Diagnosis of reflux disease

BaillieÁre's Clinical Gastroenterology Vol. 14, No. 5, pp. 759±774, 2000

doi:10.1053/bega.2000.0123, available online at http://www.idealibrary.com on

6 Diagnosis of re¯ux disease Margot A. van Herwaarden Andre J.P.M. Smout*

MD

MD

Gastrointestinal Research Unit, Departments of Gastroenterology and Surgery, University Medical Center, P.O. Box 85500, 3508 GA Utrecht, The Netherlands

There are numerous tests for which a diagnostic value in the context of gastro-oesophageal re¯ux disease has been claimed. Some of these tests (e.g. the acid perfusion test) have become obsolete after the advent of 24-hour oesophageal pH monitoring. With the latter test not only can excessive re¯ux be identi®ed, but also, and more importantly, a temporal relationship can be demonstrated between a patient's symptoms and re¯ux episodes. Radiographical examination of the oesophagus has largely been replaced by endoscopy, although the use of the former test is still indicated in certain circumstances (e.g. in the di€erentiation of sliding from paraoesophageal hiatus hernia). In clinical practice, the so-called proton pump inhibitor test has gained considerable popularity. Despite several studies on the speci®city and sensitivity of this test, its value has not yet been established with sucient accuracy. Conventional manometric evaluation of lower oesophageal sphincter pressure has been over-emphasized as a diagnostic test in gastro-oesophageal re¯ux disease. Key words: gastro-oesophageal re¯ux disease; oesophagitis; 24-hour oesophageal pH monitoring; endoscopy; ¯uoroscopy; acid perfusion test; proton pump inhibitor; manometry.

INTRODUCTION Gastro-oesophageal re¯ux disease (GORD) can manifest itself in many ways, including pathological oesophageal acid exposure, re¯ux symptoms, oesophagitis and the complications thereof, such as peptic stricture and Barrett's metaplasia. All manifestations of the disease are found more commonly in patients with hiatal hernia. The relationships between the various aspects of GORD are complex, e.g. some patients with oesophagitis or Barrett's oesophagus do not have re¯ux symptoms and at least half of the patients with re¯ux symptoms do not have oesophagitis. As a consequence, the diagnosis of GORD is complicated and requires di€erent tests in di€erent patients. This chapter aims to summarize the available tests and to provide guidelines regarding their application.

*Author to whom all correspondence should be addressed. 1521±6918/00/050759+16 $35.00/00

c 2000 Harcourt Publishers Ltd. *

760 M. A. van Herwaarden and A. J. P. M. Smout

DIAGNOSTIC TESTS TO ASSESS REFLUX AND REFLUX-RELATED SYMPTOMS Symptoms The key symptoms of GORD are heartburn and regurgitation. Typically, these symptoms occur more often after meals. A subset of patients with GORD reports that the symptoms can be provoked by bending over, straining or lying supine. The available evidence suggests that heartburn and regurgitation, when present as the predominant symptoms, are indeed speci®c for GORD. At the same time they are rather insensitive symptoms for GORD.1,2 This implies that GORD cannot be excluded when these symptoms are absent. GORD may also be associated with atypical symptoms such as hoarseness, chronic nocturnal cough, asthmatic symptoms, dyspepsia, globus sensation, hiccups and angina-like chest pain.1,3 Whereas re¯ux questionnaires have found widespread application in research, the use of questionnaires for the diagnosis of GORD has received relatively little attention.4,5 The diculties associated with using questionnaires are the variable interpretation of symptoms, like heartburn, among patients, the low sensitivity of typical GORD symptoms for GORD and the occurrence of atypical symptoms associated with GORD. However, it has been reported that a self-administered patient questionnaire that describes the symptoms might be clinically useful and may aid history-taking in patients with GORD.1,4,5

24-hour pH recording Prolonged oesophageal pH recording was ®rst described by Spencer in 1969.6 In the 1980s, systems for ambulatory pH recordings became commercially available and, today, ambulatory pH monitoring is used routinely in many centres throughout the world for the diagnosis of GORD. Twenty-four hour oesophageal pH recording has a good reproducibility for the diagnosis of GORD.7±9 The advantages of ambulatory monitoring over prolonged stationary pH monitoring are that the patient can be studied in his or her natural home or work environment pursuing normal daily activities, resulting in a more realistic assessment of acid re¯ux. In addition, ambulatory monitoring can be performed as an out-patient procedure which avoids expensive hospital admission. An example of a 24-hour pH recording is shown in Figure 1. For 24-hour oesophageal pH recording a pH electrode is positioned in the distal oesophagus at 5 cm above the proximal border of the lower oesophageal sphincter (LOS). The electrode is connected to a digital data logger. One of the most important features of the data logger is the presence of one or more buttons, that allow the patient to register the onset of symptoms. Accurate recording of the symptom episodes is essential to assess the relationship between symptoms and acid re¯ux. Universally, the total amount of acid re¯ux is expressed as the percentage of time with oesophageal pH below 4.10 Other standard parameters are the number and duration of re¯ux episodes, the number of re¯ux episodes lasting longer than 5 min and the duration of the longest re¯ux episode. Parameters that quantify the duration of re¯ux episodes re¯ect the clearing capacity of the oesophagus. Several groups have determined normal ranges for oesophageal acid exposure time (estimated by calculation of the 95th percentile or mean +2 SD), a selection of which is shown in Table 1.10±17 These normal values show a large variation which is not only caused by

Diagnosis of re¯ux disease 761 7 pH

4

Supine Meals Symptom

Figure 1. Example of a 24-hour oesophageal pH pro®le recorded from a patient with typical re¯ux symptoms but without abnormalities on endoscopy. Re¯ux during the day is excessive (time with pH 5 4: 8.3%), at night-time no re¯ux occurred. The patient indicated eight symptom episodes. Table 1. Reported limits of normal values for 24-hour oesophageal pH recording. % time oesophageal pH 5 4 References

Total 10

Johnson and DeMeester (1974) Fink and McCallum (1984)11 Vitale et al (1985)12 Schlesinger et al (1985)13 Johnsson et al (1987)14 Schindlbeck et al (1987)15 Smout et al (1989)16 545 y 445 y Richter et al (1992)17

4.2 1.9 8.6 3.4

5 12 5.8

Upright 6.3 2.8 5.9 8.8 4.6 10.5 7 16 8.2

Night 1.2 6.4 10.1 3.2 6 3 6 3.5

large inter-individual variability and relatively small group sizes but also by the use of di€erent algorithms and methods for calculation of the normal upper limit. In general, patients with oesophagitis were found to have a higher oesophageal acid exposure time than either healthy subjects or GORD patients without oesophageal lesions.2,11,15,18,19 However, the large inter-subject variation and the overlap in oesophageal acid exposure time between patients with GORD and healthy volunteers observed in several studies makes it clear that the diagnostic value of measurement of oesophageal acid exposure is limited.8,15,18 Twenty-four hour oesophageal pH monitoring also provides the possibility of investigating the temporal relationship between the patient's symptoms and acid re¯ux. This is particularly important, since a subset of those patients with normal 24-hour oesophageal acid exposure has symptoms related to acid re¯ux, whereas patients with a pathological 24-hour oesophageal acid exposure may have symptoms that are not related to acid re¯ux.20 To investigate the symptom±re¯ux correlation it is essential that subjects are able to indicate the occurrence of symptoms using an

762 M. A. van Herwaarden and A. J. P. M. Smout

7 pH

4

Symptoms 2 min

2 min

Figure 2. Detail of the 24-hour oesophageal pH plot shown in Figure 1. Note that the two symptom episodes that occurred in this period are preceded by re¯ux episodes.

event marker on the data logger. To optimize the retrieval of this information patients should also keep a written diary of their symptoms. Analysis of the acid±re¯ux association requires that the entire 24-hour recording be analysed for symptoms that are preceded by a fall in pH (Figure 2). This can be a `classical' re¯ux episode, de®ned as a fall in pH to below 4, but also a pH fall 41 unit not reaching the pH 4 level. Recently, Lam et al21 showed that the optimal time window for this type of analysis starts at 2 min before the onset of pain and ends at the onset of pain. Currently, three di€erent indices are used to investigate the relationship between symptoms and acid re¯ux: the symptom index, the symptom sensitivity index and the symptom association probability.20,22,23 The symptom index (SI), introduced in 1988 by Wiener et al20 is de®ned as the number of acid re¯ux-related symptom episodes divided by the total number of symptom episodes multiplied by 100%. Proposed thresholds for the SI vary from 25±75%.20,24 However, based on receiver operating characteristics (ROC) analysis, it was concluded that 50% is the optimal threshold for the SI.25 A drawback of the SI is that the total number of re¯ux episodes is not taken into account in the calculation. Therefore, in patients with a high number of re¯ux episodes a high SI might be caused by random association between re¯ux and symptoms. Furthermore, due to the absence of the number of re¯ux episodes in the formula for the calculation of the SI, the symptom index is a suitable tool for assessing the speci®city of a patient's re¯ux symptoms, but it does not quantify the patient's sensitivity for acid re¯ux. In an attempt to overcome these drawbacks of the SI, Breumelhof and Smout22 developed the symptom sensitivity index (SSI) as an additional parameter. The SSI is de®ned as the percentage of symptom-related re¯ux episodes. The SSI is classi®ed as high when it exceeds 10%. However, the drawbacks of this index are that it fails to take the number of symptoms into account and that the boundary between normal and abnormal outcome values is arbitrary. Unlike the SI and the SSI the symptom-associated probability (SAP) takes both the total number of symptoms and the total number of re¯ux episodes into account.23 For calculation of the SAP the 24-hour recording is divided into 2-min periods. All of these 2-min periods are evaluated for the occurrence of gastro-oesophageal re¯ux (GOR). In

Diagnosis of re¯ux disease 763

addition, all 2-min periods preceding the onset of symptom episodes are analysed for the presence or absence of re¯ux. Finally, a 2  2 contingency table is constructed and the Fisher's Exact Test is used to test the hypothesis that re¯ux and symptoms are not associated. If the resulting P value is low (50.05) an association exists. The SAP is calculated as (1 ÿ P)100% and a value of more than 95% indicates that the observed association between re¯ux and symptoms is not caused by chance. Although oesophageal pH recording is the best method for determining the oesophageal acid exposure time and for assessing whether the symptoms are related to acid re¯ux, its value is usually judged to be limited in patients with typical GORD symptoms who respond well to proton pump inhibitors (PPIs) and in GORD patients with oesophagitis during endoscopy.26 Usually, these patients can be managed without 24-hour pH monitoring. The remaining clinical indications for oesophageal pH recording are listed below. Recently, most of these have also been included in guidelines on the use of oesophageal pH recording by the American Gastroenterology Association.27 Based on the clinical indication the pH recording should be performed with acidreducing therapy continued or discontinued. . To assess pathological acid re¯ux and symptom±re¯ux association in patients with normal ®ndings on endoscopy. . To document the response to treatment in subjects with ongoing symptoms during acid-reducing therapy (recording should be performed whilst the patient is on therapy). . To detect symptoms associated with acid re¯ux in endoscopy-negative patients with angina-like chest pain, after adequate cardiac evaluation. (In these cases it is preferable to combine the ambulant oesophageal pH monitoring with ambulant oesophageal manometry.) . To assess pathological acid re¯ux and symptom association with acid re¯ux in endoscopy-negative or endoscopy-positive patients considered for anti-re¯ux surgery. . To document pathological acid re¯ux and symptoms associated with acid re¯ux in subjects with ongoing symptoms after anti-re¯ux surgery. Ambulatory oesophageal bile monitoring Continuous monitoring of bile re¯ux has become possible through the development of a device that spectrophotometrically measures the bilirubin concentration in the distal oesophagus.28 A disadvantage of the system is that to function properly, it requires the patient to use a standardized liquid diet during the study. Otherwise, false positive results may be obtained due to the ingestion of foods with absorption close to that of bilirubin and due to clogging of the measuring sensor by solid food particles. Acid and duodenal contents usually re¯ux into the oesophagus simultaneously. It has been shown that the presence of duodenal contents in the oesophagus contributes to the development of oesophagitis29, but duodenogastric-oesophageal re¯ux alone is usually not injurious to the oesophageal mucosa.29,30 However, duodenogastricoesophageal re¯ux without simultaneous acid re¯ux may cause symptoms.30 As a consequence of the above-mentioned observations, oesophageal bile monitoring deserves a modest place at best in the diagnostic armamentarium for GORD. In patients with normal gastric acid secretion, ambulatory pH monitoring will provide all the information required for the management of the patient. Even in partial gastrectomy patients, pH falls appear to be as reasonable a marker of re¯ux as rises in

764 M. A. van Herwaarden and A. J. P. M. Smout

bilirubin concentration.30 Only when gastric acid secretion is strongly diminished (e.g. after subtotal gastrectomy or during drug-induced acid inhibition) may bilirubin concentration monitoring be indicated. For instance, in a patient in whom re¯ux symptoms persist while gastric acid secretion is maximally inhibited, bile monitoring may show a relationship between symptom and bile re¯ux. Acid perfusion test The oesophageal acid perfusion test (AP test) was ®rst described by Bernstein and Baker in 1958.31 The test was not designed to identify GORD but to determine whether chest pain or heartburn was secondary to increased oesophageal sensitivity to acid. The original test involves a 30-min period of oesophageal perfusion with 0.1 N HCl at a rate of 6±7.5 ml/min directly after oesophageal perfusion with saline with the patient in sitting position. The test is considered positive when no symptoms are induced by saline and when delivery of the 0.1 N HCl elicits pain, heartburn and/or associated symptoms.31 Since the test is simple, safe and inexpensive, the original acid perfusion protocol and several variants thereof have been used widely as a screening test in patients with a radiographically or endoscopically normal oesophagus. However, several studies have shown that the test is positive in 5±15% of asymptomatic healthy volunteers.31±35 In the 1980s and 1990s it became possible to assess the sensitivity and speci®city of the test using a positive symptom index or an abnormal oesophageal acid exposure as the gold standard.20,32,36±38 Wiener et al20 showed a poor association between the symptom index and the AP test in patients with GORD. In patients with non-cardiac chest pain (NCCP), the sensitivity ranged from 32±59% and the speci®city from 59±94%.32,38 In addition, Hewson et al37 compared the outcome of the AP test with data from 24-hour combined oesophageal pH and manometric recordings in 45 NCCP patients. They observed that 46% of the patients with a positive AP test had symptoms related to spontaneous acid re¯ux. In addition, patients with a positive AP test were as likely to have a motility event as a pH event causing their symptoms. Another important ®nding in these studies was that several patients with a positive AP test were also found to be hypersensitive in other oesophageal provocation tests like the edrophonium test. These observations indicate that these patients su€er from an `irritable oesophagus'.36,37,39,40 Thus, it is felt that a positive AP test may implicate the oesophagus as the likely source of pain, but that it does not de®ne the pain mechanisms involved and does not provide reliable clues as to the optimal therapeutic approach. In some patients with coronary artery disease, pain recognition upon oesophageal acid infusion is associated with ischaemic electrocardiographical changes.41 This observation underlines the necessity of excluding coronary artery disease before commencing oesophageal testing in patients with chest pain. Several disadvantages of the AP test have been described: . The recognition of chest pain and heartburn during acid re¯ux is a subjective response with wide perceptional variability. . False positive results have been described in patients with duodenal ulcer and gastritis and in healthy subjects. . The AP test does not consider the e€ects of endogenous substances such as bile, pepsin, or pancreatic enzymes, in the production of re¯ux symptoms. . The AP test does not take into account the physiological situation in which the oesophagus might be distended by variable volumes of re¯uxed gastric contents, since the perfusion rate is constant.

Diagnosis of re¯ux disease 765

. The test cannot reproduce the wide variety of exogenous substances and daily activities that promote GOR and alter mucosal sensitivity to acid.32,38 In the light of these disadvantages, most clinicians nowadays favour 24-hour oesophageal pH recording over the AP test for the diagnosis of GORD in patients with atypical symptoms.

Fluoroscopic examination Barium studies can be employed to identify GOR. This is done by ¯uoroscopic observations of spontaneous or provoked GOR of radio-opaque material.42,43 The most commonly used provocation tests are coughing, the Valsalva manoeuvre, the water siphon test (drinking water in the supine and right posterior oblique positions), abdominal compression or rolling from the supine to the right lateral recumbent position.43±45 However, the sensitivity of these studies is quite low, since spontaneous and provoked gastro-oesophageal re¯ux is observed in only 35% of symptomatic GORD patients.42,43 Furthermore, the speci®city of radiographical studies also appears to be low, since spontaneous GOR may be demonstrated during barium studies in up to 40% of asymptomatic healthy subjects.46 Provocation manoeuvres increase the sensitivity but decrease the speci®city of these radiological techniques.42,45 These observations have led to the notion that ¯uoroscopy is an unreliable technique for assessing the presence or absence of re¯ux.47 Scintigraphic detection of re¯ux As with ¯uoroscopic techniques, GOR can also be detected by radionuclide studies. After ingestion of radioactively labelled acidi®ed water re¯ux of gastric contents is monitored scintigraphically with the patient in the supine position. Various provocation manoeuvres can be carried out. Although the technique is simple, non-invasive and involves minimal radiation exposure, its value has been debated because of its low sensitivity.48 The proton pump inhibitor test Recently, several studies have been published concerning the value of a short trial period of acid suppression for the diagnosis of GORD.49±56 Since most of these studies were performed with omeprazole, this diagnostic test has been named `the omeprazole test'. However, since there is no indication that the results of these studies would not be applicable to other PPIs, the term `PPI test' seems more appropriate. The PPI test consists of monitoring the symptomatic response to a PPI, given in a large dose for a brief period. The dose of omeprazole used in the various studies varied from 40 mg o.d.49,57, 20 mg b.i.d.50, 40 mg b.i.d.57 and 40 mg a.m. ‡ 20 mg p.m.51,52, all for a period of 1±2 weeks, to a single dose of 80 mg.54,55 The test is considered positive when a 50±75% improvement of symptoms is observed. However, the greatest accuracy of predicting GORD was reached when a cut-o€ point of 65% or higher was used.51 The advantages of the PPI test are that the test is relatively cheap, simple, safe and non-invasive. The PPI test performed in patients with non-cardiac chest pain, symptoms suggestive of GORD and dyspeptic symptoms has a sensitivity of 70±90% and a speci®city of 55±85%, depending on the doses used and the selection of patients.49±55 The importance of using a high dose of omeprazole was shown by Schindlbeck and Klauser57 who found a sensitivity of 27.2% when 40 mg of omeprazole was used, whereas the

766 M. A. van Herwaarden and A. J. P. M. Smout

sensitivity was increased to 83.3% using 80 mg omeprazole. However, approximately 20% of patients with GORD showed a 50% improvement of symptoms when using a placebo.50,51 Therefore, the relatively high sensitivity of the PPI test might be based, in part, on a high placebo e€ect in these patients. A false-negative PPI test may occur in cases in which the pharmacological response is insucient, resulting in insucient reduction of oesophageal acid exposure. In addition, we have observed that some patients who have symptoms related to acid re¯ux, as proven by the symptom index and symptom associated probability, do not respond to acid-reducing treatment although 24-hour oesophageal pH recording during acid reducing therapy shows adequate acid suppression. In these patients non-acid re¯ux presumably is the cause of the persisting symptoms. A false-positive PPI test may lead to inappropriately prolonged use of a PPI, especially in patients in whom endoscopy reveals no abnormalities. In these patients inappropriate use of PPIs for many years may even carry the risk of masking a malignancy. It is important to note that none of the previous studies on the PPI test classi®ed the patients as having acid-related symptoms using the SI 450% or SAP 495%. Rather, the classi®cation as GORD patient in these studies was based on the presence of either an abnormal upper endoscopy or a pathological oesophageal acid exposure as measured by a 24-hour oesophageal pH recording. The cut-o€ points that are used for an abnormal pH recording are arbitrary since an overlap is observed between GORD patients and asymptomatic subjects.8,15,18 In addition, a normal upper endoscopy is observed in up to 50% of patients with symptoms due to acid re¯ux.18,20,24 Therefore, subjects may have been classi®ed wrongly into the GORD-positive or -negative groups. Results of studies on the sensitivity and speci®city of the PPI test using the SI and/or the SAP scale as gold standard are eagerly awaited. Several economic analyses have shown that the PPI test will reduce the total number of diagnostic procedures by approximately 60%, resulting in a signi®cant reduction in costs for the diagnosis of GORD.51,52 However, the observed reduction in costs might be lower than expected, since in these studies it was assumed that all subjects with a false-positive PPI test would use PPIs for 1 month only.51±53 In addition, there is a risk that some of the patients with a positive test will not step down the medication towards a less expensive medical therapy for GORD and subsequently will use PPIs for the rest of their lives. Third, since the PPI test is so simple to perform, it is conceivable that more subjects are willing to undergo this diagnostic test for their (mild) symptoms. Finally, it is unknown how many patients with an initial positive PPI test will undergo an upper endoscopy or a 24-hour oesophageal pH recording at a later stage. Thus, the available information suggests that it is reasonable to perform the PPI test in subjects with symptoms suggestive of GORD. However, validation studies in which the SI and SAP are used as a reference are necessary before ®rm conclusions concerning the true sensitivity and speci®city of the test can be drawn. In addition, longterm follow-up studies in patients with negative and positive PPI tests are needed in which the use of PPIs and the number of invasive techniques are monitored. Only then can the real cost reduction related to the use of the PPI test be estimated. DIAGNOSTIC TECHNIQUES TO VISUALIZE ORGANIC ABNORMALITIES ASSOCIATED WITH GORD GORD is associated with a broad spectrum of organic abnormalities such as hiatal hernia, mucosal breaks (erosions), ulceration, peptic stricture and columnar

Diagnosis of re¯ux disease 767

metaplasia. The two techniques with which these abnormalities can be assessed are endoscopy and radiography. To date it is widely recognized that upper endoscopy is the best procedure for diagnosing oesophagitis and its complications such as a peptic stricture or Barrett's oesophagus and to rule out the possibility of other abnormalities (e.g. tumour).58 In addition, endoscopy provides valuable information to both clinicians and researchers wishing to evaluate the ecacy of treatment.59 Upper endoscopy Recently, guidelines for the practice of endoscopy were developed by the American Society for Gastrointestinal Endoscopy.60 This society stated that an upper endoscopy is the diagnostic procedure of choice in patients with heartburn if there are clinical clues that suggest that re¯ux may be severe or that other diseases may be present. Such clues include: (i) symptoms of dysphagia or odynophagia; (ii) symptoms that are persistent or progressive on therapy; (iii) extra-oesophageal symptoms or GORD; (iv) oesophageal symptoms in an immune-compromized patient; (v) the presence of a mass, stricture or ulcer on a previous oesophagogram; (vi) evidence of gastrointestinal bleeding or iron de®ciency anaemia.60 Endoscopy is not a suitable tool for assessing pathological re¯ux or for determining whether the symptoms are associated with acid, since approximately 30±60% of patients with symptoms suggestive of GORD and a normal endoscopy had acidrelated symptoms or a pathological acid exposure on 24-hour oesophageal pH monitoring.18,20,24 The desire to improve the endoscopic diagnosis of oesophagitis has resulted in the development of more than 30 classi®cation systems.58,61 However, none of these systems is universally used. A disadvantage of many classi®cation systems is the frequent use of ambiguous terminology resulting in various interpretations. Some classi®cation systems use the gradation of `minimal lesions', such as erythema and mucosal friability, which have been shown to have a low inter-observer agreement and to be unreliable for the diagnosis of re¯ux oesophagitis.61,62 A widely used oesophagitis scoring system is the Savary±Miller new endoscopic grading system, shown in Table 2.63 A major drawback is the lack of validation studies concerning these classi®cation systems.61,64 It is obvious that a single, uniformly used, clinically relevant and clear-cut classi®cation system would be of major importance for an accurate communication about the clinical status of individual patients and the interpretation of data from clinical trials.61

Table 2. Savary±Miller new endoscopic grading system. Grade I:

Single, erosive, or exudative lesion; oval or linear; involving only one longitudinal fold.

Grade II:

Non-circular, multiple erosion or exudative lesion involving more than one longitudinal fold, with or without con¯uence.

Grade III:

Circular erosive or exudative lesion.

Grade IV:

Chronic lesions: ulcers, strictures, or short oesophagus, isolated or associated with lesion grade I±III.

Grade V:

Barrett's epithelium, isolated or associated with lesion grade I±IV.

768 M. A. van Herwaarden and A. J. P. M. Smout Table 3. The Los Angeles classi®cation of oesophagitis. Grade A:

One (or more) mucosal break no longer than 5 mm, that does not extend between two tops of two mucosal folds.

Grade B:

One (or more) mucosal break more than 5 mm long, that does not extend between two tops of two mucosal folds.

Grade C:

One (or more) mucosal break that is continuous between the tops of two or more mucosal folds but which involves less than 75% of the circumference.

Grade D:

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

Recently, an international working group on endoscopic classi®cations was established with the ®nal goal of de®ning and evaluating a universal, reproducible endoscopic classi®cation of oesophagitis.61,64 This group introduced the Los Angeles grading system (Table 3). In this classi®cation system both the horizontal and longitudinal extent of the mucosal lesions are taken into account. In the Los Angeles classi®cation the term `endoscopic mucosal breaks' is used in order to avoid confusion related to the terms `ulceration' and `erosion'. An endoscopic mucosal break is de®ned as `an area of slough or erythema with a discrete line of demarcation from the adjacent, more normal looking mucosa'. Complications of the disease such as strictures and Barrett's oesophagus do not a€ect the grading in the Los Angeles classi®cation and these have to be documented as supplementary changes. Application of the de®nitive Los Angeles classi®cation system was found to be associated with an acceptable inter-observer variation. In addition, the severity of the oesophagitis scored by this scale was signi®cantly related to both the oesophageal acid exposure, as measured by 24-hour oesophageal pH monitoring, and the severity of heartburn.64 Radiographical examination Like upper endoscopy, radiological examination may give information about the presence of organic abnormalities caused by, or associated with, GORD.44 Three techniques are used to investigate the oesophagus with barium.43,44,65,66 Single-contrast technique (full-column technique) is performed by rapid ®lling of the oesophagus with barium. It is useful for observing circumferential carcinomas, strictures, ulcers and hiatal hernias. The double-contrast technique is the most sensitive radiological technique for investigating the oesophageal mucosa. During this investigation, the oesophagus is ®rst coated with high-dense barium and then distended by gas. Double-contrast studies are particularly useful for demonstrating erosions, small ulcers and polypoid lesions. However, this technique is not sensitive enough to detect small hiatal hernias and peptic strictures.43,44,65 Finally, the mucosal relief technique is used to visualize thickening of mucosal folds and various forms of oesophagitis. During this procedure the oesophagus is studied in a collapsed state and coated with a dense barium suspension. Combination of two or three of these radiographical techniques has been shown to improve the detection of peptic oesophagitis.44,66±68 The sensitivity of radiographical techniques increases with the severity of the oesophagitis, reaching a sensitivity of approximately 95±100% in patients with severe ulceration or strictures.66,67,69 However, the overall sensitivity in all grades of oesophagitis detected by endoscopic examination averages about 60±80% and the speci®city about 90%.42,66,67,69 Thus, it is

Diagnosis of re¯ux disease 769

obvious that although barium studies are readily available, relatively inexpensive and well tolerated, only a part of the abnormalities observed by endoscopy are detected. In addition, radiological studies were abnormal in only 30% of GORD patients with pathological re¯ux measured by 24-hour pH recording.70 Therefore, the value of these barium studies in the detection of GORD appears to be limited. However, radiography is still being used in the work-up of patients with GORD, e.g. in patients reluctant to undergo endoscopy, when endoscopy is not available and for the di€erentiation of para-oesophageal from sliding hiatus hernia. DIAGNOSTIC TESTS TO INVESTIGATE OESOPHAGEAL AND LOS FUNCTION IN GORD In the work-up of patients with GORD the need for assessment of oesophageal and LOS motor function may arise. As will be discussed below, however, the contribution of the outcome of such assessment to the management strategy is usually limited. The main indications for performing tests of the motor functions of the LOS and the oesophageal body in GORD patients are non-obstructive dysphagia and exclusion of severe oesophageal motor impairment preoperatively. Dysphagia is present in a substantial number of GORD patients.71 It is well known that GORD is associated with oesophageal motor dysfunction resulting in a prolonged clearance.72,73 Oesophageal acid exposure time is determined by both the duration and incidence of re¯ux episodes, the latter depending on the competence of the gastro-oesophageal barrier. The LOS plays a major role in this, since low basal LOS pressure and spontaneous transient LOS relaxations (TLOSRs) are the most important mechanisms underlying GOR in GORD patients.74 Several techniques can be used to examine oesophageal motility and clearance and the competence of the gastro-oesophageal barrier. Fluoroscopic examination Fluoroscopic observation of the oesophagus during barium swallows or passage of barium-coated bread is a useful technique for demonstrating malfunction of oesophageal emptying in patients with non-obstructive dysphagia.48 In cases like these, manometry, carried out either as a separate procedure or simultaneously with ¯uoroscopy, may provide additional information on the motor functions of the oesophageal body and LOS.75 Radionuclide scintigraphy of the oesophagus Radionuclide techniques can be used to study oesophageal transit in GORD patients. There is a reasonable agreement between stationary manometry and scintigraphy concerning the detection of oesophageal motor disorders.76,77 Advantages of scintigraphy are that the radioisotopes can be incorporated into various normal food items and that quantitative information can be obtained. Stationary oesophageal manometry Stationary oesophageal manometry is performed either by water-perfused assemblies connected to external pressure transducers or by solid state catheters in which the micro-transducers are built into the catheter itself. For prolonged measurement of

770 M. A. van Herwaarden and A. J. P. M. Smout

LOS pressure specialized sensors have been developed.78,79 The perfused sleeve sensor developed by Dent is now considered to be the best device for prolonged sphincter recording. Whereas the perfused sleeve measures the highest pressure, the other sphinctometer devices record the mean pressure of all pressures exerted on the membrane. The best way to assess basal LOS pressure with non-specialized manometric catheters is by using the station pull-through technique.75 Oesophageal peristalsis and LOS relaxation are usually investigated as response to 5 ml water swallows. Standard analysis includes quanti®cation of the proportion of peristaltic, simultaneous and non-transmitted contractions, the mean amplitudes of oesophageal contractions, basal LOS pressure and the presence of incomplete LOS relaxations. Peristaltic oesophageal dysfunction de®ned as hypotensive oesophageal peristalsis or failed peristalsis occurs in 25% of patients with mild oesophagitis and in almost half of the patients with severe oesophagitis. In addition, a hypotensive LOS is more common in GORD patients than in healthy subjects and the incidence increases with the severity of oesophagitis.73 However, detection of these manometric abnormalities does not predict GORD. The most important reasons for performing oesophageal manometry in patients suspected for GORD are, ®rst, to localize accurately the borders of the LOS, which is important for correct positioning of the pH electrode used for 24hour oesophageal manometry and, second, to detect oesophageal or LOS motility disorders in patients with dysphagia. Moreover, oesophageal manometry can detect systemic diseases that are associated with GORD, such as progressive systemic sclerosis. Another indication of oesophageal manometry in GORD patients is the preoperative assessment of oesophageal functioning. Ambulatory oesophageal manometry Although prolonged monitoring of pressures in the oesophageal body provides more information on oesophageal motility than conventional, short-term manometry, it has not been shown that prolonged manometry o€ers advantages in the diagnostic workup of patients with GORD. An exception should be made, however, for patients who present with angina-like chest pain. In these patients not only GOR but also spastic oesophageal motor disorders may be the cause of the symptoms.80,81 Although the additional yield of prolonged oesophageal pressure monitoring is relatively low, it is recommended that pH monitoring be combined with pressure monitoring in the initial approach.82,83 Measurement of gastric emptying Some studies have shown that gastric emptying is delayed in patients with GORD.84,85 However, most GORD patients have a normal gastric emptying rate, and, therefore, measurement of gastric emptying cannot be recommended for the diagnosis of GORD. SUMMARY Over the years, many tests for the diagnosis of GORD have been proposed and evaluated. It should be realized that the various tests assess di€erent aspects of the spectrum of GORD. The available evidence indicates that for the detection of mucosal lesions endoscopy is superior to radiography. For assessment of the re¯ux-related

Diagnosis of re¯ux disease 771

Reflux symptoms Upper Gl endoscopy Oesophagitis

Treatment

Intestinal metaplasia

No abnormalities

24-hour pH symptom score

Treatment + follow-up

PPI test

Score+

Score−

Positive

Negative

Treatment

?

Treatment

?

Figure 3. Algorithm for the diagnosis of GORD.

nature of symptoms ambulatory 24-hour pH monitoring is the best technique, with the PPI test as the `poor man's' alternative for it. The latter two tests are indicated mainly in patients in whom endoscopy reveals no abnormalities. Figure 3 shows an algorithm for the diagnosis of GORD that is thought to suce in the vast majority of patients with re¯ux symptoms. Additional tests, such as oesophageal manometry, radiography and oesophageal bilirubin absorbance measurement, can be indicated in small subsets of patients. REFERENCES * 1. Klauser AG, Schindlbeck NE & Muller-Lissner SA. Symptoms in gastro-oesophageal re¯ux disease. Lancet 1990; 335: 205±208. 2. Johnsson F, Joelsson B, Gudmundsson K et al. Symptoms and endoscopic ®ndings in the diagnosis of gastroesophageal re¯ux disease. Scandinavian Journal of Gastroenterology 1987; 22: 714±718. 3. Klinkenberg-Knol E & Castell DO. Clinical spectrum and diagnosis of gastroesophageal re¯ux disease. In Castell DO & Richter JE (eds) The esophagus, 3rd edn. pp 375±380. Philadelphia: Lippincott Williams & Wilkins, 1999. 4. Carlsson R, Dent J, Bolling-Sternevald E et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal re¯ux disease. Scandinavian Journal of Gastroenterology 1998; 33: 1023±1029. 5. Locke RG, Talley NJ, Weaver AL et al. A new questionnaire for gastroesophageal re¯ux disease. Mayo Clinic Proceedings 1994; 69: 539±547. 6. Spencer J. Prolonged pH recording in the study of gastro-oesophageal re¯ux. British Journal of Surgery 1969; 56: 912±914. 7. Emde C, Armstrong D, Castiglione F et al. Reproducibility of long-term ambulatory esophageal combined pH/manometry. Gastroenterology 1991; 100: 1630±1637. 8. Wiener GJ, Morgan TM, Copper JB et al. Ambulatory 24-hour esophageal pH monitoring, Reproducibility and variability of pH parameters. Digestive Diseases and Sciences 1988; 33: 1127±1133. 9. Johnsson F & Joelsson B. Reproducibility of ambulatory oesophageal pH monitoring. Gut 1988; 29: 886±889. *10. Johnson LF & DeMeester TR. Twenty-four-hour pH monitoring of the distal esophagus: a quantitative measure of gastroesophageal re¯ux. American Journal of Gastroenterology 1974; 62: 325±332. 11. Fink SM & McCallum RW. The role of prolonged esophageal pH monitoring in the diagnosis of gastroesophageal re¯ux. Journal of the American Medical Association 1984; 252: 1160±1164.

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