Anatomy of reflux: a growing health problem affecting structures of the head and neck

Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are sibling diseases that are a modern-day plague. Millions of Americans suffer from their sequelae, ranging from subtle annoyances to life-threatening illnesses such as asthma, sleep apnea, and cancer. Indeed, the recognized prevalence of GERD alone has increased threefold throughout the 1990s. Knowledge of the precise etiologies for GERD and LPR is becoming essential for proper treatment. This review focuses on the anatomical, physiological, neurobiological, and cellular aspects of these diseases. By definition, gastroesophageal reflux (GER) is the passage of gastric contents into the esophagus; when excessive and damaging to the esophageal mucosa, GERD results. Reflux that advances to the laryngopharynx and, subsequently, to other regions of the head and neck such as the larynx, oral cavity, nasopharynx, nasal cavity, paranasal sinuses, and even middle ear results in LPR. While GERD has long been identified as a source of esophageal disease, LPR has only recently been implicated in causing head and neck problems. Recent research has identified four anatomical/physiological "barriers" that serve as guardians to prevent the cranial incursion of reflux: the gastroesophageal junction, esophageal motor function and acid clearance, the upper esophageal sphincter, and pharyngeal and laryngeal mucosal resistance. Sequential failure of all four barriers is necessary to produce LPR. While it has become apparent that GER must precede both GERD and LPR, the head and neck distribution of the latter clearly separates these diseases as distinct entities warranting specialized focus and treatment.     

Assessment of the Esophageal Pressure in Gastroesophageal Reflux Disease by the Local Regression

Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal diseases. It is characterized by excessive reflux of gastric content (acid, pepsin, etc.) into the esophagus causing symptoms (heartburn, acid regurgitation, etc.) and mucosal inflammation and injuries. GERD occurs when the lower esophageal sphincter (LES) has a low resting pressure and stomach contents leak back, or reflux, into the esophagus. Therefore, the accurate measurement of the LES pressure is of great importance for the diagnosis of GERD. The LES pressure signal, involving severe respiratory contamination and motion artifacts, demands specific capabilities not provided by conventional data analysis methods. Recently, local regression has proved to be a very attractive technique to the nonparametric regression in statistics. In this contribution we apply the ideas of local regression to develop strategies for selecting smoothing parameters of local linear squares estimators, and present its application on the extraction of the LES pressure in GERD. The results from both extensive simulations and real data demonstrate the ability of local regression to characterize the LES pressure, which is consistent with the clinical observation.     

Gastroesophageal reflux disease

Physiological gastroesophageal reflux (GER) is the passage of gastric contents into the esophagus and occurs up 2/3 of normal infants; and, it resolves spontaneously around 9-12 months of age. When GER causes symptoms or complications is considered gastroesophageal reflux disease (GERD) and it is associated to growth impairment, anemia, apnea, wheezing or other chronic respiratory symptoms, asthma, recurrent pneumonia or sleeping problems. Diagnosis of GERD implies studies as upper gastrointestinal series, upper endoscopy and 24 h esophageal pH monitoring; special cases may require motility and nuclear medicine studies. GER may be successfully treated with prone elevated position (30-45 degrees), shortening the feeding intervals to 3 h and anti-GER high-viscosity formulas. The regular use of prokinetic drugs is not recommended. The efficacy of proton pump inhibitors and H2 histamine receptor antagonists in the treatment of GERD has been demonstrated in children by diminishing de acid secretion of parietal cells, lowering the gastric contents and decreasing its ability to cause peptic-acid damage to the esophagus or to the respiratory tract. Surgical treatment is indicated in chronic recurrent GERD, usually in children 5 years or older with dependent proton pump inhibitor erosive esophagitis, chronic respiratory disease and in risk-selected cases.     

Differences in Clinical Characteristics between Patients with Non-Erosive Reflux Disease and Erosive Esophagitis in Korea

Gastroesophageal reflux disease (GERD) is caused by abnormal reflux of gastric contents into the esophagus. GERD can be divided into two groups, erosive esophagitis and non-erosive reflux disease (NERD). The aim of this study was to compare the clinical characteristics of patients with erosive esophagitis to those with NERD. All participating patients underwent an upper endoscopy during a voluntary health check-up. The NERD group consisted of 500 subjects with classic GERD symptoms in the absence of esophageal mucosal injury during upper endoscopy. The erosive esophagitis group consisted of 292 subjects with superficial esophageal erosions with or without typical symptoms of GERD. Among GERD patients, male gender, high body mass index, high obesity degree, high waist-to-hip ratio, high triglycerides, alcohol intake, smoking and the presence of a hiatal hernia were positively related to the development of erosive esophagitis compared to NERD. In multivariated analysis, male gender, waist-to-hip ratio and the presence of a hiatal hernia were the significant risk factors of erosive esophagitis. We suggest that erosive esophagitis was more closely related to abdominal obesity.     

Antireflux surgery and esophageal mucosal DNA damage.

Gastroesophageal reflux disease (GERD) is characterized by reflux of gastroduodenal contents, esophagitis and oxidative tissue damage in the distal esophagus. It may ultimately lead to the development of a pre-malignant Barrett's esophagus and subsequently to carcinoma. Antireflux surgery is an effective therapeutic tool to relieve GERD symptoms and to normalize the reflux to the distal esophagus. However, antireflux surgery may be insufficient to restore oxidative insult, which can promote DNA adduct formation and subsequent initiation of carcinogenesis. Controversy exists whether antireflux surgery can reverse the development of carcinoma in the mucosa. We aimed to test the effect of antireflux surgery on DNA adduct formation in the esophagus. Patients (n = 19) with objectively confirmed GERD underwent antireflux surgery and were followed up for 6 months after which a symptom evaluation, control endoscopy, biopsy and pH-measurements were performed. The amounts of DNA adducts in the proximal and distal mucosa of the esophagus were measured using the 32-P-postlabelling method. After the surgery, esophageal acid exposure was normalized in all the patients and symptoms were relieved in all but one patient. Endoscopic examinations showed that erosive esophagitis had healed in all the cases 6 months after the surgery. Barrett's esophagus was found in six cases in preoperative biopsies. The amount of DNA adducts in the distal esophagus was higher than in the proximal esophagus both pre- and postoperatively. Antireflux surgery did not change this pattern and was thus not capable of reducing DNA adduct formation. The level of DNA damage was similar in the patients having Barrett's esophagus compared to the rest of the patients. Antireflux surgery is insufficient to normalize DNA damage due to GERD. Our observations suggest that antireflux surgery is perhaps not effective in the prevention of carcinogenesis because of the persisting DNA damage.     

Bleeding Barrett's ulcer as a complication of GERD [corrected] in physically and intellectually disabled children--report of two cases

Gastroesophageal reflux disease (GERD) is a problem frequently occurring among physically and intellectually disabled individuals. In this group of patients GERD is often overlooked, since the symptoms are usually non-specific. We present two cases of disabled children, who developed complications of GERD in the form of Barrett's esophagus, Barrett's ulceration and bleeding, the life-threatening events which were not preceded by typical GERD complaints.     

Reflux gastritis in gastroesophageal reflux disease: A histopathological study.

Increased intragastric alkaline reflux has been documented in patients with reflux esophagitis; however, the effect on gastric histology has not been investigated in this population. We examined gastric biopsies from 72 non-acid-suppressed patients with gastroesophageal reflux disease (GERD) for changes of reflux gastritis or other forms of gastritis. In the Helicobacter pylori-negative GERD patients (n = 52) using the Dixon scoring system for reflux gastritis with a threshold score of >/=11, reflux gastritis was found in 15% (three of 20) of GERD patients with erosions and in no GERD patients without erosions. When the reflux gastropathy threshold score was changed to more than 8, 90% (18 of 20) of GERD patients with erosions and 19% (six of 32) of GERD patients without erosions were classified as having reflux gastritis. Regardless of the reflux gastritis threshold used, only 14% (seven of 52) of the H pylori-negative GERD patients exhibited normal gastric histology. Inactive chronic gastritis or nonspecific reactive changes were histologic findings in those gastric biopsies not classified as reflux gastritis or normal. All H pylori-positive GERD patients (n = 20) had active chronic gastritis. We conclude that most GERD patients will exhibit some form of gastric pathology: either reflux gastritis, chronic gastritis, or nonspecific reactive changes, depending on what reflux threshold score is applied and the presence of H pylori. Studies to define the intragastric alkaline content in conjunction with gastric histopathology need to be performed to further define those reflux esophagitis patients with reflux gastritis.     

Gastroesophageal reflux disease in bronchial asthma and the response to omeprazole

The objective of this study was to determine the incidence of gastroesophageal reflux disease (GERD) in bronchial asthma and the role of omeprazole for asthmatics with symptoms of GERD. Seventy asthmatics were screened for GERD by questionnaire. Patients with a history suggestive of GERD were confirmed by Bernstein test and further investigated for airway responsiveness to instillation of HCl in the esophagus. Symptom score, drug score and spirometric values were recorded initially and after four weeks of treatment with omeprazole. It was found that 74.28% of asthmatics had a history of GERD. Forty patients tested positive by Bernstein test and also showed airway responsiveness to instillation of HCl in the esophagus. There was a significant improvement in symptom scores (p < 0.001), drug scores (p < 0.001) and spirometric values (p < 0.001) after adding omeprazole to their treatment regimen. It was concluded that bronchial asthma and GERD are associated in the majority of patients (57.14%) and such patients are likely to improve with omeprazole.     

Histopathologic changes in gastroesophageal reflux disease. A study of 126 bioptic and autoptic cases

The histologic diagnosis of reflux esophagitis is still complicated by the lack of a consensus opinion on what is the normal mucosa in the area of the gastroesophageal junction (GEJ). Most authors consider GEJ as the junction between the squamous and the cardiac epithelium. The cardiac mucosa is composed of mucinous or mixed mucinous-oxyntic glands. These glands are in fact indistinguishable from metaplastic mucosa that arises in the distal esophagus in consequence of gastroesophageal reflux (GER). The cardiac mucosa shows invariably chronic inflammatory changes referred to as "carditis". The cause of "carditis" is GER and/or Helicobacter pylori (HP) infection. In our series of 120 endoscopic biopsies of the GEJ and distal esophagus the cardia type mucosa (CM) was always present. In 15 cases, it was accompanied by oxyntocardiac mucosa. Both mucosa types showed chronic inflammation that is after exclusion of HP infection regarded as a strong diagnostic sign of the gastroesophageal reflux disease (GERD). In two cases with clinical symptoms of GERD, a few HP were found on the CM. Therefore we diagnosed them as GERD with secondary HP infection. In 17 cases, CM displayed intestinal metaplasia (IM) predominantly of incomplete type and no dysplasia. This IM expressed MUC6 in the glandular zone of the mucosa like it did in the neighboring glands, whereas in the surface and foveolar epithelium the MUC6 was negative or only slightly and focally positive. On the other hand, IM in the surface and foveolar epithelium was reactive for MUC5AC. The positivity and distribution of CK7 and CK20 was very similar in the Barrett's mucosa, cardiac mucosa and antral mucosa. In one specimen of esophagus resected for adenocarcinoma, CM with incomplete IM was found in the vicinity of the tumor. Squamous metaplastic epithelium was often seen near the orifices of submucosal esophageal glands in these areas, indicating the metaplastic nature of the glandular mucosa in the distal esophagus. In the GEJ of 5 autopsy cases of children with spastic quadriplegia (age range 7-10 years) CM in a short segment (0.5-3 mm in length), probably of metaplastic origin was identified, showing chronic inactive inflammation.     

Limited Clinical Utility of Lipid-Laden Macrophage Index of Induced Sputum in Predicting Gastroesophageal Reflux-Related Cough

Gastroesophageal reflux disease (GERD) is a common cause of chronic cough (CC). However, the diagnosis of GERD associated with CC based on 24-hour esophageal pH-monitoring or favorable response to empirical anti-reflux trials is invasive and time-consuming. Lipid-laden macrophages (LLMs) are supposed to be a biomarker for micro-aspiration of gastric content in the respiratory tract. This study was conducted to collect LLMs by the sputum induction technique and observe the relationship among the amount of LLMs, cough severity, parameters of 24-hour esophageal pH-monitoring and therapeutic response. The 24-hour esophageal pH-monitoring and sputum induction were performed on 57 patients with suspected GERD associated with CC. Thirty-four patients were followed up after empirical anti-reflux trials of 8 weeks to record the therapeutic response. Lipid-laden macrophage index (LLMI), a semiquantitative counting of LLMs, showed no significant correlation with the values of 24-hour esophageal pH monitoring at the proximal or remote electrode. No difference in LLMI or DeMeester score, as well as cough symptom association probability, were found between the responders and the non-responders. Reflux symptoms were more common in the responders (50%) compared to the non-responders (6%) (P < 0.05). Our study suggests that LLMI shows limited utility in clinically diagnosing GERD associated with CC as an underlying etiology or in predicting response to anti-reflux therapy. Anti-reflux therapy is more effective for CC patients with reflux symptoms than for those without.     

A Case of Chronic Cough Caused by Achalasia Misconceived as Gastroesophageal Reflux Disease

Cough is one of the most common symptoms that causes patients to seek outpatient medical care. If cough persists longer than 8 weeks, common causes of chronic cough, such as upper airway cough syndrome, asthma, and gastroesophageal reflux disease (GERD), should be considered. Although not a common cause of chronic cough, achalasia may cause symptoms very similar to reflux that can lead to its misdiagnosis as GERD. In this report, a 40-year-old woman presenting with chronic cough was initially diagnosed with GERD; however, her symptoms were refractory to conventional GERD treatment. Finally, she was diagnosed with achalasia. Her cough improved completely after pneumatic dilatation. Achalasia is a rare disease accompanied by dysphagia or regurgitation. If cough presumably due to GERD does not respond to treatment, or if the cause of chronic cough is uncertain, physicians should suspect achalasia.     

Pathology of the gastroesophageal junction

The gastroesophageal junction (GEJ) is a poorly defined anatomic area that represents the junction etween the distal esophagus and the proximal stomach (cardia). The true anatomic GEJ corresponds to the most proximal aspect of the gastric folds, which represents an endoscopically apparent transition oint in most individuals. Many, if not most, adults, particularly those with either physiologic or logic GERD, have a proximally displaced Z-line indicating that the histologic squamocolumnar nction (SCJ) is located above the anatomic GEJ. The histologic characteristics of short segments of columnar mucosa located above the anatomic GEJ in these individuals are similar to the gastric cardia, ng composed of either pure mucous glands or mixed mucous glands/oxyntic glands. Although controversial, some authors believe that the cardia is normally composed, at birth, of surface mucinous columnar epithelium and underlying oxyntic glands identical to the gastric corpus, whereas others maintain that the true anatomic cardia is normally composed of mucinous columnar epithelium with underlying mucous glands or mixed mucous and oxyntic glands. However, the preponderance of evidence supports the latter theory and that the length of mucosa composed of either mucous, or mixed mucous glands/oxyntic glands, increases with age and is presumed to be related to ongoing GERD. Inflammation of the true gastric cardia (carditis), which is most often due to H. pylori infection, is difficult to distinguish from columnar metaplasia of the distal esophagus secondary to GERD. From a pathologist's perspective, the differential diagnosis of true gastric carditis from esophageal columnar metaplasia of the distal esophagus in GEJ biopsies is difficult, but a variety of clinical, pathologic, and immunohistochemical methods can be used to help separate these two disorders. Nearly one-third of patients who present for upper GI endoscopy without endoscopic evidence of BE reveal foci of intestinal metaplasia in the GEJ. There are some studies to suggest that the risk of dysplasia and cancer is different in patients with intestinal metaplasia in the cardia related to H. pylori infection versus those with metaplastic columnar epithelium in the distal esophagus related to GERD. Chronic inflammation is generally considered the predominant underlying stimulus for the development of columnar metaplasia in the GEJ, regardless of the etiology. Columnar metaplasia and intestinal metaplasia in the distal esophagus represents a squamous to columnar cell transition and there is some evidence that this occurs through an intermediate, or transitional, phase of intestinalization termed multilayered epithelium. In contrast, intestinal metaplasia that develops in the true gastric cardia secondary to H. pylori infection represents a columnar to columnar metaplastic reaction. This review will focus on the clinical, pathologic, and pathogenetic aspects of GERD and H. pylori-induced inflammation of the GEJ region.     

Barrett's esophagus: a comprehensive review and update

Barrett's esophagus (BE) is a known precursor to esophageal adenocarcinoma. In the United States, a prevalence of up to 25% is reported in high risk populations and it is identified in about 5% of patients with gastroesophageal reflux disease (GERD). The diagnosis of BE requires endoscopically identifying columnar (“salmon colored”) mucosa, taking biopsies from targeted areas and then confirming histologically. The American College of Gastroenterologists updated its criteria in 2016, introducing a length requirement. This brief review addresses diagnosis of BE and its various associated challenges; identifying dysplasia, grading it, and management.     

Gastroesophageal reflux disease in preschool children with asthma]

BACKGROUND: In pediatric intractable asthma, there is occasionally an association with GERD (gastroesophageal reflux disease). It is not clear in which cases GERD should be suspected or how effective the GERD therapy is in treating the asthma. METHODS: Twenty-seven preschool children (<6 years of age) suffering from recurrent asthma attack in spite of asthma therapy underwent 24-hour esophageal pH monitoring. We examined retrospectively the incidence of GERD and the effectiveness of famotidine in GERD positive patients. RESULTS: 18 of the 27 patients (66.7%) had positive results (GERD positive group). In 12 of the 15 patients (80%) who underwent GERD therapy (famotidine), respiratory symptoms were decreased. In the GERD positive group, the incidence of acid reflux during waking hours was more frequent than during sleeping hours. In 8 of 12 patients (66.7%) in whom famotidine was effective, cough and wheeze often occurred during the daytime and corresponded with the time when acid reflux must commonly occurred. CONCLUSION: We conclude that children suffering from recurrent asthma attack in spite of asthma therapy must be examined for the presence of GERD.     

Is there a set of histologic changes that are invariably reflux associated?

Many histologic changes have been described in the esophageal squamous mucosa in patients with gastroesophageal reflux disease (GERD), including dilated intercellular spaces, balloon cells, intrapapillary vessel dilation, elongated papillae, basal cell hyperplasia, acanthosis, intraepithelial eosinophils, Langerhans cells, and p53 protein overexpression. To define a set of histologic changes that are invariably reflux associated, we examined the histologic changes in esophageal specimens from normal controls, patients with GERD, patients without GERD but with a suspicion of other pathology, and patients with esophageal carcinoma. We also examined biopsy specimens from sites with differing endoscopic features, including cloudy white and reddened mucosa. A definitive set of reflux-associated histologic changes could not be defined from the small number of biopsy specimens examined in the present study. Histologic changes indicative of GERD are likely to be found somewhere in the esophagus in all patients with GERD, but these changes are nonspecific. A set of histologic changes that are invariably reflux associated may exist, but these changes are nonspecific. To develop a set of characteristic reflux-associated features, endoscopists may perform targeted biopsies from several sites with various endoscopic features and at different stages of disease.     

Pancreatic acinar cells—a normal finding at the gastroesophageal junction? Data from a prospective Central European multicenter study

Pancreatic acinar cells are a well-recognized finding at the gastroesophageal junction, but their histogenesis and biological significance are unclear. From the prospective Central European multicenter histoGERD trial, we recruited 1,071 individuals undergoing gastroscopy for various non-selected reasons. Biopsy material was systematically sampled from the gastroesophageal junction and from the stomach. The study aimed to assess the prevalence of pancreatic acinar cells and to relate their presence to various histologic and clinical features. Overall, pancreatic acinar cells were observed in 184 (17.2 %) participants. Individuals diagnosed with pancreatic acinar cells were slightly younger than those without (median 50 vs. 53 years; p?=?0.009). There was no association with patients’ symptoms and/or complaints or with an endoscopic diagnosis of esophagitis or Barrett’s esophagus. Regarding histology, pancreatic acinar cells were not associated with features of the squamous epithelium indicating reflux disease, such as basal cell hyperplasia, papillary elongation, dilation of intercellular spaces, and inflammatory cell number, but were associated with the presence of cardiac mucosa (p?<?0.001), oxyntocardiac mucosa (p?<?0.001), and intestinal metaplasia (p?=?0.038), respectively. No association with Helicobacter pylori infection or diagnosis of gastritis was noted. In conclusion, pancreatic acinar cells are a common finding at the gastroesophageal junction, and no association with either reflux disease (histologically or endoscopically) or diagnosis of gastritis was observed. These data suggest a congenital rather than an acquired (metaplastic) origin of pancreatic acinar cells at the gastroesophageal junction. This questions the term “pancreatic acinar metaplasia” which is currently widely used for their diagnosis.     

Barrett-?sophagus

Barrett's esophagus (BE), a well-known complication of gastroesophageal reflux disease (GERD), constitutes a precancerous condition for adenocarcinoma of the distal esophagus. The so-called Barrett's carcinoma shows increasing incidences in countries of the western hemisphere; new data, however, indicate that the rise in incidence is not quite as dramatic as previously assumed. The definition of BE is currently changing: despite good reasons for a purely endoscopic definition of BE, goblet cells are still mandatory for this diagnosis in Germany and the USA. Dysplastic changes in the epithelium are the most important risk factor for the development of Barrett's adenocarcinoma and recently dysplasia was subclassified into a more frequent adenomatous (intestinal) and a non-adenomatous (gastric-foveolar) types. The gold standard for diagnosing dysplasia is still H&E staining. The histological diagnosis of dysplasia is still encumbered by a significant interobserver variability, especially regarding the differentiation between low grade dysplasia and inflammatory/reactive changes and the discrimination between high grade dysplasia and adenocarcinoma. Current data, however, show much higher interobserver agreement in endoscopic resection specimens than in biopsies. Nevertheless, the histological diagnosis of dysplasia should be corroborated by an external second opinion because of its clinical consequences. In endoscopic resections of early Barrett's adenocarcinoma, the pathological report has to include a risk stratification for the likelihood of lymphogenic metastases.     

Air column in esophagus and symptoms of gastroesophageal reflux disease

Background

During imaging of the normal esophagus, air is often detected. The purpose of this study was to determine the correlation between the appearance of air bubbles on imaging and Gastroesophageal Reflux Disease (GERD) symptoms.

Methods

The cross-sectional imaging study was conducted at Rasole Akram Hospital, Tehran, Iran. A total of 44 patients underwent X-ray computed tomography (CT) scanning; the presence of air in the esophagus and visible on CT imaging was scrutinized.

Results

The average age of the subjects was 59 and the male to female ratio was 0.83. We found a significant relationship between the presence of GERD symptoms, the size of air bubbles and esophageal dilation (ED) on the CT scan.

Conclusions

Air bubbles in the esophagus may be seen frequently in CT scans, but their size and location can vary. The GERD symptoms can arise when a small diameter air column is present within the esophagus, especially in the middle and lower parts.