The Differences between Gastroesophageal and Laryngopharyngeal Reflux

Abstract

Gastroesophageal reflux (GER) and laryngopharyngeal reflux (LPR) have different pathophysiological mechanisms of occurrence and are characterized by different clinical pictures and symptomatology. In clinical practice, it often happens that LPR remains unrecognized or is defined as atypical gastroesophageal reflux, thus, it is necessary to distinguish between these two clinical entities. Laryngopharyngeal reflux refers to the return of gastric contents from the stomach through the esophagus to the larynx, pharynx, paranasal cavities, middle ear, and lower respiratory tract, and it is part of the wider extraesophageal reflux syndrome (EER). Extraesophageal symptoms are common in GERD, and studies show an increasing prevalence of LPR in patients with GERD, as well as an association of reflux disease with cough and dysphonia symptoms. The aim of the chapter is to describe differences between GER and LPR in order to facilitate the recognition and differentiation of manifest and latent symptoms, diagnosis, and choice of therapeutic approach.

1. Introduction

The terms gastroesophageal reflux (GER) and laryngopharyngeal reflux (LPR) refer to the anatomical position and cause of the disease. Reflux sometimes escapes into the distal esophagus, which is a physiological event, but laryngeal mucosa does not possess protective mechanisms against gastric contents, so it appears that laryngopharyngeal reflux cannot be physiological. Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal disorders in Western countries, defined as a stomach content reflux into the esophagus with pathohistological changes of the esophageal mucous membrane and a series of clinical symptoms. The manifestations and symptoms of GERD have been classified into either esophageal or extra-esophageal. Extra-esophageal manifestations include upper respiratory tract manifestations, oral cavity, pulmonary, cardiac manifestation, and chest pain. Laryngopharyngeal reflux was conceptualized as the backflow of gastric contents into the laryngopharynx and other parts of the upper aerodigestive tract, causing an inflammatory reaction of the mucous membrane of pharynx, larynx, and other associated respiratory organs. In recent years it has been proven that gastroesophageal reflux is not the only cause of LPR. A growing number of clinical research support the opinion of LPRD being a new clinical entity, which is different from GERD in terms of pathogenesis, clinical manifestations, diagnostic and therapeutic possibilities, and prognosis. Physicians of various professions are involved in the diagnostic and therapeutic procedures of these pathological conditions. LPR, as well as GERD, is one of the most common causes of patient visits to their family medicine physicians. For primary care physicians, those conditions represent an important medical problem and a challenge in fast diagnostics, effective treatment, and proper selection of patients who require additional multidisciplinary diagnostic procedures [1]. The development of the diseases can be benign or malignant, with a number of potential medical complications and health-threatening and life-threatening consequences, and most of its forms can greatly affect patient’s quality of life.

2. Epidemiology

In recent years, the global prevalence of GERD is increasing. Based on geographical, lifestyle, and diet habits, in different regions of the world varies from 2.5% to 51.2%. According to epidemiological research, the prevalence of GERD appears to be the highest in Southeast Europe and South Asia (more than 25%), and lowest in Canada, France, and Southeast Asia (below 10%) [2]. The prevalence of laryngopharyngeal reflux has also been constantly rising in the Western world and today affects an alarmingly high percentage of the general population. It is estimated that clinical presentation of LPR could be found in 5–30% of individuals [1]. About 10% of patients visiting ENT clinics have symptoms attributed to LPR, which is present in up to 50% of patients with voice disorders [3].

Symptoms and findings are mainly nonspecific and some physicians believe that LPR is over-diagnosed. In clinical practice, the possibility of over- or under-diagnosed LPR depends on numerous factors, including physician’s experience, expertise, and knowledge, as well as diagnostic methods [4].

3. Esophageal anatomy and physiology

A GER episode is diagnosed when esophageal pH drops below 4.0 for at least 30 seconds. The physiological GER occurs in normal individuals, typically postprandial. Under physiological conditions, there is a number of protective mechanisms, which prevent epithelial damage due to reflux contents. These include upper esophageal sphincter (UES), lower esophageal sphincter (LES), esophageal peristalsis, the squamous mucosal barrier, salivary production, and bicarbonate buffer. Esophageal sphincters work as physical barriers to the retrograde movement of stomach contents to the esophagus and upper airway spaces. The esophagus is a 25 cm hollow fibromuscular tube that allows the passage of solids and liquids from the pharynx to the stomach, with no metabolic, digestive or endocrine function. It makes continuation with pharynx with the upper esophageal sphincter, which measures 2–4 cm in length, and is composed of striated or skeletal muscle. The cricoid cartilage and the arytenoid and inter arytenoid muscles make up the anterior parts of the sphincter. The thyropharyngeus and the cricopharyngeus muscles form the majority of the sphincter's posterior and lateral walls, with the former accounting for the upper two-thirds of the sphincter and the latter occupying the lower one-third. Contraction of the hyoid muscle that pulls the larynx forward, linked to the relaxation of the cricopharyngeus and the thyropharyngeus, leads to sphincter opening wide.

The primary role of the UES is to protect the upper airway spaces from retrograde movement of stomach contents. It also prevents a bigger amount of air from reaching the gastrointestinal tract. Lower esophageal sphincter, which measures 2.5–3.5 cm in length, is composed of smooth muscle and is not a true anatomical sphincter, but it is a physiological sphincter that is under involuntary control by the sympathetic trunk and the vagal nerve. In response to direct inhibitory signals, the smooth muscles in the LES relax, allowing the sphincter to open, and the bolus to pass. The LES and the crural diaphragm constitute a high-pressure zone that act as a mechanical anti-reflux barrier that minimizes movement of stomach contents back into the esophagus and also allows the bolus into the stomach [5].

Esophageal peristalsis is a process of simultaneous constriction and distal relaxation, which drives the bolus toward the stomach. This process ends by relaxation and opening of the LES and enabling the passage of the bolus into the stomach. The esophagus is lined with stratified squamous epithelium. The submucosal glands secrete water, bicarbonate, mucins, epidermal growth factor, and prostaglandins. This secretion is involved in mucosal clearance. At the gastroesophageal junction is a change to simple columnar epithelial cells with gastric glands and pits. This squamocolumnar junction is of special importance in patients with reflux disease—it is a critical point for the development of Barrett's esophagus, a premalignant condition that is associated with esophageal carcinoma [6].

4. Etiopathogenesis

New diagnostic methods developed in recent decades have greatly helped to understand the pathophysiology of these conditions. Numerous studies have evaluated the multifactorial background of GERD and LPR.

4.1 Etiology and pathophysiology of GERD

Various critical factors and mechanisms are contributing to GERD: LES incompetence, hiatal hernia, and hiatal anatomic changes, protrusion or herniation of the upper part of the stomach into the thorax, an altered frequency of transient LES relaxations, esophageal acid exposure, insufficient esophageal motility, and delayed gastric emptying [7]. Diet and conditions, which increase intra-abdominal pressure such as pregnancy, obesity, and straining play a role, as well as presence of Helicobacter pylori [8]. In addition, alcohol, nicotine, caffeine, and certain medications, such as calcium channel blockers or anticholinergic agents, have been shown to cause LES incompetence, which is the main cause of GERD [9].

Many GERD patients exhibit esophageal dysmotility and prolonged clearance rates [10]. GERD and psychosocial disorders often occur together and can affect each other [11]. Obstructive sleep apnea (OSA), obstructive sleep apnea syndrome (OSAS), and GERD have a strong relationship and share several common risk factors: approximately 40–60% of patients with OSA also suffer from GERD [12].

The pathological effect of refluxed gastric contents is complex and caused by acids, pepsin, bile acids, and trypsin. The overall mechanism of cell damage is penetration of the epithelium by acids at low pH and proteolysis of collagen, which disrupts the basement membrane of the squamous epithelial cells. Acid and bile reflux play a critical role—hydrochloric acid is a major cause of esophageal irritation and reflux symptoms causing injury to mucosal epithelial cells and inflammation. The abnormal secretion and activation of pepsin can also cause proteolysis and cell damage [13]. Pathohistological changes in the esophageal mucosa can be divided into three categories: nonerosive reflux disease, reflux oesophagitis, and Barett's esophagus [14].

4.2 Etiology and pathophysiology of LPRD

The pathophysiology of LPR is still incompletely understood. In the contrast to GERD, as we have already noted, LPR is never physiological, and mucosa of the upper respiratory tract is not resistant to gastric content. Although dysfunction of any previously mentioned barrier can cause LPR, the pathophysiology of LPR is primarily attributed to failure or dysfunction of the upper esophageal sphincter. The retrograde flow of gastric acid and pepsin induces mucosal inflammatory reaction and overall cell damage. Tripsin makes role in LES abnormalities and heat sensitivity disturbing barrier function. Furthermore, stress and autonomic nerve dysfunction by increasing the opening of LES and UES are probably involved in the development of LPR. In some studies, it has been hypothesized that gas refluxes carry aerosolized droplets containing hydrogen and pepsin into the proximal esophagus and upper respiratory space. Microaspiration of acid droplets is a very important mechanism for the development of mucosal inflammation [15].

4.3 Pathophysiological differences

Esophageal mucosa is more resistant to acid attacks, a critical pH is 4.0, cell death and mucosal injury occur below this point. Laryngeal mucosa damage occurs at a pH of 5.0 with short-term exposure. Laryngeal epithelium is up to 100 times more sensitive to pepsin damage than esophageal tissues, and according to some authors, it seems that pepsin plays a key role in the pathogenesis of laryngopharyngeal reflux [16]. Up to 50 GER episodes per day are considered within the normal range; however, LPR more than 3 times a week can lead to pathological changes in the laryngopharyngeal region [17]. GERD is associated with a higher body mass index (BMI), which is not observed in LPR [18]. As can be observed, GERD and LPR have some different etiological and pathogenic features, as shown in Table 1.

	GERD	LPR
Etiology	LES	UES
Critical pH	4.0	5.0
Esophageal motility	impaired	normal
Reflux	liquid	gas
Obesity	yes	no
Critical number of reflux episodes	>50/day	>3/week

Table 1.

Comparison of GERD and LPR based on etiology and pathogenesis.

5. Symptoms

GERD patients usually present with wide symptoms of esophagitis, including heartburn and burning sensation, chest pain, and acid regurgitation, which are important diagnostic factors. Patients mainly report a burning feeling in the retrosternal area, spreading into the chest and neck. It occurs mostly post-prandially. Chronic cough, dysphagia, globus sensation, and irritable throat discomfort can present as atypical manifestations in patients with GERD as extraesophageal symptoms. Some patients with GERD are asymptomatic. Some clinical studies show that reflux is the only cause of chronic cough in 10% of patients [19].

The most prevalent symptoms associated with LPR are related to the upper respiratory tract: globus sensation, hoarseness, throat clearing, excess throat mucus or postnasal drip. These symptoms, which are commonly observed in primary care medicine, are nonspecific and often intermittent. Throat pain, sore throat, expectoration, dysphagia, and halitosis can also be presented [1]. Patients with LPR are more likely to suffer from insomnia [20].

GERD symptoms typically occur in supine position, but LPR patients mainly have upright and daytime reflux events [21]. The main differences in clinical presentation are shown in Table 2.

	GERD	LPR
Heartburn	Yes	Uncommon
Acid reflux	Yes	Uncommon
Position	Supine	Upright
Occurrence	Anytime	Daytime
Sleep Disorders	OSAS	Insomnia

Table 2.

Comparison of GERD and LPR based on main symptoms.

6. Diagnosis

A presumptive diagnosis of GERD is based on typical symptomatology. Empirical proton-pump inhibitor (PPI) treatment, where the patient is prescribed a PPI for a short period of time (usually two months) to see if it resolves symptoms is in the majority of patients sufficient for diagnosis of GERD. In case when symptoms do not improve, or even worsen, when GERD is accompanied with other, atypical symptoms or, in case of suspected complications, there is a need for more invasive diagnostic tests.

While routine endoscope examination of the esophagus is not indicated for patients with typical symptoms, it is advised for patients with complicated GERD and is useful in the detection of erosive esophagitis, presence of Barett's esophagus or hiatal hernia, and other anatomic changes. The absence of esophageal mucosal injury cannot exclude GERD, because more than half of the patients with GERD have nonerosive reflux disease [22]. Routine biopsy is not recommended. The detection rate of abnormal blood vessels and epithelial micro injuries can be improved under endoscopy equipped with narrow banding imaging [22]. Barium esophagography and pH monitoring are useful to evaluate esophageal function. Esophageal manometry is of limited value but is recommended before considering anti-reflux surgery. Ambulatory reflux monitoring allows the determination of pathologic esophageal acid reflux and its frequency [23]. Blood tests are used to measure H. pylori IgG and H. pylori CagA IgG antibodies.

Standard diagnostic algorithm, which could precisely determine LPR have still not been established. LPR is mostly not recognized, and because of that it is known as a “silent reflux.” In a large number of cases diagnostic and therapeutical protocols are inadequate, so proper treatment is usually delayed. Laryngeal symptoms are most common, so patients are usually treated by otolaryngologists. Otolaryngologists have developed a Reflux Symptom Index (RSI), a validated questionnaire given to patients to score the severity of their symptoms. It is based on the importance of certain disease symptoms (the degree of hoarseness, frequency of throat clearing, degree of throat mucus or postnasal drip, dysphagia, coughing after eating or lying down, breathing difficulties, chronic cough, globus sensation, and heartburn). Reflux Finding Score (RFS) is based on frequency of pathological changes observed by laryngoscopy [24]. The laryngoscopic findings associated with LPR include posterior commissure hypertrophy, edema, arytenoid erythema, ventricular obliteration, granulation, oropharyngeal and anterior pilar erythema, coated tongue, uvula, and oropharyngeal posterior wall erythema. Many of them are nonspecific, but laryngoscopy has a very important role in diagnosis of reflux laryngitis; redness, thickness, and swelling located in the posterior parts of the larynx (posterior laryngitis) are important for the diagnosis of LPR.

This part of the larynx is anatomically more disposed to chronic irritation because both arytenoids and the interarytenoid regions are closer to the inlet of esophagus [25]. In some cases, immunoserologic pepsin detection tests are useful and easy to perform. Pepsin is produced only by the chief cells of the stomach and, therefore, the pepsin as a specific marker detected in the larynx can only be derived from refluxing gastric contents [26].

7. Differential diagnosis

GERD symptoms overlap with those of other pathological conditions:

• Infectious esophagitis;

• Eosinophilic esophagitis;

• Peptic ulcer disease;

• Gastroparesis;

• Esophageal motor disorders;

• Esophageal stricture;

• Esophageal cancer;

• Coronary artery disease;

• Biliary colic;

• Functional dyspepsia;

• Dysphagia;

• Various pulmonary diseases [23].

Many diseases and conditions of the upper respiratory tract can be presented as LPR and can be easily attributed to them:

• Postnasal drip;

• Allergies;

• Chronic laryngitis;

• Sinus inflammation;

• Vocal fold pathology;

• Various pulmonary diseases;

• Zenker's diverticulum;

• Laryngeal and pharyngeal malignancies [27].

This poses a challenge to diagnosis and can alter medical treatment.

8. Treatment

Dietary changes and lifestyle modifications are the first steps in the treatment of GERD. This includes eating low-fat and low-acid diet, small meal size, weight loss, smoking cessation, and controlling alcohol consumption. Stress management is also useful. Patients with nocturnal reflux have to eat a meal 2–3 h before bedtime and elevate the head of the bed during sleep. If these measures fail to achieve results, the widely accepted empirical management of LFR and GERD is proton pump inhibitor (PPI) treatment applied twice a day for two or three months. These drugs can suppress acid production and neutralize acidopeptidic activity in esophagus, larynx, and pharynx. PPIs are fast and strong, and the most efficacious and important factor for success of the therapy is their regular and correct usage. Patients who need PPI therapy for a longer time should be placed on the lowest dose because the long-term use of PPIs increases the risk of many complications, such as acute nephritis, gastric tumors, bacterial gastroenteritis, bone fractures, etc. [23, 28].

H2 receptor blockers are an effective alternative maintenance therapy for GERD and LPR, as well as alginates. Alginate forms a gelatinous layer on top of the gastric contents and makes a mechanical barrier, thereby reducing contact between the reflux contents and esophageal mucosa. Alginate also has a significant inhibitory effect on pepsin, and is, according to some research, non-inferior to PPI [13, 29]. Other noninvasive treatment options include using external upper esophageal sphincter compression device. If there is no response to appropriate empirical treatment, instead of increasing the dose or extending the duration of treatment, it is necessary to review the diagnosis by considering the multifactorial pathophysiology of reflux. In patients with severe reflux, surgical therapy can also be used. Endoscopic and surgical options include anti-reflux surgery, bariatric surgery, magnetic sphincter augmentation, and transoral incisionless fundoplication [22]. As can be seen, the medicament treatment of GERD and LPR is similar, but in clinical practice, patients with LPR require more aggressive and prolonged PPI treatments (six months) to achieve an improvement of laryngeal symptoms than those with typical GERD symptoms [30].

9. Complications

As already stated, untreated or unrecognized reflux episodes can be connected with a number of potential medical complications and health-threatening and life-threatening consequences. The prevalent complications of GERD include dysphagia, bleeding from erosive esophagitis, and esophageal adenocarcinoma. Dysphagia usually occurs slowly in patients with long-standing heartburn. The most common causes are peptic stricture and severe inflammation, but dysphagia can be the first symptom of pathological esophageal mucosa changes and esophageal cancer. It is considered an alarming symptom in patients with GERD that requires endoscopy [31].

Severe esophagitis is a risk factor for development of Barett's esophagus (BE). Barrett’s esophagus is a condition defined as a metaplastic transformation of the distal normal esophageal squamous epithelium into the columnar epithelium. It is considered a premalignant condition, the only known predisposing factor of epithelial dysplasia and esophageal carcinoma. Long-term and non-treated gastroesophageal reflux disease is the most important risk factor for the development of this condition. BE is found in 1.3–1.6% of the general population and 5–15% of symptomatic GERD patients undergoing endoscopy.

The incidence of GERD has been increasing significantly over the last few decades, as well as incidence of adenocarcinoma of the esophagus. As BE is the only known precursor to carcinoma, progress in the monitoring and therapy of BE are essential to enable early diagnosis and improve patient outcomes.

Lower esophageal rings (Schatzki) correlate with reflux esophagitis, too. Other complications include anemia (due to chronic blood loss), peptic ulceration, and a whole range of respiratory tract problems [32].

Laryngeal and pharyngeal mucosa has a poor self-protection capacity and poor adaptability to chemical stimuli. Some significant long-term complications of LPR are chronic otitis media, chronic rhinosinusitis, oral cavity disorders and dental erosions, recurrent bronchopulmonary infections, and cardiac problems. More serious, but not so often, laryngeal findings in patients with LPR include vocal cord nodules, laryngospasms, subglottic stenosis, and arytenoid fixation. LPR is also an independent risk factor for squamous cancer of the larynx and pharynx. Pepsin has been linked to epithelial proliferation and carcinogenesis. Namely, activated pepsin induces inflammation, destruction of the epithelial defense barrier, changes in expression of laryngeal and hypopharyngeal genes and tumorogenesis, and disruption of the function of epithelial cells [33, 34, 35, 36]. Some studies have shown that bile acids and Helicobacter pylori may play a role in the development of laryngeal and hypopharyngeal carcinoma.

10. Prognosis

Majority of patients with GERD and LPR do well with medications, but relapse after stopping medical treatment is common. In refractory cases, surgical treatment is necessary. Long-term untreated LPR, as well as GERD, can result in previously mentioned complications.

11. Conclusion

Different results of scientific studies make it difficult to establish clear approach to the symptoms and manifestations of LPR and its relation to GERD. The multifactorial pathophysiology of reflux needs to be investigated in more detail [37]. GERD typically manifests as heartburn, regurgitation, and chest pain, while LPR patients usually do not report these symptoms, and they complain about chronic cough, laryngitis, and a lump in the throat. According to some investigations, ≤50% of LPR patients have GERD, while laryngopharyngeal symptoms were present in 32.8% of GERD patients. LPR patients mainly have gaseous, upright, and daytime reflux events, and only 5.5% of laryngopharyngeal reflux events occurred at nighttime, in the supine position.

GERD could be diagnosed using multiple tools, but fewer objective diagnostic tools exist for diagnosing LPR. However, up to 50% of patients with LPR symptoms may not have classic reflux symptoms. The interindividual differences in the esophageal and laryngopharyngeal mucosa sensitivity must be taken into account, too. The esophagoscopy may be normal in more than 44% of cases and may detect esophagitis in 10–30% of LPR patients, while erosive esophagitis is found in almost 50% of GERD patients. Scientific evidence shows that LPR is not an advanced stage of GERD [17].

The independent existence of LPR in the absence of GERD can be understood through several possibilities. First, reflux can originate from the heterotopic gastric mucosa of the cervical esophagus. Second, reflux events detected in the laryngopharynx are secondary to GER, and patients met both of diagnostic criteria. Third, reflux events detected only in the laryngopharynx are secondary to GER and meet the diagnostic criteria for LPR, but do not meet the criteria for GERD. It seems that more studies would make it possible to define the reflux standard for GERD as well as put together the standard differentiation between LPR and GERD [38].

Safe standard diagnostic procedures, which could precisely determine LPR, have still not been established, and taking careful and detailed hetero-anamnestic history is important. In GERD, typical reflux symptoms usually regress with antireflux therapy, but several meta-analyses have demonstrated no diagnostic or therapeutic benefit of PPI to manage patients with LPRD. Therefore, establishing a multidisciplinary collaboration between gastroenterologists, laryngologists, family medicine physicians, pediatricians, pulmonologists, psychiatrists, and speech-language pathologists is necessary to provide a comprehensive approach to develop acceptable diagnostic and treatment modalities for the pathologic reflux.

A generally accepted view today is that, although the relationship between them is not completely understood, it is necessary to consider them as different types of medical entities and treat them in a different way. Anyway, GERD and LPR can coexist with each other and also independently as different subheadings under the main heading reflux disease [17].

Conflict of interest

The authors declare no conflict of interest.