Repeated bouts of heartburn might signal bigger problems down the line.

STOMACH BACKGROUND: ARTVILLE

In any given month, about one-quarter of Americans suffer from heartburn, which is caused by reflux, or backward flow, of stomach acid into the esophagus. We may take a little antacid and that’s the end of it. Sometimes, however, heartburn can be cause for worry; less commonly, it can be cause for serious concern. Recent studies illustrate the full scope of this condition and show that it is not always as innocuous as it may seem. One study describes a promising technique that may prevent an esophageal cancer associated with heartburn, while other studies may direct researchers to the genetic underpinnings of the precancerous and cancerous changes in the esophagus that may be associated with heartburn.

Stomach Upset
Cells (specialized columnar epithelia) in the stomach lining produce dilute hydrochloric acid for use in the digestive process. At the same time, other gastric columnar epithelia produce the mucus that coats the stomach and protects it from digestion. When we consume and swallow food, it passes through the esophagus and into the stomach, where distension triggers acid production. The acid mixes with the food and begins the digestive process. Eventually, the stomach begins passing small portions of the food–acid mixture into the small intestine, where alkaline secretions—bile—from the liver raise the pH toward neutrality. The food–acid–bile mixture, called chyme, continues through the digestive tract in that near-neutral state.

The esophagus is a simple tubular organ but lacks mucus-producing cells. Instead, it is protected from acid by a doughnut-like ring of muscle at the point where the esophagus passes through the diaphragm and empties into the stomach. That ring—the esophageal sphincter—is normally tightly closed except when it allows the downward passage of swallowed food or drink into the stomach. Stomach acid that passes upward into the esophagus despite the sphincter can injure the unprotected surface and cause the pain that we call heartburn. The normal inner lining of the esophagus is composed of layers of thin flat cells called squames. This lining, or squamous epithelium, can resist the heat and cold and the mechanical wear and tear associated with swallowing food and drink, but it cannot withstand hydrochloric acid no matter how dilute.

The Pink Cure
On occasions when the esophageal sphincter allows stomach acid to reflux into the esophagus, a simple and effective treatment is antacid. But what about cases in which heartburn is more than an occasional irritation? Studies have shown that fatty foods, chocolate, alcohol, and tobacco can decrease the pressure of the esophageal sphincter and cause heartburn. Similarly, obesity increases pressure in the abdomen and can encourage reflux. Rare causes of reflux can be neurological, where the swallowing process is poorly coordinated, or structural, where a stricture of some sort interferes with swallowing.

In the past, those who suffered recurrent heartburn were treated with antacid alone—the more severe the heartburn, the more antacid they consumed. Of course, patients were advised to avoid offending foods, alcohol, and tobacco, and many patients discovered that elevating the head of their bed would greatly relieve their symptoms. The H2 histamine receptor antagonist drugs such as cimetadine (Tagamet, Smith Kline Beecham Consumer) and famotidine (Pepcid, Merck) greatly decreased and sometimes eliminated recurrent heartburn. The more recently discovered proton pump inhibitor drugs, such as omeprazole (Prilosec, AstraZeneca) and lansoprazole (Prevacid, TAP Pharmaceuticals), also shut down acid production and are equally effective in treating heartburn. Surgery has sometimes been useful to prevent reflux in the minority of heartburn sufferers who are not helped by medication and those with mechanical problems that prevent the normal function of the esophageal sphincter.

A Cancer Connection?
Untreated or inadequately treated reflux can lead to erosive esophagitis—ulceration and bleeding of the esophagus—which, long-term, can cause esophageal scarring and strictures. Medical practitioners have long suspected that gastro-esophageal reflux disease and the erosive esophagitis it causes lead to esophageal cancer. Before the advent of the flexible endoscope, direct visualization of the lower esophagus was only possible during surgery or by means of the difficult-to-use rigid endoscope. During surgery to treat esophageal cancer, it was often noted that a condition known as Barrett’s esophagus accompanied the cancer.

Barrett’s esophagus is a condition in which the normal squamous cells of the esophagus are replaced by columnar epithelia similar to those of the stomach or intestine. Visually, Barrett’s esophagus is marked by a darker color than the normal, pale pink esophageal lining and by a different texture. Is there a connection between these conditions?

No more than 4 persons per 100,000 are stricken with esophageal cancer each year, but for them, it is a dire diagnosis—5-year survival, even today, is optimally 15%. Early on, researchers examined many avenues for preventive measures for this difficult-to-treat cancer. Since reflux appeared to be associated with this cancer, studies were begun treating the reflux vigorously in hopes of preventing the cancer. Other studies using the newly available flexible endoscope were designed to follow numerous patients with reflux, Barrett’s esophagus, or both. The flexible endoscope allows direct visualization and biopsy of the esophageal lining over a period of time. These studies could clarify the natural history of heartburn, esophagitis, Barrett’s esophagus, and esophageal cancer. Additionally, the researchers could directly visualize the effects of various treatment programs to determine which, if any, are beneficial.

Heartburn to Barrett’s to Cancer?
One study, performed by researchers at Sweden’s Karolinska Institute, Uppsala University, and Falu Hospital, looked at all Swedish patients who were diagnosed with esophageal or gastric adenocarcinoma (cancer of the columnar epithelia) or esophageal squamous cell carcinoma from 1995 to 1997. These patients and a control group were evaluated carefully for a history of heartburn. The 189 patients with esophageal adenocarcinoma and 262 with gastric adenocarcinoma represent 85% of the total number of Swedes with such cancers. The control group consisted of 820 people without cancer and 167 with esophageal squamous cell carcinoma.

Detailed interviews of all study participants showed a higher incidence of adenocarcinoma of the esophagus in those with a history of heartburn or reflux. The greater the severity of the heartburn, the higher the incidence of cancer. The most severe heartburn imposed a 40-fold increase in cancerous conversion. There was a similar though less pronounced (4-fold) relationship between heartburn and gastric adenocarcinoma. Cancer originating in the squamous cells of the esophagus, however, was not associated with reflux. Unexpectedly, only 62% of those with esophageal adenocarcinoma also had Barrett’s esophagus. However, those who did not have Barrett’s esophagus showed the same strong relationship between reflux and cancer as those with Barrett’s esophagus. Does this mean that Barrett’s esophagus is not necessarily a step between reflux and esophageal adenocarcinoma?

It may mean that long-term reflux onto the normal squamous epithelium of the esophagus can cause the conversion to the columnar epithelium of Barrett’s esophagus. In some cases, the columnar epithelium of Barrett’s esophagus will progress directly to adenocarcinoma; in others, Barrett’s esophagus persists before eventually turning cancerous. Many of the people in this study who developed esophageal cancer had been treated for their heartburn, so the question of whether vigorous treatment of heartburn will prevent cancer awaits further studies.

Photodynamic Help
Meanwhile, a British study was investigating possible ways to eliminate Barrett’s esophagus and thus perhaps prevent the cancers that ensue. Researchers at Sheffield University and Central Sheffield University Hospitals used photodynamic therapy to destroy the columnar epithelium of Barrett’s esophagus without harming normal squamous epithelium. In photodynamic therapy, a compound that absorbs light of a specific frequency is introduced into the body’s tissues. If the compound can be preferentially concentrated in cancerous tissues, then exposure to a concentrated light beam of that wavelength will release energy within the cancerous cells and kill them. The researchers gave half of their 36 patients exhibiting Barrett’s esophagus oral 5-aminolevulinic acid and the other half a placebo. The photosensitive compound occurs naturally in human metabolism and is absorbed preferentially by epithelial tissue. Four hours later, using an endoscope, laser light at a wavelength of 514 nm was directed onto the Barrett’s epithelium in all of the subjects.

All patients were examined endoscopically and biopsied at intervals of 1, 6, 12, and 24 months after treatment. Sixteen of the 18 patients given 5-aminolevulinic acid showed regression of the columnar epithelium of Barrett’s esophagus as typified by a 10–60% reduction in the affected area. By comparison, 16 of the 18 patients given placebo had no regression of columnar epithelium, while the remaining 2 showed 10% regression.

The Future
This group and others continue to investigate photodynamic therapy as a safe, minimally invasive way to destroy the columnar epithelium of Barrett’s esophagus. It may prove possible to prevent esophageal adenocarcinoma in those found to have Barrett’s esophagus. Meanwhile, other researchers are investigating genetic defects found in the cells of Barrett’s esophagus and may ultimately find a way to prevent the transformation from squamous epithelium to columnar epithelium and the cancer caused by seemingly simple heartburn.

Further Reading

• Armstrong, D. Lancet 2000, 356, 610–612.
• Jankowski, J. A.; Harrison, R. F.; Perry, I.; Balkwill, F.; Tselepis, C. Lancet 2000, 356, 2079–2085.
• Lagergren, J.; Bergström, R.; Lindgren, A.; Nyrén, O. New Engl. J. Med. 1999, 340, 825–831.
• Macdonald, C. E.; Wicks, A. C.; Playford, R. J. Brit. Med. J. 2000, 321, 1252–1255.
• McGarrity, T. J. Brit. Med. J. 2000, 321, 1238–1239.

Clyde M. Burnham is a freelance health writer living in Denver. Send your comments or questions regarding this article to tcaw@acs.org or the Editorial Office 1155 16th St N.W., Washington, DC 20036.