Pathophysiology of Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a maladaptive esophageal condition that develops from the reflux of ingested foods or stomach contents into the esophagus. GERD is estimated in approximately 10-20% of Western society, but diagnostic rates are elevated on a global scale (Badillo and Francis, 2010). Bhatia et al (2011) analyzed 3,224 questionnaires from 12 health care centers in India and estimated that 245 of those participants experienced symptoms of GERD at least once a week. In Japan, Fujiwara and Arakawa (2009) carried out a systematic review and noted a steady increase in GERD since 1990. Of the 42 studies reviewed, data revealed a 52.1% prevalence of reflux conditions in the Japanese sample. In western culture, reflux disease is classified into two types: erosive reflux disease (GERD) or non-erosive reflux disease (NERD). Differences noted between GERD and NERD are the lack of damage to the esophageal lining and responsiveness to pharmacological interventions in patients with NERD. The most prevalent form of GERD is the erosive category (Badillo and Francis, 2010).

Gilger et al (2008) reported 12.4% of 402 children that underwent upper esophageal endoscopies were found to have erosive esophagitis linked to GERD symptoms. Despite higher diagnosis of GERD in adults, manifestations are noted to be more severe in children. Acute, unmanaged GERD in children has shown to progress to cerebral palsy, esophagus related birth defects, and chronic lung disease (Gilger et al, 2008). Although behavioral issues, such as obesity, have contributed to the development of GERD in adults, in children this correlation is not clearly defined. Elitsur, Dementieva, Elitsur, and Rewalt (2009) analyzed body mass indices (BMI) of 738 children meeting full criteria for GERD based on histological lab results. The authors failed to find a correspondence between the child’s weight and GERD. However, the data collected demonstrated a slightly higher incidence of GERD in males than females.

 In adults, heartburn, regurgitation, chest pain, and dysphagia are all symptoms that provide indications of GERD. However, the two most common issues reported are heartburn and regurgitation. Symptomatology is categorized on a spectrum of typical, atypical, and extraesophageal manifestations. Heartburn and regurgitation are considered typical symptoms, but atypical symptoms have ranged from epigastric pain, dyspepsia, nausea, bloating, or belching. Extraesophageal symptoms are defined as issues that have developed because of GERD. Examples of extraesophageal symptoms include chronic coughing, asthma, laryngitis, and dental decay (Badillo and Francis, 2010). The present paper will focus on the physiological implications relevant to reflux disease to provide an understanding of symptomatology and treatment interventions. 

Pathophysiology

The Lower Esophageal Sphincter

The lower esophageal sphincter (LES) is a bundle of circular muscle fibers that separate the esophagus from the stomach. Distal to the esophagus, the LES is approximately 2-5 centimeters in length, horizontally. The objective of the sphincter is to retain stomach contents from reaching the esophagus and permit ingested foods into the stomach. Neurologically, the LES can send sensory messages to the brain via spinal and vagal afferent cells. Spinal messages indicate damage or danger to the LES, whereas vagal transmissions to the brain include non-threatening information (Sidhu and Triadafilopoulos, 2008).

The sphincter works in unison with the gastric sling and diaphragm; other bodily structures located distal to the throat. Systematization of these parts is needed for the maintenance of the “high-pressure zone” or the pressure that maintains closure of the LES. Patients with GERD are reported to have little complications with pressure maintenance. However, GERD is a result of spontaneous sphincter loosening, also known as transient lower esophageal sphincter relaxation (TLESR) (Sidhu and Triadafilopoulos, 2008). Babaei, Bhargava, Korsapati, Zheng, and Mittal (2008) investigated causes of TLESR by measuring pressure frequencies and using ultrasounds to view the LES during voluntary and involuntary sphincter relaxations. Voluntary relaxation was defined as the LES opening when eating and swallowing and involuntary was correlated with random weaknesses. The authors reported that TLESR may be attributed to longitudinal muscle contractions in the esophagus. Contractions recorded began before the sphincter relaxed, were more powerful than voluntary contractions, and sustained duration as the sphincter remained weak. Failure of the sphincter to protect the esophagus from damaging contents, such as stomach acid, has altering effects on one’s esophageal composition.

Sidhu and Triadafilopoulos (2008) hypothesized that diet may play a role in TLESR. GERD symptoms are correlated with increased body mass index (BMI) and obesity. Diets in the United States with increased consumption of saturated fat are reported to boost episodes of TLESR. Time of day meals are consumed has also been linked to sphincter relaxation. It is recommended not to eat at least two hours prior to bedtime. Laying down puts one’s body in a position that prevents healthy regurgitation.

Anatomy of the Esophagus

Aversive effects and damage caused by GERD symptoms and malfunction of the sphincter can be explained by the anatomy of the esophagus. The esophagus is compiled of four core layers. The outermost layer is referred to as the adventitia, composed of blood vessels and muscle tissues. Muscularis, the second layer, contains tightly bound muscle tissues including both striated and smooth muscle types. The final two layers of the esophageal wall are the submucosa and the mucosa. The submucosa serves the purpose of connecting the mucosa to the three outer layers through blood vessels and glands (National Institutes of Health, 2018).

Mucosal lining is composed of stratified squamous epithelium cells (Triantos, Koukias, Karamanolis, and Thomopoulos, 2015).  Bove, Vieth, Dombrowski, Ny, Ruth, and Lundell (2005) explored the effects of acid exposure to epithelium lining by examining biopsies of lower esophageal samples exposed to acid (pH <4) for 30 minutes compared to samples without. Participant’s with GERD were noted to have denser basal cell layers within mucosa than individuals without GERD. The authors also reported that thickened layers formed immediately following exposure and created changes that the epithelium sustained.  The mucosa’s general function is to protect the throat. Prolonged acid in in the esophagus signals the mucosa to release mucus as a protective mechanism (Triantos, Koukias, Karamanolis, and Thomopoulos, 2015).

Diagnosing

 GERD symptoms are hazardous to the mucosal lining of the esophagus. Patients that have presented with symptoms of GERD are advised to seek treatment right away. Health care providers can provide diagnosis of the condition through various testing. Lacy et al (2010) reviewed gastroenterology literature from 2008 and described diagnostic tools used by gastroenterologists (G.I.).

 Heartburn and regurgitation are the two most prevalent conditions associated with GERD. Sometimes, physicians can diagnose based on symptom presentation alone. Self-report questionnaires can be paired with symptom presentation. The Gastroesophageal Reflux Questionnaire (GERQ) is used by many G.I. providers. The GERQ contains 22 questions that are related to common GERD symptoms and patient and family history (Lacy et al, 2010). Typical symptoms have responded to pharmacological treatment without prior testing. This is the most cost-effective intervention. Symptoms unimproved from empirical therapy, such as proton pump inhibitor (PPI) trials, are subject to further examination (Badillo and Francis, 2014).

 More severe, atypical symptoms must be watched closely. G.I. specialists monitor the amount of acid in the throat with ambulatory pH monitoring through a wireless capsule or catheter. The capsule is implanted in the mucosal lining of the lower esophagus and sends information to a device attached to the patient’s clothing or belt. The catheter is more restricting and uncomfortable for patients but offers extra abilities; catheter monitoring can detect non-acid reflux for patients with NERD. The wireless capsule has a long-term monitoring life, but the catheter can only be placed for 24 hours (Badillo and Francis, 2014).

 Upper endoscopies, or using a camera to view the patient’s esophagus, is another alternative for individuals with severe GERD symptoms. Endoscopies have determined whether damage to the throat from prolonged acid exposure has occurred. It is not common to have an endoscopy to confirm a diagnosis of GERD, but for conditions such as Barrett’s esophagus or esophageal adenocarcinoma that are attributed to GERD.

Treatment

 Severe diseases related to GERD symptoms can be avoided when acid reflux is managed. Mentioned briefly above, medication therapy is widely used and cost-effective. Minor GERD can be treated with over-the-counter antacids. Examples of an antacid are Tums and Mylanta (Mayo Clinic Staff, 2018). Antacids do not suppress stomach acid, but balance its acidity level (Fock, Ang, Bee, and Lee, 2012). More severe cases of GERD can be treated with prescribed medications that reduce stomach acid production.

 Fock, Ang, Bee, and Lee (2012) discussed proton pump inhibitors (PPIs); acid reducers with immediate, irreversible effects. PPIs permanently alter parietal cell membranes in the stomach to lessen acid secretion. PPIs are offered to individuals experiencing symptoms two or more times a week. Binding to the hydrogen-potassium pumps of stomach cells, PPIs were reported most effective at alleviating heartburn than the alternative medication, histamine-receptor antagonists (H₂RAs) (Sigterman, Van Pinxteren, Bonis, Lau, and Numans (2013). PPIs initiate parietal cell’s conversion from acid catalysts to reactive species. Expanding on the benefits of PPIs, Badillo and Francis (2014) indicated an increased healing of damaged esophageal lining in patients prescribed inhibitors as opposed to H₂RAs.

 Histamine 2 receptor antagonists are offered to patients with both symptoms of GERD and NERD. Examples of H₂RAs are Pepcid AC and Zantac. Compared to over-the-counter antacids, histamine 2 antagonists are considered metabotropic and decrease symptoms from 4 to 10 hours.  Like PPIs, H₂RAs attach to histamine receptors of parietal cells to block the cell’s acid production. Different from PPIs, H₂RAs have a short half-life and are not recommended for individuals with severe esophageal damage. Compared to placebo trials, H₂RAs had increased healing rate, but in comparison to PPIs, H₂RAs were not effective (Kahrlias, 2018).

 Considering the pathophysiology of GERD and the malfunction of the LES, some agonists have been studied to eliminate sphincter weakness. Sidhu and Triadafilopoulos (2008) studied the effect of Baclofen, a GABA-b agonist, in patients with GERD. It was previously stated that the sphincter is controlled through both spinal and vagal connections. Baclofen has been shown to inhibit vagal message transmission which decreases sphincter relaxation. In clinical trials, this drug has been used with other appropriate PPIs or H₂RAs.

 Aside from pharmacological interventions, individuals with recurrent GERD may be referred for surgical techniques. Surgery is extended to patients with a noncompliance with medications, individuals that have experienced aversive side effects to drugs, recurring acid exposure or esophagus damage, and hiatal hernias (Badillo and Francis, 2014). According to Sidhu and Triadafilopoulos (2008), laparoscopic fundoplication is performed when patients fail to respond to acid reducing medications.  This is a two-hour surgery in which a piece of the stomach is wrapped around the failing sphincter to stop acid reflux. Richter (2013) indicated a low mortality rate for this anti-reflux surgery, but some postsurgical complications are possible. Aversive effects include bloating, dysphagia, diarrhea, and heartburn, but patients stated issues improved between three- and six-months following procedures.

Untreated GERD

 Without proper treatment, GERD can develop into more serious conditions. Barrett’s esophagus is the “specialized intestinal replacing the squamous epithelium of the esophageal mucosa in response to gastroesophageal reflux”. Barrett’s name is derived from the British physician, Norman Barrett, that noticed columnar cells in the lower esophagus of a patient. Healthy esophageal mucosa is composed of squamous epithelium. Columnar cells in the mucosa convert from squamous cells through a process called metaplasia. As a protective mechanism, cells in the esophagus convert to cells similar to our stomachs to withstand prolonged exposure to stomach acid. Increased metaplasia becomes dangerous because it increases the occurrence of dysplasia, or rapid cell growth. Consequently, the esophagus attempts to protect itself from acid exposure escalades the opportunity for esophageal adenocarcinoma to occur (Gulliem, 2005).

 GERD is a common, but serious condition that occurs when stomach acid and contents backflow into the esophagus. Reported in both children and adults, malfunctions of the lower esophageal sphincter (LES) are attributed most to the pathophysiology of GERD. Heartburn and regurgitation are the most prevalent symptoms presented in primary care and gastroenterology settings.  To avoid damage to the mucosal lining of the esophagus, PPIs, H2RAs, or surgical techniques can be utilized to decrease acid secretion or stop acid reflux entirely. Prolonged exposure of stomach contents to healthy squamous epithelium induces the conversion of squamous to columnar cells and conditions such as Barrett’s esophagus or esophageal adenocarcinoma. Familiarity with GERD and its symptoms should be considered by all individuals working in a health care setting. Managed GERD decreases the risk of fatal conditions and improves patient’s quality of life.

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