Gastroesophageal reflux/laryngopharyngeal reflux disease: a critical ...

Eur Arch Otorhinolaryngol (2010) 267:171–179 DOI 10.1007/s00405-009-1176-4

REVIEW ARTICLE

Gastroesophageal reflux/laryngopharyngeal reflux disease: a critical analysis of the literature M. N. Kotby • O. Hassan • Aly M. N. El-Makhzangy M. Farahat • M. Shadi • P. Milad

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Received: 31 October 2009 / Accepted: 27 November 2009 / Published online: 24 December 2009 Springer-Verlag 2009

Abstract Despite the wealth of publications on the topic of gastroesophageal reflux and its variants, there are still many unsettled questions before one accepts the prevalent cult of ‘‘reflux disease’’. This study is summarizing the results of the critical analysis of the literature, 436 articles, during the last 30 years. The golden test to identify the patient group suffering from this rather common phenomenon is still lacking. The claimed extra-esophageal manifestations especially in the larynx are non-specific and may be caused by other factors well-known within the domain of vocology. The response to therapeutic intervention still lacks serious well-controlled studies to allow drawing reasonable conclusions. An outstanding feature of the publications is that most of them fall in the category of ‘‘review’’. It seems that there is a tendency to perpetuate the concept without objective criticism. Following the analysis, a recommendation for a new plan of original well-controlled multi-center studies is highlighted. Keywords Gastroesophageal reflux Extra-esophageal reflux Laryngopharyngeal reflux

M. N. Kotby M. Farahat M. Shadi Phoniatric Unit of the Otorhinolaryngology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt e-mail: [email protected] O. Hassan A. M. N. El-Makhzangy (&) P. Milad Department of Otorhinolaryngology, Faculty of Medicine, Ain Shams University, Cairo, Egypt e-mail: [email protected]

Introduction The cause–effect relation between gastroesophageal reflux disease (GERD) and its extra-esophageal manifestations is not explicitly proven. It should be highlighted that the phenomenon of gastroesophageal reflux is a common finding as an asymptomatic condition. This is found in 65–75% of normal individuals [23, 40, 52]. The problem is further complicated by the fact that there is no ‘‘gold standard’’ test for the diagnosis of symptom-causing reflux. In addition, the symptoms and signs of the claimed extra-esophageal (laryngeal) manifestations are non-specific and vaguely described and sparsely documented. These controversies prompted us to make an endeavor to critically and systematically analyze the published literature on the topic of laryngopharyngeal (LPRD)/GERD during the last 30 years.

Literature search strategy An electronic medical literature search was performed on March 9, 2008, utilizing one of the most widespread medical databases, the Medline, provided by the National Library of Medicine through the webpage http://www.ncbi.nlm.nih. gov/pubmed/. The following keywords were used: ‘‘gastroesophageal reflux disease’’ and ‘‘larynx’’, which yielded 436 abstracts, ‘‘laryngopharyngeal reflux’’, which yielded 193 abstracts, and ‘‘extra-esophageal reflux’’, which yielded 145 abstracts. Several publications were retrieved by one or more keywords, thus the total of 774 culminated into 436 articles. No limits were set to the language or the year of publication. Further analysis, however, showed that the yielded abstracts were from publications spanning 30 years duration from 1977 to 2008 (Fig. 1). Most of the articles identified are published in English, 383 out of 436.

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Eur Arch Otorhinolaryngol (2010) 267:171–179

Fig. 1 Bar chart illustrates the relative distribution of the publications over the last 30 years

Literature analysis

distribution, by the Centers for Disease Control and Prevention (CDC), in Atlanta, Georgia.

The articles were analyzed by the reviewers concerning: • • •

•

• •

the scope of the study (etiology, diagnosis, therapy or review); whether the aim was only to describe (descriptive) or to compare at least two groups (comparative); whether the setting of the study was an experiment, including studies in which a procedure was performed, or a survey. In contrast to surveys, experimental studies are characterized by an intervention in which the investigators intentionally apply and measure its effect(s) on the studied groups; whether the study evaluates the effect of a therapeutic or causative agent (cause–effect or impact research), or is it concerned with the quality of a certain process (process research); the temporal orientation of the investigation (crosssectional, retrospective, and prospective); and whether the groups under investigation are comparable or not (homodemic/heterodemic).

The structured approach to analysis of the literature was modified from that detailed by Feinstein [17]. The reviewers added their comments on the adequacy of sample size, appropriateness of statistical analysis, and feasibility of the authors’ conclusion. Naturally, the year and language of publication were recorded. The nature of the review articles did not allow an analysis according to the approach suggested by Feinstein [17]. The data from each abstract were fed in a spreadsheet program for further analysis using Epi Info. Epi Info is a series of programs for general database and statistics applications, made available in the public domain and freely available for use, copying, translation and

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Results Scope of the studies Etiology of GERD/LPRD has been reported in 35 articles. We labeled the scope of studies describing the role of GERD in causing other diseases as ‘‘pathogenesis’’. Such studies summed up to 18. Articles reporting on diagnostic methods for GERD were 149. Seventy-three articles focused on different pharmacologic and surgical treatments of GERD/LPRD. A total of 152 review articles, editorials, consensuses and comments were identified (Fig. 2).

160

Scope

140 120 100 80 60 40 20 0

Review

Etiology

Pathogenesis Diagnosis

Treatment

Fig. 2 Bar chart illustrates the various categories of the studied publications. The majority are falling into the categories of review and diagnosis


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Descriptive versus comparative aims

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Studies in which the authors only describe their findings whether after applying a diagnostic or a therapeutic maneuver are labeled ‘‘descriptive’’. If the authors have compared their findings prior to and after therapeutic measures, whether in the same group of patients or in 2 or more different groups, the aim is labeled ‘‘comparative’’. Similarly, if the authors have compared the findings of two different diagnostic modalities, the label is still ‘‘comparative’’. Descriptive studies were 168, while comparative studies were 150.

100

Experimental, procedural or survey studies

80 60 40 20 0 Retrospective

Forty-one experimental studies were identified including two randomized trials. Special apparatuses were used, mostly pH double probes, in 139 studies. These were labeled by the reviewers/authors as ‘‘procedural’’. Survey studies were 112 (Fig. 3).

Cross-sectional

Prospective

Fig. 4 Illustrates the relative occurrence of the study models on the time domain

Studied groups comparability Cause–effect versus process research If the investigators are interested in the impact of a certain etiologic or therapeutic agent on their study group(s), then they are seeking the outcome of such agent. In 163 articles, the investigators were interested in an ‘‘outcome’’ (cause– effect/impact research). When the investigators are testing the qualities of a measuring process, then they are interested in an ‘‘output’’ by conducting process research. One hundred and forty-four articles reported on qualities of different diagnostic tests. Temporal orientation There were 105 cross-sectional studies. Retrospective studies were 41, while prospective studies were 63 (Fig. 4).

Studies in which the investigated groups are comparable, e.g., in which a subject acts as self-control, are labeled ‘‘homodemic’’, for human subjects, or homozoic, for experimental animals. If the groups are different, they are labeled ‘‘hetero’’-demic, or -zoic. Homodemic groups were reported on in 232 articles, heterodemic groups in 43 articles, homozoic groups in 9 and heterozoic in 1 article. Sample size adequacy Sample size was not mentioned in the abstracts of 27 articles. It was inadequate in 113 articles and adequate in 148 articles. Appropriateness of statistical analysis

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In 18 articles, the statistical test was inappropriate, while it was appropriate in 122. Most of the rest were review articles with no statistical specifications.

120 100 80

Discussion 60

Features of the reviewed literature

40 20 0 Experimental

Procedural

Survey

Fig. 3 There are a high number of survey studies. The high number of procedure studies lies in the domain of diagnostics of reflux

The interest in the topic, as judged from the number of publications per year, started to mount in the late 1990s. The interest was steadily rising in the beginning of the millennium, peaking up from 2006 to 2008 (Fig. 1). It seems from the number of articles that the questions of diagnosis and management of GERD and LPRD are the

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front runners regarding the focus of studies. This reflects a state of uncertainty of the answer to these questions. Analysis of the literature from 1977 to 2008 yielded 436 articles. Publications came from three main areas: chest, gastroenterology, and oto-laryngology. The majority of the publications are review studies (Fig. 2). This points to the lack of originality and the production of new data. It is a tendency of non-critical copying of earlier studies. The next most common scope of studies involves diagnostic procedures (procedural). However, the claimed ‘‘gold standard’’ is still lacking. The reviewers considered that studies reporting on less than 30 subjects in total, or in each group, were of an inadequate size since at least 30 subjects in each group is required to apply the central limit theorem, on which mathematics of most of the statistical tests depends. The reviewers considered the statistical test inappropriate based on the types of studied variables. If the investigators utilized a statistical test that compares means of variables that cannot have a true arithmetic mean, e.g., then the test is deemed inappropriate. Most of the studies are descriptive vis-a`-vis comparative. This may reflect a tendency to less penetrating investigations of the phenomena at hand. Similarly, only 41 studies were of experimental nature meaning that only few included an intervention process. Most of the reported studies were procedural (Fig. 3). The authors use this term to describe studies utilizing apparatuses and equipment usually used for diagnosis, e.g., double probe pH metry. None of these studies, however, identified an efficient and reliable diagnostic test. Also, no studies tried to modify the procedure of these tests in order to avoid fallacies and to improve results. The next common study design is survey, which is suitable only for estimating the incidence of the disease. Most of the studies reviewed were cross-sectional (Fig. 4). This temporal orientation is usually not suitable to assess the efficacy of treatment. Moreover, the description of ‘‘prospective’’ is sometimes mis-used. The authors consider that studies are appropriately described as prospective if the investigators have an intervention and wait for its effect to be measured, or if the mere passage of time may have an effect in which the investigators are interested in. The conclusion was justifiable in 130 articles. Two hundred and seven articles were inconclusive, while in 40 articles, the findings could not explain the conclusion given by the investigators and thus we considered that the investigators have ‘‘mis-concluded’’ the matter. Many articles with ‘‘inconclusive’’ judgment reflects the situation of uncertainty that still prevails in the field, specially regarding diagnosis, management as well as clinical picture of LPRD.

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The contents of the reviewed literature Definition and pathogenesis Reflux as taken from Latin shall mean: re, back; fluxus, flow. Thus, the English equivalent is ‘‘back flow’’. Two main ‘‘pathological’’ conditions are recognized: a.

gastroesophageal reflux disease (excessive reflux of gastric contents into the esophagus exceeding epithelium defenses and eliciting symptoms (i.e., heartburn) or histopathologic injury (i.e., esophagitis or Barrett metaplasia) [30] and b. extra-esophageal reflux disease, ‘‘laryngopharyngeal/ hypopharyngeal reflux’’! Laryngopharyngeal reflux (LPR) is the back flow of gastric contents (refluxate) to the laryngopharynx where it comes in contact with tissues of the upper aerodigestive tract. This term was adopted by the American Academy of Otolaryngology, Head and Neck Surgery in its 2002 Position Statement on LPR [39]. It is important to draw the attention to a possible source of inconsistency in concept of terminology. • •

Gastroesophageal is a term denoting movement from a location into the other, i.e., to say it is ‘‘directional’’. Laryngopharyngeal indicates a location/site, namely the hypopharynx. The term laryngopharyngeal, in itself, does not indicate any penetration or aspiration of a pharyngeal content into the larynx.

The harmful effect of the ‘‘refluxate’’ in those locations may be caused by its acid content or by the presence of the gastric enzyme pepsin. Acid alone is not very damaging under physiological conditions of tissue protection. However, in high concentrations and in the presence of pepsin, the chance of mucosal damage is increased [60]. Acidified pepsin causes a break in the mucosal barrier function through an alteration in the intercellular junctional complex [21]. The chemical composition of the refluxate should be taken into consideration when planning future research focused on explanation of the mechanism of possible damage caused by the refluxate. Diagnostic considerations In a condition which is a normal phenomenon in about 65–75% of normal persons [23, 40, 52], the use of a reliable and sensitive test to distinguish and isolate cases from non-complaining normals is essential. The presence of such a ‘‘golden’’ test is not yet available [11]. Despite the improvement in the 24-h double probe pH and pressure recording in the esophagus and pharynx, the results of the


measurements are still equivocal [47]. Ambulatory 24-h pH metry often shows a poor association between spontaneous acid reflux and esophageal or extra-esophageal symptoms, particularly in patients ‘on’ proton-pump inhibitor (PPI) treatment [54]. It seems that, after all, the ambulatory 24-h double probe is far from being the ideal test to diagnose LPRD. The reported sensitivity of this test is only 50–80%. Further, 12% of patients cannot tolerate the procedure [25]. Dietary modifications to standardize the test may lead to false negative results. Finally, pH metry is expensive and not widely available [37]. The study of Ylitalo [64] does not confirm increased prevalence for H. pylori infection in contact granuloma patients. This finding may suggest that such a lesion commonly believed to be caused by reflux disease is actually not influenced by direct contact with gastric secretions containing the H. pylori organisms. The study also shows that the occurrence of H. pylori infection was not correlated to the amount of pharyngeal or esophageal acid exposure. Since the pH monitoring is not a sufficiently sensitive and reliable diagnostic test, there is a widespread acceptance of the notion that the diagnosis of a pathological reflux shall rely, instead, on a therapeutic test using ProtonPump Inhibitors (PPI) since the pH monitoring is not sufficiently sensitive and reliable [1, 59]. This tendency is based on the assumption that PPI is the right treatment of the symptomatic LP reflux disease. It has to be highlighted, however, that the reliance on a therapeutic test using an agent that might not be effective in the (therapy) management of the claimed condition presents itself to serious criticism [58]. The problems of the absence of a ‘‘golden’’ reliable diagnostic test of the pathology causing reflux should be on the top priority of the agenda of future research in the condition of GERD and LPRD.

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Fig. 5 Two normal larynges (a and b) showing folding of the mucosal lining of the posterior wall of the posterior glottis during partial adduction

Clinical outcome Clinical manifestations and complications of the 2 types of reflux are distinct: •

•

The gastroesophageal type has: heart burn, epigastric pain, erosive esophagitis, esophageal stricture, precancerous conditions; Barrett’s metaplasia, and, adenocarcinoma [2]. The extra-esophageal (laryngopharyngeal (LPR)/hypopharyngeal reflux may have: Bronchial: asthma with related symptoms, oropharyngeal dysphagia [16]. b. Laryngeal: this is some times coined as ‘‘Reflux Laryngitis’’ [50]. Symptoms: globus! hoarseness/dysphonia, frequent clearing of the throat; signs: posterior laryngitis [55], inter-arytenoid pachydermia [26]

Fig. 6 The angulation of the scope towards one side (right) of the glottis may expose the sub-glottic slope of the vocal fold giving the impression of duplication (pseudo-sulcus). The right ventricle is widely opened due to that angulation, while the left ventricle’s opening seems ‘‘obliterated’’

a.

c.

(Fig. 5a, b), inter-arytenoid bar [43], hypertrophy of the posterior commissure [33], post-cricoid edema [13], arytenoid edema, erythema of the arytenoid and vocal folds [38], pseudo-sulcus [28], ventricular obliteration [40] (Fig. 6), granuloma [18] (Fig. 7). Others: sinus disease, otitis media, dental caries [8, 15].

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Fig. 7 Contact granuloma without causing change of voice

The cause–effect relationship of the laryngeal symptoms and signs to reflux is, however, not clear The reason for the assumption that the laryngeal manifestations, varied as they are, are due to LPR may be that some of them just co-exists with the reflux, while a causal link is difficult to prove [62]. Pontes and Tiago [49] stated that ‘‘this set of signs and symptoms may be related to other causes, and the results of management, based on clinical presentation, vary widely and have low cure index.’’ Most of the laryngeal manifestations mentioned in relation to LPR are non-specific to that claimed causative agent [14, 18, 43, 50, 61]. They may be part of other categories of voice disorders where no symptoms of acid reflux are encountered. Vocal symptoms can occur in the absence of conclusive laryngeal physical findings, and they can be non-specific [36]. For example, dysphonia can be caused not only by LPR, but also by neoplasia and by geriatric, neurologic, and behavioral disorders [5]. Extra-esophageal manifestations and their association with gastroesophageal reflux are still very controversial [31]. Thus, the cause-and-effect relationship between LPR and laryngeal symptom and signs has yet to be definitively elucidated [25].


The laryngeal manifestations present, however, a multidimensional problem First, non-organic dysphonia versus ‘‘reflux laryngitis’’: It is well known in the field of phoniatrics and vocology that vocal complaints may present with subtle or no morphological changes in the larynx and glottis. This condition is referred to as non-organic (functional) voice disorders. These complaints are known to be predisposed by excessive and faulty vocal use. Smoking and other sources of pollution are important causative factors. In some instances, LPRD or ‘‘reflux laryngitis’’ is described as the cause of the vocal complaint because there are no other clear positive physical signs in the larynx. Non-organic dysphonia is a category in the classification of voice disorders, where there is a voice symptom/complaint in the absence of detectable organic morphological changes in the larynx/glottis to justify it. Non-organic dysphonia is recognized and applied in clinical practice for decades [3, 9, 19, 20, 22, 35, 42, 44–46, 48]. Thus, one does not need a justification, like a refluxate, to explain voice problems when apparent laryngeal physical signs are absent. It is welcomed for any research to produce an explanation for the absence of morphological change while vocal symptoms are there. Second, the significance of the claimed clinical manifestations: 1.

Critical assessment of the claimed laryngeal manifestations Though esophageal manifestations of GERD are specific and well documented, extra-esophageal pathologies are diffuse, non-specific and far from being well documented objectively. The tracheo-bronchial manifestations including the oro-pharyngeal swallowing problem part are more supported by clinical and objective measures. The supra laryngeal pathologies, as otitis media, sinus disease, and dental caries, claimed to be caused or even facilitated by LPR are too hypothetical to warrant further discussion.

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2.

Some of the symptoms are non-specific and controversial. A common symptom attributed to LPRD is globus. Globus is usually referred to as diffuse feelings in the throat—inability to cough up and swallow sticky secretions—commonly found in phonasthenia known also as ‘‘voice fatigue’’. This symptom (globus) is sometimes referred to by the patient as a lump in the throat. There is no evidence of the presence of a lump in the throat [51, 63]. On the other hand, a common symptom of GERD and LPRD is laryngeal spasms that occur in response to the contact of the refluxate with the laryngeal inlet. This symptom is easily understood as a protective mechanism against laryngeal penetration or aspiration. Loughlin et al. [41] stated that ‘‘Supra glottic chemo receptors in the canine larynx respond by laryngeal spasm when exposed to acid stimuli’’. Some of the terminologies give rise to some uncertainties in interpretation. a.

Posterior laryngitis: It is contradictory to describe hoarseness of voice/dysphonia as a symptom of posterior laryngitis. The posterior glottis does not vibrate during phonation thus its pathology should not give rise to change of voice ‘‘hoarseness’’ [56]. Lesions in the posterior glottis may, however, give rise to phonasthenic symptoms but not dysphonia (Fig. 7).


Inter-arytenoid pachydermia: This is described as thickening of the inter-arytenoid region. The apparent thickening in this region frequently observed in the adducting posterior glottis is a normal phenomenon resulting from the folding and creasing of the mucosa lining the posterior wall of the posterior glottis during adduction. In the state of full abduction, mucosa appears flat and straight [27] (Fig. 5). Accordingly, it is recommended that laryngeal office examination should allow sufficient inspection of the glottis during breathing with full abduction. It is confusing when signs are ascribed to parts of the glottis that are questionable, as the posterior commissure [27, 56]. Karkos et al. [33] describe a ‘‘hypertrophy of the posterior commissure’’. The posterior glottis as described by Hirano et al. [27], and Sodersten [56], shows a posterior wall, thus there is no posterior commissure.

more than the other. This may show the sub-glottic slope of the vocal fold thus giving the impression of fullness and hence the diagnosis of ‘‘pseudo-sulcus’’ [18] (Fig. 6). Similarly, variations in angulations of the scope may show one ventricle widely opened while the other side appears as a slit. This may have given rise to the description of ventricular obliteration as a sign of LPRD while searching for convincing physical signs [43] (Fig. 6). The position of the scope is also important when follow-up observation is made to decide the changes in the size of a lesion, as, e.g., edema of the arytenoid. The distance of the tip of the scope from the glottis has to be kept as much as possible stable in order to avoid differences in size due to variation in picture magnification [53]. Thus, it is vital to give guidelines regarding what to look for in the laryngogarms to raise the sensitivity and specificity of interpreting these laryngogarms [1].

Some signs are ill defined and are vaguely described. An example may be the erythema and edema in the arytenoid region and vocal folds. Branski et al. [8] highlighted this aspect in the following quotation, ‘‘Accurate clinical assessment of laryngeal involvement with LPRD is likely to be difficult because laryngeal physical findings cannot be reliably determined from clinician to clinician. Such variability makes the precise laryngoscopic diagnosis of LPRD highly subjective’’. Pathogenesis and significance of some ascribed signs: There is no description of the causative relation of some of the signs described to LPRD to the claimed causative factor, the ‘‘refluxate’’. The pathogenesis of a pseudo-sulcus, a ventricular obliteration, or an interarytenoid bar in relation to reflux is not clear. Furthermore, there are no convincing attempts to relate these claimed structural changes in the glottis to the symptoms usually ascribed to LPRD as hoarseness, throat clearance and ‘‘globus’’. Pitfalls in the use of the laryngeal endoscope: There is a possibility that some of the signs ascribed to LPRD might be due to the use of the flexible endoscope as compared to the rigid telescope to visualize the larynx. The flexible endoscope seems to be more sensitive but less specific [43]. The vocal folds may appear thickened when using the flexible endoscope as compared to the telescope, thus giving a false impression of edema. The pseudo-sulcus which is an impression of sub-vocal fold fullness may be due to the angle of vision while inspecting the glottis. When the telescope is not exactly central, it may expose one side of the glottis

It should be highlighted that despite the reliance on the diagnosis of ‘‘Reflux Laryngitis’’ on some ascribed physical signs of the glottis, there is a remarkable absence of laryngogarms from most of the publications on LPRD [6, 7]. The quality of the laryngogarms found in some of the articles is questionable [6, 7, 12].

b.

c.

3.

4.

5.

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Reflux in children The problem of LPRD in children shows similar tendencies to that in adults. Its verification as a causative factor of the child’s complaint is even more difficult [57]. Management of the condition PPI is the usual treatment of ‘‘reflux laryngitis’’. Despite some recorded positive therapeutic results, this treatment is, hitherto, given on empirical bases [59]. The exclusion of a possible placebo effect cannot be ruled out. The efficacy of such a treatment is not tested [18, 29, 32, 47]. Some studies showed that PPI treatment may be inferior to simple measures as modifying life style [58]. The role of non-invasive measures such as behavior readjustment voice therapy (BRAT) is not discussed as a possible line of treatment. BRAT proved to be effective in the management of many of the manifestations attributed to LPRD [4, 34, 35]. Recommendations What is needed at present is a sober revision by • •

new unbiased studies; well-controlled studies;

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• • • • • •


investigation of the chemical characteristics of the refluxate; studies with statistically appropriate size of patient material; development of valid and reliable diagnostic tools; multi-disciplinary studies; a laryngo-vocologist should be included in the team; objective documentation of the observations in the larynx; multi-center studies.

Conflict of interest statement no conflict of interest.

The authors declare that they have

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