The main symptoms of gastroesophageal reflux consist of heartburn or epigastric (upper abdominal) discomfort, regurgitation of food or liquids particularly when bending over or laying down, and with more advanced disease there may be enough injury to the esophagus to produce a stricture or scar, and this can produce dysphagia. Dysphagia refers to the sensation that food is hanging up or not passing down into the stomach properly. Other causes for dysphagia include a motility abnormality of the esophagus as well as the development of a cancer or other growth within the esophagus. Gastroesophageal reflux disease is a significant problem for millions of Americans. While many people get by with relatively minor dietary or lifestyle modifications, others require medication to control their symptoms. Often thought to be a benign, or non-life threatening condition, we now know that gastroesophageal reflux disease can not only produce a very poor quality of life, it can also be the direct cause of a problem that can claim a person's life. One of these problems is the development of pulmonary fibrosis. This can occur as a consequence of repetitive aspiration episodes which occur when gastric juice is regurgitated up and spills into the windpipe. At USC several patients have required lung transplantation for end-stage lung disease secondary to chronic gastroesophageal reflux. An even more significant problem is the potential for the development of Barrett's esophagus and adenocarcinoma of the esophagus in patients with chronic gastroesophageal reflux. Consequently, at USC we believe that gastroesophageal reflux disease should be taken seriously, and anyone with more than the occasional episode of heartburn or regurgitation, and in particular anyone with dysphagia, should be evaluated. While many patients may be successfully treated long-term with medical therapy, others will be best served with an antireflux procedure which restores the function of the lower esophageal sphincter and allows a return to normal eating and lifestyle habits.

The Challenges of Restoring Lower Esophageal Sphincter Function

The fact that the incidence of adenocarcinoma of the esophagus and cardia are increasing at a rate faster than any other malignant tumor in the United States gives new urgency to the Thoracic-Foregut team's interest in gastroesophageal reflux and Barrett's metaplasia. Previous studies have shown that chronic reflux disease is directly related to the development of Barrett's metaplasia, and longitudinal studies have demonstrated progression from Barrett's metaplasia to dysplasia to carcinoma-thereby linking the common problem of gastroesophageal reflux disease with one of the most lethal malignancies known to mankind.

Studies on the natural history of gastroesophageal reflux disease indicate that most patients who have limited disease respond to simple lifestyle, dietary and medical therapy, and do not go on to develop complications. However, approximately 25 percent of patients with reflux disease will develop recurrent or progressive disease. It is this population of patients who are best suited to surgical therapy, and for whom an antireflux procedure provides the only effective long-term therapy.

Consequently, the challenge for the Thoracic-Foregut Group at USC is to educate physicians and patients about the risk posed by gastroesophageal reflux disease and long-term dependence on acid suppression therapy, and to offer surgical solutions that can reduce the risk of Barrett's metaplasia and improve the quality of life for these patients. Indeed, an interest in gastroesophageal reflux disease lies at the core of the Thoracic-Foregut Group; each member is involved in understanding, diagnosing and treating diseases directly related to reflux.

The Pulmonary Connection

The typical symptoms of reflux disease include heartburn, indigestion and stomach pain. However many patients have what are referred to as respiratory symptoms, including aspiration, chronic cough, hoarseness-even asthma. The esophagus, stomach and pharynx are intimately related to the lungs, from the beginning of our development in the womb. As a result of the close relationship between the esophagus and windpipe, pulmonary and foregut disease should be considered together.

Chronic aspiration of gastroduodenal juice, which typically occurs at night when patients are Iying down and reflux can come up more freely, can severely damage the lungs and vocal cords. Some patients will actually wake up hoarse. Long-standing aspiration can even cause pulmonary fibrosis, and in rare cases lead to the need for lung transplantation. In fact, a number of patients who have had lung transplantations at USC University Hospital have also undergone antireflux procedures to avoid further pulmonary complications resulting from reflux disease.

There is a relationship between asthma and reflux disease; in some situations reflux disease can actually cause the asthma, particularly adult-onset asthma. In other cases the reflux can potentiate existing asthma, making it difficult to control. In yet other cases, the asthma, because it causes exaggerated pulmonary dynamics, magnifies the pleural and abdominal pressure differential, encouraging reflux. So there is a "chicken and egg" problem.

Many physicians do not recognize chronic cough or severe asthma as a symptom of reflux, and may not identify it as such unless they specifically ask the patient. While patients' symptoms of heartburn may go away with medical therapy, the respiratory symptoms continue because nothing is being done to stop the reflux from occurring. Thus, it is important for physicians to consider the possibility of reflux disease when treating patients with these pulmonary problems.

Focus on the Stomach

The Thoracic-Foregut team believes that future research on gastroesophageal reflux will focus more on the stomach. "We are probably at the same level of understanding of the stomach today as we were about the esophagus 20 or 30 years ago," says Dr. Crookes. "In actuality, the stomach is more complex than the esophagus. And the world is filled with people who complain of stomach problems yet their physicians often attribute their ailments to nerves or stress. Although some of this may be true, stomach problems represent an entire area of medicine that requires more research."

To better understand the physiology of the stomach, Dr. Crookes is developing a tool called the barostat to measure the tone of the stomach and its ability to relax. This procedure involves placing a tightly rolled up balloon at the end of a catheter and placing the balloon into the stomach. The balloon is then filled with air and maintains the pressure in the stomach. As pressure increases in the stomach, a certain amount of gas in the balloon will escape, providing insight into what is occurring to the tone of the stomach.

Dr. Bremner is also interested in focusing his research interests on the pyloric sphincter, which is how the pylorus (the lower part of the stomach) communicates with the duodenal portion of the small intestine. He views the lower esophageal sphincter and the pyloric sphincter as "inseparable." To understand the workings of the lower esophageal sphincter, it is necessary to consider the role of the pyloric sphincter. "I think many cases of reflux can be attributed to incompetence of the pyloric sphincter, allowing duodenal contents to come up into the stomach and eventually reflux up into the esophagus," Dr. Bremner notes. "Research in this area would certainly further our understanding of gastroesophageal reflux disease."

Barrett's Esophagus

Barrett's esophagus is a condition caused by chronic gastroesophageal reflux. In this condition the normal squamous (skin-like) mucosa of the esophagus is changed to an intestinalized columnar (intestine-like) mucosa. The diagnosis of Barrett's esophagus requires that an endoscopy is performed and a biopsy taken. Endoscopy in a patient with Barrett's esophagus shows that the normal pale-white squamous mucosa has changed to a reddish mucosa, typically in the lower portion of the esophagus. On biopsy columnar cells with goblet cells indicative of intestinal metaplasia must be seen in order for a diagnosis of Barrett's esophagus to be made. Columnar cells without goblet cells is not Barrett's esophagus. The importance of identifying Barrett's esophagus is that it is pre-malignant, and most cases of esophageal cancer arise from Barrett's esophagus.

Anyone with long-standing (5 or more years) of reflux symptoms is at risk to have or develop Barrett's. White males with reflux symptoms are at particular risk. Interestingly, the Barrett's mucosa seems to be less sensitive to acid, and consequently reflux symptoms may improve with the development of Barrett's esophagus. Any difficulty swallowing in association with reflux symptoms is concerning as it may herald the presence of a stricture or tumor. Those patients known to have Barrett's esophagus should be enrolled in an endoscopic surveillance program to watch for any progression of the Barrett's on to cancer.

Gaining New Insight into Reflux Disease and Barrett's Esophagus

The link between reflux disease and Barrett's esophagus has been known for some time. However, recent research by members of the Thoracic-Foregut Group into the actual contents of the reflux has resulted in some fascinating findings. Their research has shown that about 50 percent of people reflux both gastric (acid) and duodenal (bile) contents- and these individuals are the patients who tend to get Barrett's metaplasia, as opposed to those people who only reflux acid. (Annals of Surgery, October 1995, Vol. 222, No. 4, 523-533). Members of the Thoracic-Foregut Group took this research one step further. "When we caused the reflux of both bile and acid in animal models," says Dr. DeMeester, "we found a high incidence of both Barrett's and adenocarcinoma. In addition, this research indicated that when acid is not present in the reflux, the incidence of tumors dramatically increases-indicating that the noxious agent in reflux is duodenal juice, and that acid can play a protective role. The animals that had acid present had a lower incidence of tumors." (Annals of Surgery, September 1996, Vol. 224, No. 3).

These findings have important ramifications for those who depend on acid-suppression therapy, which may ease the symptoms of reflux but does not address the cause of the problem-thereby allowing reflux to injure the esophageal lining year after year. Chronic acid-suppression therapy may not be in the patient's best interest if he or she has both acid and duodenal juice in the reflux, because the acid suppression unleashes the duodenal contents, perhaps placing the patient at increased risk for Barrett's or adenocarcinoma. Chronic acid suppression also reduces one's protection against the ingestion of bacteria. Not only does acid help with digestion, but it also protects us from food contaminated with bacteria. So if you shut off the acid, you have a higher chance of contracting an intestinal infection.

Another consequence of these findings relates to what Dr. DeMeester refers to as the "bile-acid" sink. Dr. DeMeester explains that "in most cases nature has used acid as a protective mechanism against our own bile-one of the components of duodenal juice." In fact, bile has always posed many mysteries as it can be very detrimental to the body in its dissolvable form, but when it comes back into the acid environment of the stomach, it flocculates out like sand and cannot be redissolved - even if the pH levels are changed. "However, he says, " if you shut the acid down by taking a medication, or if you have so much bile coming back that you neutralize the acid, then you increase the pH and it doesn't precipitate out. It stays in solution and can cause destruction of the esophageal lining, and may even induce metaplasia."

Dr. DeMeester believes that for these reasons, the increasing reliance on powerful acid suppression medication is directly linked to the rise in Barrett's esophagus and the cancer related to it. Although he is concerned that increasing availability of over-the-counter H 2 blockers may exacerbate the problem even further, he cautioned that the acid- suppression therapy link with Barrett's is not necessarily a cause-and- effect relationship. "However," says Dr. DeMeester, "all the data we have on lung cancer and smoking is based on the same kind of relationship, and I cannot dispense this relationship as being unimportant."

A Biomechanical Malfunction

As complex as the reflux issue appears, the solution is relatively straightforward because reflux and its complications are actually caused by a biomechanical malfunction. The pharynx, esophagus and stomach are basically mechanical organs. They don't absorb food or nutrients but rather are designed to function in the process of ingestion -taking in the food and preparing it for the small intestine, where absorption becomes the important function. Thus, the solution to the problem of reflux is to correct the mechanical problem through surgery. Antireflux procedures such as Nissen fundoplication re-establish the barrier between the esophagus and stomach, and keep both gastric and duodenal juice out of the esophagus, abolishing the environment that places patients at risk for Barrett's metaplasia.

The Nissen Fundoplication procedure is used to construct a new valve between between the stomach and the esophagus when there is normal motility of food and normal esophageal length. The stomach is pulled up and around the esophagus, then secured around the esophagus, and the valve is then placed into the abdomen below the diaphragm.

Surgical solutions call for a greater understanding of biomechanics of ingestion, and this interest extends to the stomach. Thoracic-Foregut team members are beginning to focus on the stomach and its function in the process of ingestion, as it may be another factor in the increasing incidence of Barrett's metaplasia in the cardia, the very end of the esophagus where it meets the stomach. Normally when we eat, our stomach goes through the process of active relaxation where the stomach and surrounding abdominal muscles of the belly relax, allowing food to enter without increasing pressure within the stomach. However, in some instances, a combination of overeating and slow gastric emptying (which can result from a very high intake of fatty foods) causes the sphincter or valve between the esophagus and stomach to become shorter-much like the shortening of the neck of a balloon as it is filled with air. As the sphincter becomes shorter, it is taken up by the distending stomach-exposing its lining to gastric juice-and damaging the lower rim of the sphincter from the gastric juice that is bathing it.

Minimally Invasive Surgical Approaches to Treat Reflux Disease

In the past, an open surgical procedure was necessary to surgically stop gastroesophageal reflux in patients with severe disease. Today this can be done laparoscopically. Small ports are pushed through the belly wall (about five are used). One contains a video camera and shows the surgeon the inside of the abdomen. This allows the defective valve between the esophagus and stomach to be augmented without opening the abdomen. Much of the work in laparoscopic Nissen fundoplication was pioneered at USC. Designed to reconstruct the valve between the stomach and esophagus to eliminate gastroesophageal reflux, the surgery entails a complete 360-degree fundoplication where the upper stomach is folded around the lower esophagus. The procedure takes approximately two hours and patients can return home one or two days after the operation.

A Tailored Approach to Surgery

The Thoracic-Foregut Group at USC takes a tailored approach to antireflux surgery. While some patients with severe reflux disease may benefit from the laparoscopic Nissen fundoplication, a transthoracic Nissen may be more appropriate in patients with normal esophageal body function and questionable esophageal length or obesity. For abnormal esophageal body function with normal esophageal length, a partial fundoplication may be appropriate. This procedure only brings the fundus 270 degrees around the esophagus. For short esophageal length, a Collis gastroplasty (using part of the stomach to add length to the esophagus) and constructing a fundoplication over the added "neo-esophageal" segment represents the optimal approach.

To determine if a surgical approach is appropriate, and, if so, which one, the Thoracic-Foregut Group at USC depends upon the expertise of the Esophageal Function Laboratory.

A variety of tests can be performed at this state-of-the-art facility, located adjacent to USC University Hospital. These tests include esophageal manometry, which measures the pressures in the tubular portion of the esophagus and the valve between it and the stomach; 24 hour esophageal pH/bile monitoring to identify the contents of the reflux; and upper Gl endoscopy.

"We recently acquired a manofluorography machine, which correlates esophageal pressures with video X-rays as the patient swallows barium, to more accurately diagnose the problem within the esophagus," notes Sue Corkrill, R.N., nurse coordinator for the lab. "All of these tests help the members of the Foregut-Pulmonary Group determine if the patient's problem can be corrected surgically or should be managed with medical therapy.