Update in Pathogenesis, Treatment of GERD

Gastroesophageal reflux disease (GERD) is the most common disease of the gastrointestinal tract, affecting up to 40 percent of the entire population on a monthly basis. Patients may develop symptoms of GERD at any age, but it is particularly troublesome in the elderly. Although heartburn and regurgitation are the hallmark symptoms of GERD, many other associated symptoms or complications may impair quality of life, including chest pain, hoarseness, weight loss, asthma, chronic cough, pneumonia, otitis media and atypical loss of dental enamel.^1-6 Studies have confirmed a strong relationship between the development of Barrett’s esophagus, esophageal adenocarcinoma and a prolonged history of frequent and severe acid reflux.⁷ GERD has also been linked with sudden infant death syndrome.^8,9 Not all gastroesophageal reflux produces clinical symptoms, however, and spontaneous acid reflux not associated with symptoms is described as “physiologic reflux.”

Pathogenesis of GERD

Gastroesophageal reflux (GER) is often described as retrosternal burning and regurgitation produced by the reflux of chyme (acidic gastric contents) from the stomach into the esophagus. GERD describes the symptoms and tissue injury related to this acid reflux condition. The development of GERD is the consequence of disturbed motility of the upper gut principally related to inappropriate relaxation of the lower esophageal sphincter.¹⁰ These inappropriate sphincter relaxations are most common during the daytime and when upright. Patients of any age can experience GER, but the risks for developing GERD or lower esophageal sphincter dysfunction increase with age. Other risk factors included obesity, gender, smoking, caffeine use, high fat intake, increasing abdominal pressure, vomiting, coughing and weight lifting.¹¹

There are many factors that affect lower esophageal sphincter pressures. These factors include the function of intrinsic and extrinsic nerves, neuropeptides and circulating hormones. Extrinsic nerves of the lower esophageal sphincter have parasympathetic and sympathetic properties, and these nerves mediate the movement of the esophagus in peristaltic waves. In this way, the upper esophageal sphincter and the lower esophageal sphincter relax simultaneously to clear or move food from the esophagus. The muscles within the wall of the esophagus consist of striated and smooth muscles. Striated muscles are dependent on excitatory nerve activity, and an increase in nerve activity increases the lower esophageal sphincter pressure. Likewise, a decrease in nerve activity decreases the lower esophageal sphincter pressure, thus causing the sphincter to relax and allow acid to reflux. Tonic vagal or parasympathetic nerves exert an excitatory affect in the smooth muscle by the postganglionic cholinergic neurons.

Hormones may also affect the function of the lower esophageal sphincterpressure. Excitatory hormones include gastrin, motilin and bovine pancreatic polypeptide. The action of these excitatory hormones is to increase the lower esophageal sphincter pressure. Inhibitory agents include secretin, cholecystokinin, glucagon and gastric inhibitory peptide. In addition to these hormones, prostaglandins also reduce the lower esophageal sphincter pressure. Not only do hormones affect the function of esophageal motility, they also regulate gastric acid production. Specifically, histamine, gastrin and acetylcholine all promote gastric acid secretion. Prostaglandins, on the other hand, are derivatives of arachidonic acid and have an inhibitory effect on gastric acid secretion. If the level of prostaglandins is decreased, as occurs with the use of antiinflammatory medications such as aspirin or NSAIDs, then gastric acid production is increased.^12-13

Other factors contributing to GERD include the presence of a hiatal hernia that separates the lower esophageal sphincter from the support of the diaphragm and serves as an “acid trap” and delays esophageal peristalsis. Reduced esophageal peristalsis and decreased saliva production may worsen symptoms of GERD in some patients because of the loss of the acid-neutralizing effect of saliva. This may particularly be important in patients with autoimmune disorders or who have previously undergone radiation treatment. Delayed gastric emptying (gastroparesis) also worsens GERD. This occurs because gastroparesis prolongs the period of time during which reflux may occur and by increasing the acidity of chyme. In the setting of gastroparesis, patients are quite susceptible to worsened GERD symptoms after eating certain fatty foods. This is because the digestion of fat is much slower than protein digestion. In the duodenum, the bile excreted from the liver enzymes and from the pancreas forms products of fat digestion. This results in the secretion of cholecystokinin. Cholecystokinin inhibits gastric motility and decreases gastric emptying so that fats are not emptied into the duodenum at a rate that exceeds the rate of bile production and enzyme secretion. Osmoreceptors within the wall of the duodenum are sensitive to the osmotic pressure of the duodenal contents. Osmoreceptors are activated when gastric contents are either hyper or hypotonic. Equalizing the gastric acid facilitates an iso-osmotic duodenal environment. Secretions from the pancreas, liver, and duodenal mucosa in conjunction neutralize the duodenal gastric acid,¹² thus affecting the motility rate of acids and foods through the gastrointestinal tract. So increased dietary intake of fat decreases gastric motility, which, in turn, increases the gastric acidity. Increasing the gastric acidity increases the risk, incidence and severity of reflux within the gastroesophageal junction.^14,15

Esophagitis, Barrett’s Esophagus and Esophagus Adenocarcinoma

Damage to the lining of the mucosa caused by GERD is usually manifested by presence of esophagitis, Barrett’s esophagus or esophageal cancer. The mucosal tissue of squamous epithelium lining the esophagus is exposed to mucus and saliva with a normal pH level of 6.0. If the acid exposure within the esophagus drops the pH level to less than 4.0, erosions and tissue damage occurs. If the chyme is highly acidic or contains bile salts and pancreatic enzymes, then reflux esophagitis damage can be severe. While the squamous epithelium of the esophagus is very sensitive to acid-induced injury, the columnar epithelium of the stomach covered with a thick layer of mucus is able to withstand constant exposure to acid and chyme at a pH level of 1.0. The point at which the esophagus meets the stomach is called the gastroesophageal junction or the squamo-columnar junction. This junction is also where the lower esophageal sphincter is located. When working correctly, the lower esophageal sphincter exerts a pressure of 10-20mmHg. This pressure keeps the gastroesophageal junction closed and prevents acid refluxing up into the esophagus.¹⁶

Prolonged exposure of the squamous lining of the esophagus to acid refluxate will cause cellular injury. As these injured cells die, replacement cells develop within the glands within the wall of the esophagus. Barrett’s esophagus occurs when a stomach-like (intestinal-type) mucosa replaces the normal esophageal mucosa that has been damaged by acid reflux.¹⁷ The incidence of Barrett’s esophagus is rapidly increasing and is the major risk factor for the development of esophageal adenocarcinoma. The development of cancer usually occurs in a progression from normal cells to hyperplastic cells, meaning there is an increase in the number of cells as a result of cellular division. Metaplasia describes the reversible replacement of one mature cell type by another type, as occurs with the development of Barrett’s esophagus. As these cells become more distorted with abnormal cell shape, size and organization, the term dysplasia is used to describe the development of pre-cancerous changes. The pre-cancerous changes of dysplasia are graded as minor (low-grade dysplasia) or advanced (high grade dysplasia). Advanced changes of Barrett’s highgrade dysplasia are generally thought to ultimately lead to the development of esophageal adenocarcinoma.^10-18

Treatment of GERD, Complications

There are several nursing considerations regarding the care of a patient with GERD including lifestyle modifications such as elevating of the head of bed more than six inches, not eating for at least three hours prior to lying down, eating smaller evening meals and reducing dietary fat and caffeine intake. Managing weight, quitting smoking and avoiding medications that decrease lower esophageal sphincter pressure or produce esophageal irritation can also reduce reflux-associated symptoms. Lying on the left side may also help complications related to severe reflux while sleeping.^11,15

The medical management of GERD was revolutionized by the development of histamine type 2 receptor blockers (H2 blockers) in the late 1970s. H2 blockers inhibit the histamine-stimulated secretion of gastric acid. These agents, such as cimetidine, ranitidine, famotidine and nizatidine, are available today without prescription. Even in prescription strength, however, they are only able to control acid reflux in patients with mild disease.

Proton pump inhibitors irreversibly block the hydrogen ion pumps located in the parietal cell membrane. Their action prevents hydrogen ion production and reduces the acidity within the stomach. Reducing the acid within the stomach reduces high acid exposure causing a decrease in reflux incidence. The decrease in reflux permits healing of all but the most severe cases of esophagitis. These drugs provide more complete control of gastric acid than the H2 blockers and are the most effective agents in the medical therapy of GERD.^19,20 Proton pump inhibitors are generally given once or twice a day, 30 to 60 minutes prior to a meal, as are H2 blockers. Although these drugs perform similar functions, proton pump inhibitors and H2 blockers are sometimes used in conjunction with each other.²¹

Since the underlying problem in GERD is dysfunction of the lower esophageal sphincter, these medical treatments are considered to be “quick fixes” or “Bandaids ®” that mask the fundamental problem. Despite very effective control of GERD symptoms, these medications do not address the malfunction of the lower esophageal sphincter or presence of a hiatal hernia. In this regard, surgical management may be considered superior to drug therapy for treatment of reflux symptoms. Fundoplication, performed either by the open approach or laparoscopically, is the most common surgical treatment. The fundoplication procedure is the wrapping the stomach fundus around the distal esophagus at the level of the gastroesophageal junction. This wrap can be a complete 360- degree fundoplication (Nissen) or a partial, 279-degree fundoplication (Toupet). Thewrap produces external support and tightening of the lower esophageal sphincter and reduces the hiatal hernia. After fundoplication, most patients are able to significantly reduce or discontinue pharmacological therapy. In approximately one-third of patients, however, fundoplication may be complicated by symptoms of dysphagia, inability to belch, and bloating with excessive flatulence or diarrhea.²² Post-operative dysphagia generally responds well to endoscopic dilation although treatment of other symptoms is more problematic. Fundoplication is contraindicated in patients with dysplastic Barrett’s esophagus as surveillance endoscopy may not be reliable and the metaplastic tissue may not heal easily after a trauma to the lining causing harmful complications.^23,24

Recently, endoscopic anti-reflux procedures have been devised and approved for use²⁵. The most advanced of these techniques is the Stretta procedure, a minimally invasive GERD therapy that was approved by the FDA in 2000. This endoscopic procedure, performed under conscious sedation, delivers temperaturecontrolled radiofrequency energy to the gastroesophageal junction producing heat-induced collagen shrinkage and wound healing.²⁶ Clinical trials of the Stretta procedure, including a sham-controlled study, have confirmed significant improvement in GERD symptoms and significant decreases in esophageal acid reflux and medication use.^27-33 The Stretta procedure appears to represent an important advance as a minimally invasive endoscopic treatment alternative to lifelong drug therapy and anti-reflux surgery³⁴. Additional minimally invasive techniques including endoscopic suture and injection techniques have been approved and are currently in use.³⁵ Among the contraindications for these procedures are the presence of Barrett’s dysplasia, large hiatal hernia, poor esophageal peristalsis and inability to tolerate endoscopic procedures. The complication profile of these procedures appears similar, including transient swallowing problems and chest discomfort.^27-31,36

Gastroesophageal reflux disease is a common and serious condition. While most patients have typical symptoms of heartburn and regurgitation, others may have atypical symptoms such as chest pain, pulmonary or head and neck symptoms. GERD can be associated with a spectrum of esophageal mucosal changes including normal mucosa, esophagitis, Barrett’s esophagus and adenocarcinoma.

Although this disease is associated principally with abnormalities of the lower esophageal sphincter, the major emphasis of drug therapy is suppression of gastric acid. Current medical and surgical treatments are very effective in healing esophagitis and controlling GERD symptoms in most patients. Endoscopic, minimally invasive techniques such as the Stretta procedure represent an important advance in the treatment of GERD.

Shannon Mercer, RN, is an experienced gastrointestinal endoscopy registered nurse and SGNA member who enjoys endoscopy-based clinical research. Her areas of special expertise include invasive procedures such as photodynamic therapy and endoscopic anti-reflux techniques such as the Stretta procedure.

Herbert Wolfsen, MD, FACP, FACG, is an associate professor of medicine who serves as the director of the esophageal disease clinic. As director of photodynamic therapy, he has treated more than 80 patients with early esophageal cancer or Barrett’s high-grade dysplasia since 1997.

Did You Know?
Simply elevating the head of the bed four to six inches and sleeping on the left side can dramatically reduce reflux pain at night. Lying on the right side puts pressure on the lower esophageal sphincter, while lying on the left side shifts the stomach slightly lower than the sphincter, thus allowing stomach contents to flow more quickly into the small intestine and reducing the ability of acid to reflux up the esophagus.