophagus.

ManometryManometry has no role in the diagnosis of GERD. Manometry is used to diagnose symptomatic major esophageal motor disorders and to exclude their presence in patients proposed for antireflux surgery. Manometry may be helpful in identifying symptom-atically tight fundoplication wraps when endoscopic and radiologic testing is inconclusive. Manometry is also used for locating the position of the LES for placement of pH probes.

pH/impedance monitoringAmbulatory pH monitoring allows the quantification of the degree of esophageal acid exposure and the correlation of symptoms with reflux events. A major problem with such testing is that no cutoff value for acid exposure completely separates normal subjects from those with GERD. The accuracy of pH testing

n Noncompliance n Improper timing n Inadequate dosage n Inadequate delivery/bioavailability n Rapid medication metabolizer; true PPI resistance n Nocturnal acid breakthrough n Nonacid/weakly acid/duodenogastric reflux n Patient does not have GERD (prior test false-positive) n Patient has another esophageal disorder (e.g., achalasia, EoE) n Patient has a functional disorder (functional heartburn,

hypersensitive esophagus, rumination) n Patient has a nonesophageal disorder (cardiac disease, asthma) n Patient has GERD plus another disorder n Zollinger-Ellison syndrome n EoE n Connective tissue disease (e.g., scleroderma) n Celiac disease n Medication injury n Infection n Delayed gastric emptying n Functional gastrointestinal disorder

Table 1.11

Reasons for Therapeutic Failure in Patients Diagnosed with GERD


is at best about 90% in patients with GERD.188 Test-ing can be performed with either catheter-based or mucosally-attached sensors. The latter have the ad-vantage of better tolerability by the patient and lon-ger recording times; disadvantages include the cost of a second endoscopy often used to place the probe (and occasionally a third to remove probes causing intolerable pain), and premature dislodgement and migration of the sensor distally. This latter event can give the false appearance of prolonged esophageal acid exposure time. Distal single-site pH sensors are unable to provide any information about the proxi-mal distribution of reflux events, which is a determi-nant of symptom occurrence.

Probes are also available that record intralumi-nal pH and impedance changes, the latter being used to detect nonacid reflux events. Impedance can also be used to prevent mistaking undocumented inges-tion of acid foods as reflux events, which is a problem for single-point pH sensors.189

Ambulatory studies can be performed off or on acid suppressive therapy, depending on whether the goal is to help make the initial diagnosis of GERD or to try to determine if persistent symptoms while on therapy result from GERD that is not adequately treat-ed under the current regimen. These studies can also assess the temporal association of the patient’s symp-toms with preceding acid or nonacid reflux events. Limitations are failure to have a symptom event re-ported during the recording period. Symptom asso-ciations on studies with few events are unreliable.190 For cough, it is often not possible to distinguish be-tween coughs caused by reflux events or vice versa.191

Illustrative Clinical CaseA 53-year-old woman presents with a 3-month histo-ry of worsening heartburn and a 1-month history of persistent dysphagia for breads and meats. She has had occasional heartburn for years that she treated with over-the-counter antacids. However, she has been having more heartburn in the evening and night, and started taking an over-the-counter hista-mine2-receptor antagonists at bedtime last month without much improvement. Her medical history is

pertinent for asthma, hypertension, hyperlipidemia, obesity, and degenerative joint disease. Her other medications are albuterol and fluticasone inhalers, simvastatin, enalapril, and over-the-counter ibupro-fen. Physical examination shows a blood pressure (BP) of 134/80 mmHg and a body mass index (BMI) of 32 kg/m2, but is otherwise unremarkable.

Because of the new-onset solid-food dysphagia, she undergoes an upper endoscopy, with findings of Los Angeles Grade B erosive esophagitis at the gastroesophageal junction, a 13-mm diameter ring-type stricture at the gastroesophageal junction, and a 2-cm fixed hiatal hernia. The ring is disrupted with a 16-mm diameter balloon dilator, and the patient is switched to a PPI before breakfast and advised to use acetaminophen instead of ibuprofen for joint pain. On follow-up one month later, dysphagia has resolved, but she is having heartburn 3 nights per week. Addition of a second dose of PPI before the evening meal results in essentially complete resolution of her symptoms after 2 additional months.

She does well until 2 years later, when she develops burning substernal pain that can last for hours and can awaken her, even though she continues on her reflux medication. She intermittently notices pain when swallowing her pills. Interval history is of a new diagnosis of osteoporosis, which is being treated with alendronate. She undergoes repeat endoscopy, showing erosions at 25 cm from the incisors and at 4 cm above the gastroesophageal junction. Biopsies are negative for EoE or infection, and she is advised to discontinue the alendronate, with resolution of her symptoms over the next week.

She again does well until 2 years later, when she develops substernal chest discomfort at mealtime or when walking her dog. An associated symptom is nausea, and additional over-the-counter antacid tablets do not help. Examination is unchanged except for BMI of 34 kg/m2 and BP of 148/92 mmHg. She is referred to a cardiologist who performs a coronary angiogram, showing a 90% occlusion in the right coronary artery. A drug eluting stent is placed, and she is begun on clopidogrel and low-dose aspirin, with resolution of these symptoms.

This case illustrates several important concepts in the evaluation and management of esophageal


disorders. The patient had several risk factors for her primary esophageal disorder of GERD. She had symptoms that should prompt endoscopic evaluation (and treatment). She required medication adjustments to provide adequate symptom relief. While her condition is a chronic one, she required careful reevaluation when she later experienced new symptoms while on effective therapy, due to the subsequent development of a new esophageal disorder and coronary artery disease.

Pearls and Pitfalls for the Board Exam

n Beware of “white spots” in the esophagus: these could be from Candida or EoE!

n Be able to recognize reflux events on pH/impedance tracings.

n No treatment is approved or has consensus recommendation for cancer prevention in Barrett’s esophagus without dysplasia.

n Recall the criteria for diagnosis of EoE, as well as the differential diagnosis of esophageal eosinophilia.

n Identify the different treatment options for EoE, including the condition of PPI responsive esophageal eosinophilia.

n Understand the concept of TLESR, but recognize that the presence of these by themselves do not distinguish GERD patients from healthy people.

n Be familiar with the appropriate dosage, timing, and duration of PPI administration

n Watch out for the dysphagia patient with a “negative” EGD in which no biopsies were taken. What could have been missed: EoE, subtle ring/ stricture, major motor disorder.

n Be aware of what normal and abnormal post-fundoplication anatomy looks like on EGD.

n Esophageal ulcers distant from the z-line? Think bugs and drugs (pill injury).

n Upper abdomen or chest discomfort not responding to PPI? Don’t forget the heart!

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Most Efficient Source Review for Exam Preparation

n Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013; 108(3):308-28.

n AGA Institute Medical Position Panel. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology 2011;140:1084–1091.

n AGA Institute Medical Position Panel. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135: 1392–1413.

n Dellon ES,Gonsalves N,Hirano I,Furuta GT,Liacouras CA,Katzka DA. ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol 2013; 108:679–692.

n Papadopoulou A1, Koletzko S, Heuschkel R, Dias JA, Allen KJ, Murch SH, Chong S, Gottrand F, Husby S, Lionetti P, Mearin ML, Ruemmele FM, Schäppi MG, Staiano A, Wilschanski M, Vandenplas Y; ESPGHAN Eosinophilic Esophagitis Working Group and the Gastroenterology Committee. Management guidelines of eosinophilic esophagitis in childhood. J Pediatr Gastroenterol Nutr 2014;58(1):107-18.

n ASGE Standards of Practice Committee, Ikenberry SO, Jue TL, Anderson MA, Appalaneni V, Banerjee S, Ben-Menachem T, Decker GA, Fanelli RD, Fisher LR, Fukami N, Harrison ME, Jain R, Khan KM, Krinsky ML, Maple JT, Sharaf R, Strohmeyer L, Dominitz JA. Management of ingested foreign bodies and food impactions. Gastrointest Endosc 2011;73(6):1085-91.

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