Extraesophageal and atypical manifestations of GERD

Abstract   Extraesophageal manifestations of gastroesophageal reflux disease (GERD) are essentially complications of GERD that primarily involve organs that are in proximity to the esophagus. Non-cardiac chest pain (NCCP) is an atypical manifestation of GERD, because symptoms originate in essence from the esophagus. In both atypical and extraesophageal manifestation of GERD frequent heartburn is uncommon and lack of GERD symptoms is not unusual. Esophageal mucosal injury is rarely present making upper endoscopy a low-yield procedure in both conditions. While association with GERD has been commonly reported, the extent of causality remains unknown. In NCCP, the usefulness of the proton pump inhibitor (PPI) test in diagnosing GERD-related NCCP has been established. Similar value in extraesophageal manifestations of GERD has been proposed, but rarely studied. While treatment of extraesophageal manifestations of GERD remains a challenge, PPIs in at least double the standard dose, should be considered for the initial therapy. Properly designed therapeutic studies are still lacking as well as the exact role of antireflux surgery in this patient population.     

Effect of Antisecretory Therapy on Atypical Symptoms in Gastroesophageal Reflux Disease

The effect of proton pump inhibitor (PPI) therapy on extraesophageal or atypical manifestations of gastroesophageal reflux disease (GERD) remains unclear. This study aimed to evaluate the prevalence of atypical manifestations in patients with acid reflux disease and the effect of PPI treatment. Patients with symptoms and signs suggestive of reflux were enrolled. Erosive esophagitis was stratified using the Los Angeles classification. Demographic data and symptoms were assessed using a questionnaire and included typical symptoms (heartburn, regurgitation, dysphagia, odynophagia), and atypical symptoms (e.g., chest pain, sialorrhea, hoarseness, globus sensation, chronic coughing, episodic bronchospasm, hiccup, eructations, laryngitis, and pharyngitis). Symptoms were reassessed after a 3-month course of b.i.d. PPI therapy. A total of 266 patients with a first diagnosis of GERD (erosive, 166; non-erosive, 100) were entered in the study. Presentation with atypical symptoms was approximately equal in those with erosive GERD and with non-erosive GERD, 72% vs 79% (P = 0.18). None of the study variables showed a significant association with the body mass index. PPI therapy resulted in complete symptom resolution in 69% (162/237) of the participants, 12% (28) had improved symptoms, and 20% (47) had minimal or no improvement. We conclude that atypical symptoms are frequent in patients with GERD. A trial of PPI therapy should be considered prior to referring these patients to specialists.     

Empirical trials in treatment of gastroesophageal reflux disease

The assortment of diagnostic tests that are currently available for detecting gastroesophageal reflux disease (GERD) are invasive, costly and not readily available to community-based physicians. In contrast, a short course of high-dose proton pump inhibitor (PPI) as an empirical trial is an attractive alternative. This simple diagnostic test has been demonstrated to be accurate and cost-effective in patients with symptoms suggestive of GERD and those with noncardiac chest pain. Early studies in patients with extraesophageal manifestations of GERD have yielded promising results. Cost assessment of the PPI empirical trial revealed significant cost savings, mainly due to a marked decrease in utilization of invasive diagnostic tests. Thus the PPI empirical trial should be considered as the initial diagnostic step in patients with the disease spectrum of GERD.     

The proton pump inhibitor (PPI) test in GERD: does it still have a role?

The proton pump inhibitor (PPI) test is a short course of high-dose PPI, used to diagnose gastroesophageal reflux disease (GERD). This diagnostic strategy is commonly used globally, primarily because of its availability, simplicity, and high sensitivity. The PPI test has been proven to be a sensitive tool for diagnosing GERD in noncardiac chest pain patients and in preliminary trials in extraesophageal manifestations of GERD. Several recent meta-analyses reevaluated the value of the PPI test in patients with classic GERD-related symptoms and noncardiac chest pain. Although the results were conflicting, the PPI test remains a popular tool for determining the presence of GERD. Attempts to challenge the PPI test without offering attractive alternatives are unlikely to alter clinical practice.     

Can symptoms predict esophageal motor function or acid exposure in gastroesophageal reflux disease? A comparison of esophageal manometric and twenty-four-hour pH parameters in typical and extraesophageal gastroesophageal reflux disease

It has been suggested that patterns of esophageal motor function and acid exposure may differ between those patients with gastroesophageal reflux disease (GERD) with classic symptoms and those with extraesophageal manifestations. Our objective was to compare various parameters of esophageal motility and acid exposure between groups of patients who had presented with extraesophageal manifestations of GERD alone, a combination of classic and extraesophageal manifestations, or classic GERD symptoms alone. A retrospective review of consecutive patients undergoing esophageal manometry and 24-hour dual-channel esophageal pH testing was performed. Information on patient demographics, symptoms, and results of various manometric and pH testing parameters was examined. We evaluated 84 patients: 32 with extraesophageal symptoms alone, 24 with both classic and extraesophageal symptoms, and 28 with classic symptoms alone. Apart from a trend toward less supine acid exposure in those with extraesophageal symptoms alone, no significant differences were evident among the three patient groups in any of the other parameters of proximal or distal esophageal acid reflux. With respect to motility parameters, lower esophageal sphincter pressure was lower in those with combined symptoms; otherwise, manometric findings were similar in the three patient groups. Our data do not support the hypothesis that the nature of the clinical presentation of GERD, whether in the form of classic or extraesophageal manifestations, is related to differing patterns of esophageal motor function or esophageal acid exposure.     

Proton pump inhibitors in gastroesophageal reflux disease: "a custom-tailored therapeutic regimen"

The Montreal Definition and Classification divides Gastroesophageal Reflux Disease (GERD) into esophageal symptomatic syndromes (and with mucosal damage) and extraesophageal syndromes (with acid established association and proposed association). In typical GERD symptoms, an 8-week treatment with PPIs is satisfactory in most cases (> 90%). Response rates to PPIs in GERD are highly variable, as they also rely on an appropriate clinical diagnosis of the disease; endoscopy differentiates the macroscopic GERD phenotype. The non-erosive variety (50-70% prevalence) has a different symptomatic response rate, as gastric acid is not the sole etiology of symptoms. The possible explanations of treatment failure include treatment adherence, PPI metabolism alterations and characteristics, and inadequate diagnosis. Refractory symptoms are related to gastric content neutralization by the chronic use of PPIs.Extraesophageal manifestations are associated with other pathophysiological mechanisms where an autonomic nervous system disturbance gives rise to symptoms. In these clinical entities, the relationship between symptoms and acid needs to be established in order to determine the use of PPIs, or consider other drugs. In other words, so as to "custom-tailor the best-fitting therapy" we need to answer the questions for whom, for what, how and for how long. Finally, PPI safety and tolerability are factors to be considered in elderly patients requiring chronic PPI use, who usually have chronic concomitant illnesses.     

Esophageal manometry and pH monitoring: gastroenterologists' adherence to published guidelines

GOALS: To determine whether gastroenterologists use esophageal manometry (EM) and esophageal pH recording (pHR) in accordance with published guidelines. STUDY: Questionnaires were mailed to 900 randomly selected gastroenterologists nationwide. Each questionnaire requested demographic information and contained 11 case scenario-based questions, followed by a choice of management options. RESULTS: A total of 275 completed questionnaires (30.6%) were returned. 63.6% and 64.4% of respondents were aware of published guidelines regarding the use of EM and pHR, respectively. The majority of respondents ordered EM appropriately: 1) to confirm a suspected diagnosis of achalasia (97.1%); 2) to establish a diagnosis of connective tissue disease (89.7%); 3) as part of the preoperative evaluation for anti-reflux surgery (74.6%); and 4) to ensure the proper placement of pH probes (69.4%). EM was rarely ordered for the initial workup of noncardiac chest pain. The majority of responding gastroenterologists would order pHR for the evaluation of: 1) endoscopy-negative patients being considered for anti-reflux surgery (79.1%); 2) patients with recurrent GERD symptoms after anti-reflux surgery (62.5%); 3) endoscopy-negative patients with GERD symptoms refractory to proton pump inhibitor (PPI) therapy; and 4) patients with extraesophageal manifestations of GERD that are refractory to PPI therapy (88.7%). CONCLUSIONS: The majority of gastroenterologists in our study order EM and pHR in accordance with published guidelines. However, EM appears to be used less than expected for preoperative evaluation before anti-reflux surgery and for ensuring the proper placement of pH probes. In addition, the use of pHR to evaluate persistent GERD symptoms after anti-reflux surgery was less than anticipated.     

胃食管反流病食管外表现的临床研究

目的探讨胃食管反流病（GERD）食管外表现（EED）的临床特征和质子泵抑制剂对EED的治疗效果。方法本研究为多中心、开放、前瞻性临床研究,在上海市的4家医院同期入选GERD患者,均符合内镜下有反流性食管炎（RE）的诊断标准,无RE者则为24h食管pH监测阳性的非糜烂性反流病（NERD）。进行GERD典型症状和EED相关症状的问卷调查并记录积分,有EED症状者行电子喉镜检查并记录有关征象,然后对上述资料进行统计、比较分析。结果共分析200例符合标准的GERD患者,伴有EED者95例,无EED者105例;NERD患者66例,RE134例,其中65例为具有EED的RE患者。EED的症状最常见的为咽球感和（或）咽部异物感,发生率为27％,其他常见的依次为咳嗽、咽喉灼痛、声音嘶哑,哮喘较少,其发生率分别为21％、16％、11％、3％。有EED的患者中并存典型GERD症状的发生率为56％,EED症状的严重程度在RE和NERD患者间差异无统计学意义。喉镜检查示声带红斑、水肿32％,杓区红肿25％,咽后壁淋巴增生20％,未见明显异常的42％。95％的EED患者治疗8周后症状基本消失。结论较大比例的GERD患者中有EED存在,而喉镜、常规24hpH监测对诊断的阳性预测值不高,高剂量质子泵抑制剂对EED的治疗有效。     

Extraesophageal gastroesophageal reflux disease. Presentations and approach to treatment

Prevalence of gastroesophageal reflux disease (GERD) is common in the adult US population, but likely is underestimated as many patients present with symptoms other than heartburn or regurgitation. Ears, nose, throat, pulmonary, and cardiac symptoms also frequently are related to GERD. The diagnosis of GERD as a cause of these symptoms can be difficult and treatment strategies are much less clear than in patients presenting with heartburn or regurgitation. This article discusses the epidemiology, pathogenesis, diagnosis, and treatment of some of the manifestations of extraesophageal reflux disease.     

Key points in the management of gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is a relatively common condition with a prevalence ranging from 10% to 20% in Western countries and 5% to 10% in Asian populations [1]. In a recent evidence-based consensus [2], GERD was defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms or complications. This global definition emphasizes the syndromic nature of the disease and subdivides the patients in different groups depending on the presence of mucosal complications (ie, esophagitis, metaplasia, stenosis) and on the prevalent clinical manifestations (ie, typical reflux symptoms or extraesophageal/supraesophageal syndromes). General practitioners, gastroenterologists, and specialists from different branches of medicine generally share the management of GERD patients, and basically they need to address the following four issues.     

Extraesophageal manifestations of GERD

The association between gastroesophageal reflux disease (GERD) and extraesophageal disease is often referred to as extraesophageal reflux (EER). This article reviews EER, discussing epidemiology, pathogenesis, diagnosis, and treatment with a focus on the most studied and convincing EER disorders-asthma, cough, and laryngitis. Although EER comprises a heterogeneous group of disorders, some general characterizations can be made, as follows. First, although GERD's association with extraesophageal diseases is well-established, definitive evidence of causation has been more elusive, rendering epidemiological data scarce. Secondly, regarding the pathogenesis of EER, 2 basic models have been proposed: direct injury to extraesophageal tissue by acid and pepsin exposure or injury mediated through an esophageal reflex mechanism. Third, because heartburn and regurgitation are often absent in patients with EER, GERD may not be suspected. Even when GERD is suspected, the diagnosis may be difficult to confirm. Although endoscopy and barium esophagram remain important tools for detecting esophageal complications, they may fail to establish the presence of GERD. Even when GERD is diagnosed by endoscopy or barium esophagram, causation between GERD and extraesophageal symptoms cannot be determined. Esophageal pH is the most sensitive tool for detecting GERD, and it plays an important role in EER. However, even pH testing cannot establish GERD's causative relationship to extraesophageal symptoms. In this regard, effective treatment of GERD resulting in significant improvement or remission of the extraesophageal symptoms provides the best evidence for GERD's pathogenic role. Finally, EER generally requires more prolonged and aggressive antisecretory therapy than typical GERD requires.     

Pediatric otolaryngologic manifestations of gastroesophageal reflux disease

In adults, an estimated 4% to 10% of chronic, nonspecific laryngeal disease seen in otolaryngologic clinics is associated with gastroesophageal reflux disease (GERD). Although no such estimates exist in children, many investigators have reported extraesophageal manifestations of GERD, of which the most common is the association of GERD with asthma and chronic cough. A variety of signs and symptoms of otolaryngologic disease also have been attributed to GERD, including hoarseness, laryngitis, chronic rhinitis, sinusitis, globus pharyngeus, recurrent croup, laryngomalacia, stridor, subglottic stenosis, otalgia, vocal cord granulomas, and oropharyngeal dysphagia. However, proof of the association between these manifestations of otolaryngologic disease and GERD is sparse. Furthermore, the manifestations of otolaryngologic disease often occur in the absence of such classic systems of GERD as heartburn or chest pain. This review explores the role of GERD in otolaryngologic disease in children.     

Extraösophageale Manifestationen der Refluxerkrankung an den Atmungsorganen

Gastroesophageal reflux disease (GERD) is a common medical condition with a prevalence of 10–20% in the western world and almost every third GERD-patient presents with extraesophageal symptoms. The extraesophageal symptoms and disorders associated with GERD are chronic cough, bronchial asthma, sleep disturbances or aggravation of sleep disordered breathing, hoarseness, dental erosions and non-cardiac chest pain. The severity of the symptoms is variable. Typical GERD symptoms like heartburn and regurgitation can occur only faintly or not at all, and extraesophageal symptoms may be predominant. Causality and pathogenesis are not clarified conclusively, however recurrent microaspirations and nerval mechanisms are suggested. Recurrent aspirations, especially in patients with structural oesophageal disorders predispose to pulmonary infections. One hypothesis postulates a causal relationship between microaspirations and idopathic pulmonary fibrosis. This article gives an overview of reflux associated bronchopulmonary diseases and summarizes treatment options.     

Pharmacologic management of gastroesophageal reflux disease

The burden of gastroesophageal reflux disease (GERD) results from its widespread prevalence and the unfavorable impact of its symptoms on well-being and quality of life. Whereas abnormalities of the antireflux barrier (lower esophageal sphincter) are important in the pathophysiology of GERD, pharmacologic therapy for GERD is based on suppression of acid, which is responsible for the majority of the symptoms and for epithelial damage. Proton pump inhibitors (PPIs) are the agents of choice for achieving the goals of medical therapy in GERD, which include symptom relief, improvement in quality of life, and healing and prevention of mucosal injury. As a class, these drugs are extremely safe. The newest PPI, esomeprazole, brings a statistically significant increase in healing of mucosal injury and symptom relief in patients with erosive esophagitis, compared with omeprazole and lansoprazole. This article reviews the role of medical therapy in the short-and long-term management of symptomatic patients with or without erosive esophagitis, including extraesophageal presentations, GERD during pregnancy, and Barrett’s esophagus. Management of refractory patients is addressed.     

Functional heartburn, nonerosive reflux disease, and reflux esophagitis are all distinct conditions—A debate: Con

Opinion statement Gastroesophageal reflux disease (GERD) is currently defined as a condition that develops when the reflux of stomach contents causes recurrent symptoms and/or complications. The clinical presentation of GERD has been recognized to be much broader than before, when the typical symptoms of heartburn and acid regurgitation were considered as the main clinical presentation. However, now it is recognized that GERD can present with various other mainly extraesophageal symptoms, abdominal pain, and even sleep disturbance. Moreover, there is an important overlap with functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome. The morphologic spectrum of esophageal involvement in GERD encompasses erosive (erosive reflux disease [ERD]), Barrett’s esophagus (BE), and nonerosive reflux disease (NERD). However, there is still no consensus on whether GERD represents one disease that can progress from NERD to ERD and BE, or whether it is a spectrum of different conditions with its own clinical, pathophysiologic, and endoscopic characteristics. Recently published data suggest that mild erosive esophagitis behaves in a way similar to NERD and that there is considerable movement between these categories. But follow-up data also show that after 2 years, some patients with NERD or GERD Los Angeles A or B went on to develop severe GERD or even BE. A practical approach is to categorize patients with reflux symptoms into “functional heartburn” (ie, reflux symptoms and negative endoscopy and absent objective evidence of acid reflux into the esophagus), NERD (negative endoscopy but positive documentation of acid reflux into the esophagus), and ERD (erosions documented endoscopically). In conclusion, it appears that GERD is a disease with a spectrum of clinical and endoscopic manifestations, with characteristics that make it a continuum and not a categorical condition with separate entities. It is difficult to clearly delineate the spectrum of GERD based on the clinical, endoscopic, and pathophysiologic characteristics, but therapeutic trials and follow-up studies suggest that GERD is not composed of different conditions.     

Gastroesophageal reflux

Gastroesophageal reflux disease (GERD) is the most common disease of the gastrointestinal system. Heartburn, regurgitation, and dysphagia are the most common symptoms of GERD. However, chest pain, chronic cough, laryngitis, hoarseness, and other otolaryngologic manifestation can be the primary manifestations of the disease. Endoscopy, barium studies, and especially pH monitoring and therapeutic trials may help in establishing the diagnosis of GERD. The introduction of H2 antagonists and especially of proton pump inhibitors (PPI) has brought symptomatic relief in most patients. However, surgical procedures, especially laparoscopic fundoplication, are still required in some patients. Barrett's esophagitis is the most common complication of GERD and is associated with a high prevalence of esophageal adenocarcinoma. Whether or not treatment with either PPIs or H2 antagonists can prevent this complication is still under investigation.     

How relevant is symptom evaluation in NERD?

Most patients presenting with esophageal and extraesophageal symptoms of gastroesophageal reflux disease (GERD) have negative endoscopic findings and are defined as being affected by non-erosive reflux disease (NERD). A correct recognition and analysis of symptoms in these patients is essential for an appropriate clinical management, as well as for scientific purposes. Symptoms alone do not capture all the clinical implications of NERD, but since their frequency and severity are strictly related to their influence on quality of life, they provide a sufficiently reliable picture of the disease. Most studies were carried out on patients with heartburn and regurgitation, and information about other clinical manifestations of NERD is extremely limited. Inclusion criteria and primary end-points of clinical trials are ill defined, particularly, when extraesophageal manifestations are considered. A new, validated instrument is now available to correctly measure all possible complains of GERD patients, including general well-being. This scale has been used also to identify the level of symptom frequency and severity that can be present in perfectly healthy, self-considering asymptomatic individuals, thus providing the first objective definition of 'complete symptom relief'. Through instruments like this, our understanding of NERD and its management will certainly further improve in the years to come.     

Extra-Esophageal Manifestations of Gerd: Who Responds to GERD Therapy?

Gastroesophageal reflux disease (GERD) is a common disease that is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms. In addition to the esophageal manifestations of heartburn and regurgitation, the role of GERD in causing extra-esophageal symptoms, such as laryngitis, asthma, cough, chest pain, and dental erosions, is increasingly recognized with renewed interest. Due to the poor sensitivity of endoscopy and pH monitoring, and the poor specificity of laryngoscopy, empiric therapy with proton pump inhibitors (PPI) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. In those who are unresponsive to such therapy, other diagnostic testing such as impedance/pH monitoring may be reasonable in order to exclude continued acid or weakly acid reflux. Recent data suggest that patients with extra-esophageal symptoms who have concomitant typical symptoms, moderate-sized hiatal hernia and moderate reflux on pH testing may respond better to acid suppressive therapy. This group only accounts for 20?30 % of patients commonly referred for suspected GERD. PPI-unresponsive patients usually have causes other than GERD for their extra-esophageal signs and symptoms and continued PPI therapy in this group is not recommended.     

Pharmacologic management of gastroesophageal reflux disease

Opinion statement The burden of gastroesophageal reflux disease (GERD) results from its widespread prevalence and the unfavorable impact of its symptoms on well-being and quality of life. Whereas abnormalities of the antireflux barrier (lower esophageal sphincter) are important in the pathophysiology of GERD, pharmacologic therapy for GERD is based on suppression of acid, which is responsible for the majority of the symptoms and for epithelial damage. Proton pump inhibitors (PPIs) are the agents of choice for achieving the goals of medical therapy in GERD, which include symptom relief, improvement in quality of life, and healing and prevention of mucosal injury. As a class, these drugs are extremely safe. The newest PPI, esomeprazole, brings a statistically significant increase in healing of mucosal injury and symptom relief in patients with erosive esophagitis, compared with omeprazole and lansoprazole. This article reviews the role of medical therapy in the short- and long-term management of symptomatic patients with or without erosive esophagitis, including extraesophageal presentations, GERD during pregnancy, and Barrett’s esophagus. Management of refractory patients is addressed.