DIAGNOSIS OF GASTROESOPHAGEAL REFLUX DISEASE: ROLE OF ENDOSCOPY

DIAGNOSIS OF GASTROESOPHAGEAL REFLUX DISEASE:

ROLE OF ENDOSCOPY

A. Bansal and P. Sharma

University of Kansas, School of Medicine and Veteran Affairs Medical Center, Kansas City, MO, USA

Introduction

The diagnosis of gastroesophageal reflux disease

can be made by a number of methods in- cluding endoscopy, patient’s symptoms, Bernstein test, 24 hr ambulatory pH and by using a short course of acid suppressive therapy (proton pump in- hibitors). Newer techniques including magnetoence- phalography, postiron emission tomography and functional magnetic resonance imaging

are currently being evaluated for the diagnosis of

[1]. None of these tests can be considered as the gold standard for the diagnosis of

. The role of endoscopy in

is to evaluate changes in the mucosa of the distal esophagus and offers the poten- tial to obtain biopsies, treat reflux induced strictures and rule out other structural lesions in the upper gas- trointestinal tract. However, endoscopy is relatively insensitive for making a diagnosis of

since only 40–50% of patients with typical reflux symp- toms undergoing endoscopy may have

in- duced changes. Utilization of newer techniques like chromoendoscopy, high resolution and magnification endoscopy may play an important role in the endo- scopic evaluation of

in the near future.

Endoscopic findings suggestive of GERD

The findings at endoscopy that suggest a diagnosis of

include the presence of erosive esopha- gitis, Barrett’s esophagus and peptic stricture. In combination with reflux symptoms, these findings are highly suggestive for a diagnosis of

. In this chapter, we will discuss the findings of erosive esophagitis, Barrett’s esophagus, role of esophageal biopsies and the impact of a negative endoscopy in patients with

.

Erosive esophagitis

Multiple studies have shown that only 30–40% of pa- tients with typical reflux symptoms (i.e., heartburn, regurgitation) have evidence of erosive esophagitis (Fig. 1) on upper endoscopy whereas the other 60–70%

of patients even with troublesome reflux symptoms have no clear-cut esophageal mucosal abnormalities [2]–[7]. Thus, overall endoscopy is an insensitive test for diagnosing reflux disease. However, if detected, erosive esophagitis has a good positive predictive value for the diagnosis of

as discussed below.

Role in diagnosis

A number of different classification systems for grad- ing erosive esophagitis have been described inclu- ding the Savary-Miller, Los Angeles (LA) (Table 1), Hetzel-Dent etc. [8]–[11]. The LA classification is a well validated, widely used system and is listed in Table 1. In general, as the grade of erosive esophagitis worsens, the degree of esophageal acid exposure in- creases. Lundell et al showed that the severity of esophageal acid exposure was significantly (p  0.001)

Fig. 1. Endoscopic appearance of erosive esophagitis

[15]. In another study of 100 patients with reflux symptoms, 51% and 48% of patients respectively with grades 1 and 2 esophagitis had a normal DeMeester’s score ( 14.7) [16]. This raises questions whether mil- der grades of esophagitis on endoscopy may overdiag- nose

, if other causes of esophagitis may have been present and last but not the least, if results of 24-hr pH monitoring may have been falsely negative. Fur- thermore, some patients may be susceptible to esopha- geal damage at relatively low levels of acid exposure.

All these studies have compared endoscopic find- ings to 24-h ambulatory pH – using it as the gold standard, which is less than a perfect test for the diag- nosis of

. Studies have shown that 37–60% of patients with non erosive reflux disease

, as de- fined either by symptom response to

or significant symptom correlation with reflux episodes, will have normal ambulatory 24-H esophageal pH results [4], [6], [17], [18]. Moreover, when the reproducibility of prolonged esophageal pH testing is measured on two separate days in patients with reflux symptoms or with esophagitis, the results change the diagnosis (normal or abnormal based on the percentage time pH  4.0) in 11% of the cases [19]. Thus, comparison with 24-h pH monitoring may lower the sensitivity of milder forms of erosive esophagitis in the diagnosis of

. It is possible that these shortcomings may be overcome by using the new Bravo wireless pH device and correlat- ing these pH results to the presence of erosive esopha- gitis. Results of such studies are as yet awaited.

Overall, in the presence of typical reflux symptoms (i.e. heartburn), detection of macroscopic endoscopic injury is strongly predictive of the diagnosis of

.

Role in prognosis

Given the lack of efficacy of non-drug measures and antacids and the relatively low efficacy of H2 receptor antagonists, the majority of patients with erosive esophagitis require acid suppression therapy using

’s (proton pump inhibitors) [2]. Also, patients with erosive esophagitis, especially those with higher grades are less likely to be effectively managed with less than standard dose of

therapy, and step-down attempts in this group are less successful [20]. Castell et al [21]

noted in a large study (n  5,241) declining efficacy of

’s in patients with more severe grades of esophagitis (healing at 8 weeks- 92–94% in grades A/B compared to 70–72% in grades C/D).

related to the grade of esophagitis as judged by the LA classification for erosive esophagitis [10]. Another study of 150 patients demonstrated a significantly higher duration of esophageal acid exposure in patients with grade-III/-IV esophagitis compared to grade-II esophagitis (percent time pH  4.0 17.5%

vs. 10.4%; p  0.001). Both groups (i.e., patients with esophagitis) had significantly higher pH scores com- pared to control subjects (percent time pH  4.0 1.8%; p  0.0001) [12].

The presence of erosive esophagitis has a good cor- relation with results of 24 h pH monitoring showing increased esophageal acid exposure. In a study by DeMeester et al [13], the combination of typical reflux symptoms (i.e., grade-II or -III heartburn and/or regurgitation, scale of severity 0–3) and the presence of erosive esophagitis or Barrett’s esophagus on en- doscopy had a 64% sensitivity and 97% specificity for accurately diagnosing

as defined by a positive 24-hr ambulatory pH result. A study of 24 controls and 64 patients with reflux symptoms (all of whom underwent 24-hr pH monitoring), showed that the distinction in degree of esophageal acid exposure was excellent between asymptomatic controls and patients with severe erosive esophagitis (sensitivity and specific- ity both 100% by logistic regression) but discrimination was relatively poor when asymptomatic controls were compared to symptomatic patients without esophagitis (71% and 79% by logistic regression) [14].

On the other hand, a study from Spain showed that 34% of patients with grade-I and -II esophagitis show- ed variable patterns of reflux whereas most patients (76.2%) with grade-III and -IV esophagitis showed a clearly defined pattern of gastroesophageal reflux in both the supine and the upright positions (p  0.05)

Table 1. The Los Angeles Classification System for the end- oscopic assessment of grade of esophagitis [10]

(A) One or more mucosal breaks no longer than 5 mm, none of which extends between the tops of the mucosal folds (B) One or more mucosal breaks more than 5 mm long, none

of which extends between the tops of two mucosal folds (c) Mucosal breaks that extend between the tops of two or

more mucosal folds, but which involve less than 75% of the oesophageal circumference

(D) Mucosal breaks which involve at least 75% of the oesophageal circumference

Multiple studies have also shown that the presence of erosive esophagitis at baseline is predictive of the need for chronic acid suppression [22], [23]. A long term follow up study ( 3 years) in elderly patients ( 65 years) with documented esophagitis as a inclu- sion criterion suggested that the presence of severe grades of esophagitis at baseline (p  0.009) was a risk factor for relapse of esophagitis, suggesting need for maintenance therapy in this group of patients [24].

Thus, it is clear that more severe grades of esophagitis require more complete acid suppression for intial healing as well as for maintenance of hea- ling [10]. However,

is a symptom driven disorder and this information may not be necessary to guide therapy in all patients [25].

Barrett’s esophagus

The definition of Barrett’s esophagus

, as discussed at a recent evidence based workshop, is based on a com- bination of endoscopic and histologic criteria consisting of an abnormal appearing distal esophageal lining (end- oscopic

) with histologic evidence of intestinal meta- plasia (confirmed

). Barrett’s esophagus has been arbitrarily divided into long ( 3 cm) and short seg- ment ( 3 cm), although there is no evidence that a risk gradient for complications (i.e., dysplasia/cancer risk) may be demarcated at a particular segment length [26]. The role of gastroesophageal reflux in the develop- ment of BE has been consistently shown in animal and human studies. In a rat model,

could be induced in 80% of the animals following a jejunoesophageal loop.

In a recent prospective study of 40 patients who under- went esophagogastrostomy and sub-total esophagectomy (done for adenocarcinoma or squamous cell carcinoma), 10 developed

above the anastomosis [27].

Role in diagnosis

Longer lengths of

have been found to be highly predictive of gastro esophageal reflux. In some studies, the sensitivity of pH testing in

patients is reported to be as high as 90% [28]. Some studies have also found a significant correlation between the percent to- tal time pH  4 and the length of BE (r  0.6234, p  0.0005) [29], [30]. Other investigators have per- formed studies correlating esophageal acid exposure in long segment BE and erosive esophagitis patients compared to controls. Most studies have demonstrat-

ed that

patients have more pronounced acid reflux than patients with mild-moderate esophagitis (grades-I and -II Savary-Miller) and controls [31]–[34]. In a study of 150 patients, no significant difference was observed in esophageal acid exposure between patients with grades-III/IV esophagitis and long segment BE, although both groups had signifi- cantly higher values compared to controls (17.5% vs.

21.5% vs. 1.8%, respectively) [12]. Similarly, other studies have also shown the duration of reflux in

patients to be significantly higher compared to controls, but not different than patients with grades- III/-IV erosive esophagitis [35]–[37].

The shorter lengths of

have attracted consider- able attention in recent years. The issues around this are more complex than traditional or long segment

[2], [3], [38]–[41]. A study comparing 21 patients with short segment BE and 18 with long segment

showed that the percent time pH  4.0 was signifi- cantly lower in short segment (8.6%) compared to long segment

(24.4%) patients. These numbers were significantly higher compared to controls (1.8%) arguing that short segment

may be a true patho- logical finding albeit reflecting a lower severity of esophageal acid exposure [42]. In a recent interesting study, a group of predominantly male, Caucasian patients undergoing colorectal cancer screening were offered an upper endoscopy. Long segment

was detected in 0.36% and short segment

in 5.24% of subjects without any history of heartburn compared to 2.6% and 5.7% respectively in those with a history of heartburn [43]. These results raise many questions, the most relevant to this discussion is whether the finding of

in asymptomatic individuals is equivalent to pathological reflux.

In conclusion, the presence of longer lengths of

may be reliable for the diagnosis of

but shorter lengths as a diagnostic criterion for

by itself may have poor specificity.

Newer endoscopic techniques to increase yield of Barrett’s esophagus (BE)

Chromoendoscopy, i.e., endoscopy with dye spraying

has been utilized to increase the detection of intestinal

metaplasia in the columnar lined segment. Different

stains that have been used include methylene blue, in-

digo carmine and Lugol’s iodine. In an intial report of

14 patients with known

and 12 controls, Canto

et al reported a sensitivity of 95%, specificity of 97%

and positive predictive value of 98% with methylene blue staining for detecting intestinal metaplasia [44].

Sharma et al showed that methylene blue increased the yield of intestinal metaplasia in shorter segments of

compared to controls that had undergone ran- dom biopsies (61% vs. 42%; p  0.02) [45]. A recent study from Greece also showed that chromoendos- copy done immediately following conventional en- doscopy increased the yield of intestinal metaplasia from 1.6% to 3.5% (p  0.001) [46]. On the other hand, in a crossover study by Wo et al [47], the sensitivity and specificity of methylene blue staining to detect intestinal metaplasia were poor at 53% and 51%

and for dysplasia 51% and 48%, respectively.

The addition of magnification endoscopy to methylene blue staining may further increase the yield of metaplastic and dysplastic tissue by identify- ing specific mucosal patterns. Yagi et al [48] found this combination to have a sensitivity of 84.8% and specificity of 91.7% for detecting intestinal meta- plasia. The pattern suggestive of intestinal metaplasia on magnification chromoendoscopy was a tubular, cavernous or elliptical appearance of the mucosa.

Using a combination of indigo carmine with magni- fication endoscopy in 80 patients, Sharma et al showed that the presence of a ridge/villous pattern had a sensitivity of 97%, specificity of 76% and

of 92% for the detection of intestinal metaplasia [49]. Six patients with an irregular/distorted pattern proved to have high grade dysplasia on biopsies.

Thus, chromo and magnification endoscopy of- fers great promise in the diagnosis and follow up of patients with

and further large multicenter trial are awaited in this field.

Endoscopically normal mucosa

The absence of changes in the distal esophagus on conventional endoscopy does not rule out the di- agnosis of

. It is estimated that upto 70% of patients with typical symptoms of

have nor- mal esophageal mucosa on upper endoscopy

[4], [6], [7]. At least, two different approaches have been attempted in these patients: biopsies of the nor- mal appearing squamous mucosa and evaluation of the distal esophagus with newer techniques such as high resolution and magnification endoscopy.

Role of biopsy

Histologically, acute reflux damage consists of superfi- cial epithelial swelling and/or necrosis accompanied by intraepithelial neutrophilic infiltrates. Chronic reflux induces eosinophilic infiltrates, basal cell hyperplasia, epithelial thickening, and elongation of the vascular papillae (Ismail-Beigi Criteria) [50], [51]. Basal hyper- plasia in excess of 15% and papillary elongation in excess of 2/3 of the epithelial thickness have been pro- posed as criterion to diagnose reflux esophagitis (Fig. 2). The number of eosinophils in reflux esophagi- tis is usually 1–20/high power field. More than 20 eosinophils/

should alert the clinician to the possi- bility of an alternative diagnosis such as eosinophilic esophagitis [52]. However, the lack of eosinophils does not rule out reflux esophagitis [53].

Although, initial reports in 1970s suggested that histologic features of basal cell hyperplasia and loca- tion of the papillae close to the epithelial surface correlated well with the presence of

[50], [51], other studies directly comparing esophageal 24-hr pH results to histology have attested to the lack of discriminatory value of these histological criteria. In a report of 100 patients, (69 with positive pH studies), Johnson et al [54] found a significant correlation be- tween esophageal acid exposure and the length of both the papillary and basal cell zones, although the corre- lation coefficients were low (none exceeding 0.33). In

Fig. 2. Biopsy of the squamous mucosa in a patient with reflux symptoms showing histological signs of reflux esoph- agitis. (A) represents Basal cell hyperplasia; (B) represents papillary elongation

another study, Schindlbeck and colleagues found only minor differences in the prevalence of histological fea- tures between 13

patients, 11 patient controls, and 7 healthy controls [55].

In a recent study, the correlation between the histological criteria and 24 hour pH testing was pre- dominantly negative, with the exception of neutro- phil inflammation [56]. However, another recent study, which analyzed data from a large prospective

trial (the Pro

study; n  1475), found that elongation of papillae and basal cell hyperplasia were seen in 40.7% and 12.7% of

patients and 46.1% and 15.7% of patients with erosive esophagitis, respectively, at 2 cm above the z-line.

The presence of intraepithelial inflammatory cells showed a high specificity but very low sensitivity [57]. However, the lack of a clearly defined control group makes it hard to make conclusive recommen- dations as some of these histological findings may be observed in biopsies from asymptomatic individuals.

Some other groups have evaluated the presence of dilated intercellular spaces

as a marker for

. Calabrese et al used transmission electron mi- croscopy to study

in patients with

and duodenal gastro-esophageal reflux disease

. Patients with

and

had intercellular spa- ces dilated to at least two times greater than controls and there was no significant difference in

between patients with erosive esophagitis and

[58].

At this time, unless histological criteria are up- dated or better correlated to either symptoms, 24 h pH results or response to acid suppressive therapy, biopsies of the distal normal appearing distal esopha- geal mucosa cannot be routinely recommended for the diagnosis of

.

Role of newer techniques

High resolution and magnification endoscopy has recently been used to develop endoscopic criteria for non-erosive esophageal injury from gastroesopha- geal reflux [59]. Lugol’s Iodine was used in 13 patients with heartburn and pathologic 24-hour esophageal acid exposure but with no erosions on standard endoscopy and in 10 asymptomatic volun- teers with normal esophageal acid exposure. A few subtle endoscopic findings, such as pin-point vessels and triangular indentation of the squamocolumnar junction upward into the squamous mucosa, were

found in

patients using high-resolution magnification chromoendoscopy with Lugol’s stain- ing [60]. These preliminary findings demonstrate that

patients may show minimal mucosal changes on high-resolution endoscopy.

A recent elegant study correlated histologic and endoscopic findings in patients with

with the help of magnification endoscopy before and after

treatment [61]. Patients with

, more of- ten than controls, showed endoscopic changes of minimal change esophagitis with punctate erythema as the most important finding, which resolved after

therapy. A sensitivity of 64%, specificity of 85%

and a positive predictive value of 80% were deter- mined for these findings on magnifying endoscopy.

In the same study, an increased length of papillae (14/39 with

vs. 2/39 in controls; p  0.005) and basal cell hyperplasia (17/39 vs. 4/39; p  0.009) were seen in the

group which resolved in the majority of patients after

therapy. These new techniques appear very promising for the future but are not yet ready for routine clinical practice.

Utility of endoscopy in addition to confirmation of diagnosis

In patients with atypical symptoms or symptoms over and above those of typical reflux, endoscopy may also have utility in ruling out alternative dis- eases, such as peptic ulcer disease, eosinophilic esophagitis and complications like adenocarcinoma.

Eosinophilic esophagitis, also known as primary eosinophilic esophagitis or idiopathic eosinophilic esophagitis, occurs in adults and in children and represents a subset of eosinophilic gastroenteritis with an isolated severe esophageal eosinophilia.

Patients with eosinophilic esophagitis present with

symptoms similar to those of gastroesophageal re-

flux but may be less responsive to antireflux medi-

cation. The importance of recognizing this entity,

especially in children is underscored by the need for

different treatment approaches, e.g., dietary restric-

tion or corticosteroids and in preventing unneces-

sary fundoplication [62]. Dyspepsia and

may overlap and sometimes they may be difficult to

distinguish by symptoms alone. Many patients with

upper gastrointestinal symptoms have significant

anxiety about their diagnosis, including fear of

Finally, endoscopy may be useful to rule out other dise- ases in the upper gastrointestinal tract.

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Conclusions

Endoscopy is relatively insensitive for making the diag-

nosis of gastro esophageal reflux disease. However, the

presence of erosive esophagitis and/or

is highly

suggestive of

. The presence of normal mucosa

at endoscopy does not rule out the diagnosis of

.

At present, the role of biopsies in these situations is un-

settled and more data are needed. Newer endoscopic

techniques such as chromoendoscopy, magnification

and high resolution may demonstrate minimal changes

in the distal squamous mucosa such as punctate

erythema, pinpoint vessels etc. not seen by standard

endoscopy. Some of these changes may respond to

therapy with proton pump inhibitor. Endoscopy re-

mains the best test to rule out complications of

and allows histological confirmation of esophageal pa-

thology such as intestinal metaplasia, dysplasia and

adenocarcinoma. Identifying the patient group with

severe erosive esophagitis,

and peptic strictures may

help focus aggressive management that may potentially

prevent future complications in these patient groups.

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