|Year : 2019 | Volume
| Issue : 1 | Page : 1-9
Extraoesophageal reflux manifestations of gastro-oesophageal reflux disease
Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria
|Date of Web Publication||27-Feb-2019|
Department of Otorhinolaryngology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna
Source of Support: None, Conflict of Interest: None
Gastro-oesophageal reflux disease (GERD) is defined as a condition when the reflux of gastric content causes troublesome symptoms or complications. Gastro-oesophageal reflux is associated with numerous pathologic conditions of the upper aerodigestive tract. GERD can be subclassified into oesophageal and extraoesophageal syndromes. Extraoesophageal manifestations can be either pulmonary or otorhinolaryngological. This review provides an overview of most important extra-oesophageal reflux manifestations in GERD patients.
Keywords: Chronic cough, extraoesophageal reflux, gastro-oesophageal reflux disease, globus pharyngeus, pepsin, reflux laryngitis
|How to cite this article:|
Schneider-Stickler B. Extraoesophageal reflux manifestations of gastro-oesophageal reflux disease. Hamdan Med J 2019;12:1-9
| Classification of Gastro-Oesophageal Reflux Disease|| |
Gastro-oesophageal reflux is associated with numerous pathologic conditions of the upper aerodigestive tract. Regarding a global evidence-based consensus (Montreal definition and classification, 2006), gastro-oesophageal reflux disease (GERD) is defined as a condition when the reflux of gastric content causes troublesome symptoms or complications. GERD can be subclassified into oesophageal and extraoesophageal syndromes [Table 1].
|Table 1: The evidence-based consensus of the overall definition of gastro-oesophageal reflux disease and its constituent syndromes|
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Extraoesophageal reflux (EER) manifestation has become a major pathophysiological problem with increasing clinical importance. EER can be either primary cause or major contributing factor to a variety of commonly occurring extraoesophageal problems.
| Pathomechanism of Extraoesophageal Reflux Manifestation|| |
Increased attention to GERD has shifted focus to how and under which circumstances reflux influences physiologic processes in the upper airway beyond the oesophagus.
As demonstrated in [Table 2], EER results in either direct reflux-associated symptoms due to direct contact between stomach content and mucosal structures or indirect vagal reflex responses elicited from the oesophagus.
The clinical experience shows that symptoms mediated by EER are often non-specific and overlap with those of other medical conditions.
As long as patients report on classic GERD symptoms (i.e. heartburn, epigastric regurgitation), upper respiratory tract ailments seem to be associated with EER. Nevertheless, even in the absence of classic GERD symptoms, EER has to be considered and reviewed in all circumstances of any unspecific upper airways disorder. Even 'silent reflux' can manifest in unspecific upper airway symptoms. The percentage of patients with 'silent' EER situation devoid of classic GERD symptoms is meanwhile estimated at about 20%.
| Pepsin as Biomarker and Mediator of Reflux Symptoms|| |
The history of pepsin dates back to 1836, when Theodor Schwann discovered in the gastric juice a substance which he called 'pepsin'. Pepsin is now considered to be the most aggressive proteolytic enzyme in gastric refluxate. Pepsin has been identified as a biomarker of gastric reflux into oesophageal and extraoesophageal areas and could be detected in the saliva, sputum and secretion from the upper respiratory tract. Pepsin has been shown to cause inflammation independent of the pH-value of the refluxate and thus despite acid suppression therapy with for example, proton-pump inhibitor (PPI).
| Extraoesophageal Reflux Manifestation|| |
The physiologic mechanism of EER manifestation can be attributed to a breakdown of one or more of the four barriers to reflux:
- Upper oesophageal sphincter
- Lower oesophageal sphincter
- Oesophageal acid clearance
- Epithelial resistance.
If the barrier functions of lower and upper oesophageal sphincters are not working properly, the direct mechanism of refluxate aspiration can trigger a tracheal or bronchial cough reflex. In case of a reflex-associated process, a vagally mediated bronchoconstriction can be found.
A further important risk factor for EER seems to be excessive diaphragm activity in forced breathing tasks with special stress to the lower oesophageal sphincter. Recent studies pointed out that GERD and EER might be considered to be work related in certain professional groups. An increased intra-abdominal pressure seems to initiate GERD with extraoesophageal manifestations, such as in opera singers, wind players and glassblowers.,,
The interdisciplinary holistic approach for diagnostics of EER syndromes is essential, as usually general medicine, internal medicine, pulmonology or otorhinolaryngology is the first point of contact for patients with partly unspecific complaints. It is important to consider EER manifestation in a broad range of diseases of the upper respiratory tract [Table 1].
From the interdisciplinary point of view of the medical occupational group classification, EER symptoms can be divided into pulmonary and otorhinolaryngological symptoms as demonstrated in [Table 3].
|Table 3: Extraoesophageal reflux symptoms in pulmonology and otorhinolaryngology (Richter, 2001)|
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Given the increasing prevalence of GERD and its role in oropharyngeal, laryngeal and pulmonary alterations, there is a growing need for better understanding of the underlying mechanism of pathophysiology.
| Pulmonary Extraoesophageal Reflux Manifestation|| |
Among pulmonary patients, special emphasis is given to the high percentage of GERD related cofactors to bronchial asthma, chronic bronchitis and chronic cough.,
Asthma as an inflammatory lung disease with reversible airflow obstruction and bronchospasm causes episodes of wheezing, coughing, chest tightness and shortness of breath. Aetiologically, environmental factors such as allergens or other aeroirritants, genetic factors, side effects of medication and viral/bacterial infection have to be taken into consideration as well as the direct or indirect impact by extraoesophageal refluxate.
| Chronic Cough|| |
Chronic cough has a significant impact on the well-being of patients and stresses the healthcare services in many ways. Cough is one of the most common conditions seen worldwide by primary care physicians and specialists.
Meanwhile, GERD has to be regarded as one the three most important aetiologies of chronic cough. Afferent triggers are mediated by chemoreceptors and nociceptors within the respiratory system. They provide feedback to the cough centre within the medulla, which, in turn, activates an efferent cascade and reflex that involves instantaneously the closure of the glottis. Tight laryngeal closure permits creation of an increasing subglottic pressure and a transglottic pressure gradient, which is the precondition for expectorating material from the respiratory tract when the subglottic pressure threshold is exceeded.
The traditional approach to chronic cough considers first of all smoking and regular medication with angiotensin-converting enzyme inhibitors. Meanwhile, the focus has extended to the diagnosis and management of other cough trigger components. Further classic triggers are aerogenic irritants/allergies, post-nasal drip, respiratory infection, bronchial asthma, voice mis-/overuse and other reactive airway diseases. These aetiologies have to be excluded before suspecting, that reflux may play a major role in developing chronic cough syndrome.,
Chronic cough syndrome related to reflux is often considered a diagnosis of exclusion. In clinical practice, the evaluation of patients with chronic cough frequently involves trials of empiric therapy before initiating respective diagnostics. Patients are usually referred to further interdisciplinary examinations, if the empiric therapy trial could not solve the problem.
A common medical problem is the worsening of chronic cough symptoms by phonation in patients with underlying irritable larynx syndrome. Irritable larynx syndrome describes throat irritation that results from repeated vocal fold trauma by voice mis- and overuse. It can manifest as a sensory neuropathy during chronic cough., If the cough threshold is already decreased, then voice use can lead easily to heavy cough attacks.
Chronic cough can cause repeated trauma to the vocal fold tissue resulting in irritation and swelling of the vocal folds with a foreign body sensation in the larynx. This often requires a behavioural change of a person's reaction to this cough sensation and vocalisation. A swallow of water might help to break the cycle and overcome the cough reflex.
| Globus Pharyngeus|| |
Globus pharyngeus (GP) is a symptom regularly reported by patients in ear, nose and throat (ENT) practice. It makes up to 4% of ENT referrals and is reported to have been experienced by up to 45% of the population. GP is usually multifactorial and cannot simply be reduced to a single hypothetical factor.
It describes the subjective feeling of a painless lump in the throat or an abnormal laryngopharyngeal sensation. Although there may not be an identifiable physical cause for the symptom, it is often associated with persistent clearing of the throat, chronic cough, hoarseness and swallowing impairment.
It has been proposed that regurgitation of stomach acid and digestive enzymes in EER induces chronic inflammation of the laryngopharyngeal structures resulting in unspecific inflammatory symptoms and GP symptoms. Antireflux treatment can often improve the clinical situation, when EER plays a role on aetiopathogenesis. However, EER is often only a cofactor and not the only cause, as gastro-oesophageal reflux can be diagnosed in two-third of patients with GP. However, the clinician should have in mind that EER can also be found in symptom-free controls without GP. Thus, GP is likely to be responsible for a subgroup of GP patients but cannot explain all GP cases.
| Tonsil Hypertrophy|| |
Tonsil hypertrophy is one of the most common indications for tonsillectomy, especially in early childhood. The hypertrophy can be caused by an increase of lymphocytes usually after bacterial colonisation and inflammation. However, the total number of lymphocytes can be increased even in the absence of a clinical bacterial infection. As EER is responsible for a variety of pharyngeal symptoms, there is also evidence that pepsin is involved in the pathogenesis of tonsil hypertrophy. Kim et al. (2016) could show that pepsin is involved in stimulating tonsil hypertrophy mediated by macrophages that recognise the extraoesophageal pepsin as an antigen. Pepsin can activate lymphocytes and can be inhibited by Pepstatin.
| Laryngopharyngeal Reflux Manifestation: Hoarseness, Vocal Fold Granuloma, Benign Vocal Fold Alterations|| |
Unspecific vocal and throat changes, which cannot be explained by other organic or functional voice disorders, indicate the possible influence of gastric or gastroduodenal reflux as a contributing or exacerbating factor, even in patients with no history of typical GERD. Laryngopharyngeal reflux (LPR) manifestation is often associated with chronic cough syndrome.
In 1991, Koufman operationalised LPR. A careful anamnesis and laryngostroboscopic examination can exclude laryngeal malignancy, neurologic deficits or phonation-associated vocal fold alterations (e.g., mid-fold fibrosis, vocal fold polyp).
Typical laryngostroboscopic findings of laryngeal reflux manifestation are sulcus vocalis [Figure 1], pseudosulcus, thick secretions in the glottis, irregular free edges, erythema and interarytenoid mucosal oedema [Figure 2], posterior injuries such as ulcers and granuloma [Figure 3] and paradoxical movement of vocal.
|Figure 1: Laryngeal findings in extraoesophageal reflux: Bilateral sulcus vocalis|
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|Figure 2: Laryngeal findings in extraoesophageal reflux: Erythema of the arytaenoid region and posterior commissure mucosal thickening|
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|Figure 3: Laryngeal findings in extraoesophageal reflux: Granuloma in the cartilaginous part of the left vocal fold|
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Ulceration or granuloma in the cartilaginous part of the vocal fold has been strongly linked to reflux. The mucosal damage by refluxate and the contact forces during phonation can cause either ulceration (contact ulceration) or granuloma (contact granuloma) as it is to be seen in Figures 3. It is still difficult to determine the pathophysiologic relationship between reflux and granuloma, as reflux might be a causal factor or cofactor.
Meanwhile, LPR has been associated with numerous other laryngeal alterations, including muscle tension dysphonia, Reinke's oedema, laryngeal hyperirritability, laryngospasm, diffuse laryngitis, leucoplakia, glottic and subglottic stenosis, cricoarytenoid joint ankylosis, carcinoma and other conditions.,
Many benign vocal fold lesions are of varying aetiology and can be caused phonotraumatic secondary to voice overuse, misuse or abuse. In situ ations without identifiable mass lesion or neurologic deficit, clinicians see a connection between vocal situation and reflux disease. EER is made responsible as a cofactor in many voice professionals and voice users if the voice use alone cannot explain the development of the vocal situation. Reflux is believed to be a factor which negatively affects healing of vocal fold alterations after inflammation, phonotrauma and also after laryngeal surgery.
For semiquantitative evaluation and documentation of LPR manifestation, the Reflux Finding Score (RFS) has been developed and validated. The RFS is an 8-item clinical severity scale based on the findings during fibreoptic laryngoscopy [Table 4]. The final items of RFS include subglottic oedema, ventricular obliteration, erythema/hyperaemia, vocal fold oedema, diffuse laryngeal oedema, posterior commissure hypertrophy, granuloma/granulation tissue and excessive thick endolaryngeal mucus production. The scale ranges from 0 (no abnormal findings) to a maximum of 26 (worst score possible).
The current controversies on LPR and GERD underline the problem of clinical interpretation of laryngo- and laryngostroboscopic findings as being reflux-related. Although clinical experience underlines the connection between LPR and EER, little success has been reached with correlation investigations between specific laryngoscopic findings and the presence of reflux.,,
So far, patient symptoms have become a primary decision-driving method to identify those with LPR. Patient-reported outcome measures have become a principal diagnostic tool for LPR and monitoring the treatment outcomes., The most common patient-reported outcome measures related to LPR have been summarised in [Table 5].
|Table 5: Overview of patient-related outcome measure related to laryngopharyngeal reflux (modified after [Francis: 2016fl])|
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The current controversies on LPR and GERD underline the problem of clinical interpretation of laryngostroboscopic findings as being reflux-related. Although clinical experience underline the connection between LPR and EER, little success has been reached with correlation investigations between specific laryngoscopic findings and the presence of reflux.,,
Regarding the need for further diagnostics, many colleagues argue that it is easier and more cost-effective to treat LPR empirically with a PPI than to spend additional time and effort investigating possible EER.
| Vocal Cord Dysfunction|| |
For the vocal cord dysfunction (VCD), several synonyms are in clinical use: paradoxical vocal fold movement (PVFM), PVFM disorder and induced laryngeal obstruction (ILO). VCD is a functional laryngeal dysfunction first described in the 19th century, as VCD causes paradoxical closing/adduction of vocal folds during inspiration, resulting in acute, episodic dyspnoea. VCD is often mistaken for asthma but is not responding to typical anti-asthmatic treatment. Laryngoscopy during the acute respiratory event remains a gold standard for the diagnosis of VCD. Exercise, psychological conditions, airborne irritants, rhinosinusitis, GERD or use of certain medications may trigger VCD. For many individuals, the role of post-nasal drip and GERD in the pathogenesis of VCD is central, as they are often associated with VCD and likely lead to increased laryngopharyngeal sensitivity and hyperreactivity. The patients need to be further examined in terms of the underlying pathogenesis of VCD. Management of VCD requires identification and treatment of underlying disorders. Treatment of acute episodes includes reassurance, breathing instruction and inhalation of a helium and oxygen mixture (heliox). Long-term management strategies include treatment for symptom triggers and speech.
VCD can be diagnosed already in children. Usually, respiratory struggle during physical exertion (exercised ILO), asthma and respiratory allergies have been suspected as underlying pathological factor. Refluxate of gastric contents can also induce laryngospasm and VCD. An interdisciplinary approach is needed to avoid unnecessary utilisation of medical resources and potential delays of proper treatment. In patients with suspected VCD, a gastroenterological examination including gastroscopy is strongly recommended.
| Dental Erosions|| |
Dental erosion can be considered as an extraoesophageal manifestation of GERD.,, The association between acid reflux and dental erosion was first described by Howden in 1971. As dental erosion occur more often in patients with GERD, patients with unexplained dental erosions should be referred to gastroenterologists for further diagnostics.
Dental erosions are defined as a physical result of pathological, chronic, localised, painless loss of dental hard tissue, the outer surface is chemically destroyed by acid or chelates. Dental erosions are usually of multifactorial aetiology. Even the interaction of all aetiologic factors may cause a synergistic effect. According to the depth of the lesions they might be divided into surface and deep ones, according to the localisation into generalised and localised ones and according to pathogenic activities into manifesting and latent ones.
The connection between GERD and erosive changes on teeth is not absolute because not everyone with a diagnosed GERD represents also erosive teeth changes. GERD may be a risk factor for dental erosions only if it is in combination with refluxate regurgitation.
Further reasons for dental erosions might be attrition, abrasion and abfraction:
- Attrition is a defect of both dental tissue and restoration and is caused by tooth to tooth contact during mastication or para-functioning. Occlusal surfaces are smooth, shiny, evened and hard and on amalgam fillings facets are observable. The bottom of the defect may be located both in enamel and in dentine
- Abrasions occur with direct contact between the tooth and an external substance (tooth whitening paste, anti-nicotine, soda.). Dental abrasion is most commonly seen at the cervical necks of teeth, but can occur in any area, even interdentally from vigorous and incorrect use of dental floss. Acid erosion has been implicated in the initiation and progress of the cervical lesion, while toothbrush abrasion has long been held as the prime cause of cervical abrasion
- Abfraction is a defect which is characterised by loss of dental tissue in the cervical region. It is caused by compression and stretching forces which take place during dental flexure. At inadequate occlusal relation, the changes are localised mainly vestibular and they are of a wedged shape.
Dental erosion can result in tooth sensitivity, poor aesthetic appearance, loss of occlusal vertical dimension and functional problems. Clinicians must have thorough understanding of the causes of dental erosion as identification of the cause is the first step in its management. The inspection of the oral cavity in search for dental erosion should become a routine manoeuvre in patients with have GERD.
| Post-Nasal Drainage|| |
Daily, the human body produces between 0.75 and 1.5 L of secretions from the upper airway, which is swallowed into the oesophagus. Thus, post-nasal drainage is not a syndrome but has to be considered as a rather normal physiologic process.
Clinical experience is that patients describing post-nasal drip/drainage often complain on significantly thickened secretions, which the body recognises as abnormal, thus manifesting in frequent throat clearing and cough.
Patients with globus sensation, post-nasal drainage or cough traditionally are first of all thought to be allergic. Thus, they are initially treated with antihistamines, decongestants and cough protecting drops. All of these interventions usually increase the viscosity of the secretion and can exacerbate symptoms.
Therefore, hydration and avoidance of any drying medications can improve the symptoms.
Nevertheless, in patients with therapy resistant and persistent post-nasal drainage symptoms also extraoesophageal symptom manifestation has to be considered.
| Chronic Rhinosinusitis With and Without Nasal Polyposis|| |
The prevalence of chronic rhinitis is estimated to be high as 30% of the total population.
Chronic rhinosinusitis (CRS) is defined as an inflammatory disorder of the nose and the paranasal sinuses lasting for at least 12 weeks.
According to the European Position Paper on Rhinosinusitis and Nasal Polyps 2012, it is characterised by the following clinical features:
- Nasal blockage/congestion/obstruction and/or
- Rhinorrhoea: nasal discharge, anteriorly or posteriorly
- ± Facial pain/pressure
- ± Reduction/loss of smell
and either endoscopic signs of:
- Polyps and/or
- Mucopurulent discharge and/or oedema primarily in the middle meatus and/or
- Changes within the ostiomeatal complex and/or sinuses on computer tomography.
It affects approximately 15% of the adult population and may be divided into three clinical subtypes:
- CRS without nasal polyps (CRSsNP) in [Figure 4]
- CRS with nasal polyps (CRScNP),
- Allergic fungal rhinosinusitis.
|Figure 4: Coronal computer tomographic image of a patient with hypertrophy of lower turbinates, obstruction of ostiomeatal complex and chronic sinusitis due to extraoesophageal reflux|
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Allergic rhinitis is considered as the most common aetiology of a symptomatic disorder of the nose induced by an immunoglobulin Emediated inflammation of the membranes lining the nose after allergen exposure.
Over the past decade, EER has been hypothesised to be one of the possible factors of the non-allergic rhinitis with nasal hyperreactivity that contribute to the development and worsening of CRS. EER has to be excluded in any non-allergic, non-infectious chronic rhinitis. Otherwise, the treatment outcome might be poor.
From the pathophysiologic point of view, two potential mechanisms are considered in order to explain how GERD and CRS may interact: direct cytotoxic effect of gastric refluxate displaced to the nasal cavity or an indirect mechanism due to a reflex from oesophagus to the sinuses through the autonomic nervous system. Several studies have tried to identify reflux or reflux components in the nasal cavity. As to acid, it has so far not been possible to document an increased incidence in patients with CRS compared to controls,, but in a small group of medically refractory CRS, most patients had a positive pharyngeal pH probe.
In other studies, in patients with recurrent CRS significantly more reflux events in the oesophagus, but no more direct EER signs could be found.
However, pepsin could be found in nasal lavage in patients with CRS. In addition, Helicobacter pylori could be found in the nasal and paranasal cavities. H. pylori was detected in the mucosa from ethmoid cells in more patients with CRS than in controls. It was also found with the same percentage in both patients with CRS and individuals of a control population.
When it comes to an indirect GERD manifestation as the pathophysiological mechanism explaining CRS, it is believed that this can be an analogue of the reflex between gastro-oesophageal reflux and bronchial constriction. Wong made an acid infusion test by installing saline and acid in the oesophagus and measured an increased nasal mucus production. However, the number of participants in this study was low and the result was not statistically significant.
| Otitis Media|| |
Acute otitis media (AOM) and chronic otitis media with effusion (OME) are among the most frequent causes for visits to the doctor, especially in children in the age of 1–3 years.
There are several well-known conditions that cause or facilitate the development of middle ear infections. The most important aetiologic factors seem to be upper respiratory infections (including bacterial infections), anatomical characteristics, an immature immune system, allergies and enlarged adenoids. The AOM with purulent effusion (AOM) is predominantly caused be single microorganism, most commonly Haemophilus influenzae, but also Streptococcus pneumoniae, Alloiococcus otitis or Moraxella catarrhalis, whereas otitis media with non-purulent effusions (chronic seromucotympanon) seems to be caused by predominantly polymicrobial entities and non-bacterial agents.
Enlarged adenoids are considered as the main reason for chronic dysfunction of the Eustachian tube resulting in OME in younger children. Usually, it can be treated successfully with adenoidectomy and paracentesis. In few children, the symptom of middle ear effusion reoccurs after adenoidectomy.
Here, in consequence, it is necessary to identify other possible risk factors. EER is considered as one contributing risk factors of OME.
EER can cause inflammatory changes in the Eustachian tube and middle ear, with consequential development of middle ear inflammation. 24-h monitoring of oropharyngeal pH and detection of pepsin in the middle ear fluid are suitable methods for detecting EER in children with OME.
OME occurs frequently in younger children with resulting conductive hearing loss. This is one of the important causes of hearing loss, which can lead to profound effects on language skills and cognitive development of children.
Pepsin and pepsinogen in OME are predominantly caused by LPR and should be considered as LPR predictors.,
| Diagnostics and Management|| |
Patients with EER symptoms may require in general antireflux treatment and/or referral to a gastroenterologist for further appropriate diagnostics.
Diagnosis of EER manifestation has traditionally relied on symptomatology, questionnaires, laryngoscopy, stroboscopy, endoscopy and pH-monitoring and radiologic examinations including barium swallow.
Combined multichannel intraluminal impedance and pH-monitoring provide an advance in EER/LPR diagnostics.
The Peptest, an immunoassay used to detect pepsin, can be used to diagnose EER, especially in children with chronic OME.
First-line therapy for patients with EER symptoms are lifestyle changes. Certain foods, body position, smoking, alcohol and obesity should be considered in the GERD treatment.
Current guidelines for EER manifestation suggest an initial empiric trial of PPIs for at least 3 months in patients with suspected GERD symptoms. For those patients who improve with PPIs, GERD is presumed to be the aetiology. In patients with refractory reflux and failure to respond to a 3-months trail of behavioural changer and gastric suppression by adequate doses of PPI, combined multichannel impedance/pH monitoring might provide the single best strategy for evaluating reflux symptoms.
Nevertheless, the treatment of any extraoesophageal manifestation has to consider not only the antacid medication (PPI) but also surgical intervention, lifestyle changes/diet, voice therapy, antiallergic co-medication and any other disorder-related treatment.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]