Q. Have newer therapies helped GERD patients?
A. New pharmaceutical agents have changed the situation dramatically for these patients. We can achieve far greater degrees of acid suppression with the proton pump inhibitors (PPIs) (omeprazole, lansoprazole, and the newest agent, rabeprazole) than we could with the H2 blockers (cimetidine, ranitidine, etc.), and since acid suppression is key, this is a major advance. The reason for this increased acid suppression is that while H2 blockers only block one of the three known receptors (for histamine, acetylcholine, and gastrin) on the gastric parietal cell, the PPIs block the hydrogen-potassium ATPase-dependent pump at the parietal cell’s luminal border. This pump is the final common pathway for gastric-acid generation, and it is therefore much harder to override. Despite initial concerns about long-term safety of the PPIs due to reports of development of gastric carcinoids in rats, these data have not been borne out in humans. No carcinoids have been reported, and PPIs are now considered eminently safe enough for long-term use.
Prokinetic agents produce an increase in LES tone, which, along with acid suppression, plays a key role in bringing reflux under control. Cisapride, a prokinetic agent currently obtainable only under strict research guidelines, has essentially been withdrawn from the market because of cardiac side effects, especially when used with certain other medications. Like metoclopramide, cisapride is a peripheral dopamine antagonist; unlike metoclopramide, it does not cross the blood-brain barrier and hence does not cause central nervous system side effects. The problem with both prokinetic agents is that while they raise basal LES pressure, they probably do little to abolish completely the intermittent relaxation of the LES. They may attenuate it, however, and transient LES relaxation is probably the more important mechanism in producing GERD symptoms.
Q. Which therapies are considered first line?
A. I prefer to use a PPI as a first-line agent. For one thing, the patient feels better more quickly, and presumably, healing gets under way faster. For another, the prokinetic agent may not be treating the reflux completely, given what we know about chronic versus intermittent LES relaxation. I usually reserve a prokinetic agent for the patient in whom a PPI has helped—but not completely—and especially if there is overnight symptomatology, in which case a bedtime dose of metoclopramide can be useful. I often use metoclopramide first, however, in the patient whose major symptom is belching, hiccups, or regurgitation without acid heartburn.
Q. Are there new drugs on the horizon?
A. No new agents are currently being developed, except for the second-generation PPIs. Domperidone, a motility agent available in Canada, may be useful in some patients, but it is unlikely to be marketed in the United States anytime soon.
In our rush to embrace newer medications, we often forget about those dietary and lifestyle modifications that are an important part of the therapeutic armamentarium. Patients should be counseled to avoid certain foods (coffee, chocolate, alcohol, fried fatty foods, garlic, onions, and peppermint) that tend to decrease lower esophageal tone and thus favor reflux. Cigarette smoking should also be proscribed. Elevating the head of the bed during sleep takes advantage of gravity to help lessen nocturnal reflux. Patients should also be advised against the use of nonsteroidal anti-inflammatory agents, both prescription and OTC. Despite these precautions, however, most symptomatic patients will require the use of pharmacologic agents for some period of time.
Q. When is surgery an option?
A. Surgery should be considered for patients who fail to respond to dietary/lifestyle changes and medical therapy, who have documented reflux either endoscopically or by pH probe, and who have adequate esophageal motility. The surgery is a fundoplication, in which the upper end of the stomach is wrapped around the distal esophagus to create a sphincter mechanism to prevent further reflux. The ability to perform this procedure laparoscopically has been a major advance in its utility. Surgery is not acceptable in patients with GERD complicated by stricture and is not sufficient in Barrett’s esophagus. In addition, patients should undergo preoperative esophageal manometry to determine that they have adequate esophageal peristalsis.
Q. How does Barrett’s esophagus fit into the GERD picture?
A. In Barrett’s esophagus, variable lengths of the distal esophageal mucosa (normally consisting of stratified squamous epithelium) have been replaced by columnar epithelium of the type typically found in the stomach. These changes are seen as a chronic consequence of reflux. Recent guidelines from the American College of Gastroenterology narrow the definition by requiring intestinal metaplasia in the columnar segment for the diagnosis. This is important because the intestinal metaplasia is thought to be the keystone in the progression of this lesion to adenocarcinoma, and it is this progression that lends import to identifying Barrett’s in the first place. Barrett’s may occur in short-segment (within 3 cm of the gastroesophageal junction) or long-segment (extending >3 cm from the junction) variants. Interestingly, the presence of intestinal metaplasia on the gastric side of the gastroesophageal junction is associated with H. pylori infection but not with reflux or adenocarcinoma.
Q. Will all Barrett’s result in cancer?
A. No. It is clear that not all Barrett’s leads to cancer, but the incidence of adenocarcinoma of the esophagus in patients who have long-segment Barrett’s is 30-60 times that of the general population. Long-segment Barrett’s esophagus occurs in three to five percent of symptomatic GERD patients undergoing endoscopy. Given the abysmal survival statistics with this malignancy, the development of a Barrett’s lesion in GERD must be taken very seriously.
Q. How does one screen for Barrett’s?
A. All chronically symptomatic GERD patients should undergo one screening endoscopy, given the downside of missing the diagnosis. If no Barrett’s is found, patients need be rescreened only if symptoms change in nature or intractability or at some defined date in the future, such as a 10-year interval—although there is no consensus on this recommendation. If Barrett’s is found but no dysplasia is noted on biopsy, repeat endoscopy should be done in one year. If those results remain negative for dysplasia, then endoscopy should be repeated every two to three years thereafter. The presence of low-grade dysplasia would warrant endoscopy in six months, and then yearly. High-grade dysplasia should be confirmed by an independent pathologist. If confirmed, I would favor definitive therapy: elective resection or, in some cases, photoablation of the mucosa. Less desirable is patient commitment to endoscopic surveillance every three months.
Q. What is the preferred treatment?
A. At present, surgery is the standard. Photoablation is an exciting and innovative approach, and patient acceptance is certainly much greater than with distal esophagectomy. However, photoablation is still a relatively new procedure that requires further experience, and we still don’t know which method (Nd:YAG laser, argon laser, photodynamic therapy, etc.) is best. Photoablation may well become the treatment of choice in the near future. It is worth noting that following ablation of the mucosa, healing is pH-dependent: In an acid environment, repair is with columnar epithelium, while in an alkaline environment, repair is with squamous epithelium. Therefore, acid-suppressive therapy obviously remains an important adjunct.
Q. What issues are most important about GERD?
A. The recognition that some patients with chronic GERD will develop cancer is cause for reasoned concern but not panic. Patients should be assessed endoscopically to define individual risk, with treatment and surveillance based on those results. Most patients will improve on medical therapy, and those who do not may be offered surgery. Education is key to ensuring that patients are recognizing and reporting symptoms so that appropriate therapy is instituted. The iceberg will never melt as long as most of it remains submerged in freezing waters.