Surprise cause of gastritis revolutionizes ulcer treatment


Mention "ulcer" and most people envision a stressed-out, workaholic, junk-food-gobbling worrywart. Since the turn of the century, ulcers have been equated with stress and poor diet. But that image may be substantially incorrect. Now, the medical community is beginning to look at painful ulcers in a new light--as an easily treatable bacterial infection. The name of the bug--Helicobacter pylori.

For many of the 4 million ulcer sufferers in the United States, the new view of ulcers may mean a course of antibiotics. This treatment may reduce recurrence to below the 10 to 15 percent a year for current, non-antibiotic drug therapies. In ulcer sufferers who receive no treatment, recurrence is up to 80 percent.

"Now there is the possibility of curing the condition, which was unthought of before," says Hugo Gallo-Torres, M.D., medical officer in the Food and Drug Administration's division of gastrointestinal and coagulation drug products.

The agency is considering particular combinations of drugs for ulcer treatment, following conclusions of a consensus development conference convened by the National Institutes of Health in February 1994. The conference gathered experts to review data accumulating since 1983 implicating bacteria in causing ulcers. The drugs under consideration aren't new, but their use to treat ulcers is.

Anatomy of an Ulcer
Sufferers describe an ulcer as a burning, cramping, gnawing, or aching in the abdomen that comes in waves, for three to four days at a time, but may subside completely for weeks or months. Pain is worst before meals and at bedtime, when the stomach is usually empty. The ulcer itself is an open sore in the lining of the stomach (gastric ulcer) or in the upper part of the small intestine, or duodenum (duodenal ulcer). Both types are also called peptic ulcers.

The stomach is the most acidic part of the body, setting the stage both for ulcer development and infection. Three types of cells pump out the ingredients of gastric juice: mucous-secreting cells, chief cells that release digestive enzymes, and parietal cells that produce hydrochloric acid. The mucous-secreting cells also produce histamine, which stimulates the parietal cells to release acid. The stomach needs the acid environment for the digestive enzyme pepsin to break down proteins in foods.

Acidity is measured using the pH scale. A neutral pH is neither acid nor base--it has a value of 7: acids are less than 7, and bases (also called alkaline substances) are greater than 7. Many body fluids, including blood, tears, pancreatic juice, and bile, are in the 7 to 8 pH range. Gastric juice, in contrast, has a pH of 1.6 to 1.8. That's more acidic than lemon juice, cola drinks, and coffee. The environment in the small intestine is far less acidic than in the stomach, but because it receives the acidic mixture of semi-digested food from the stomach, it is prone to ulceration too.

The stomach's innermost lining, the mucosa, protects it from digesting itself. The mucosa consists of lining cells, connective tissue, and muscle. An ulcer hurts when it penetrates the mucosa into the underlying submucosa, which is rich in nerves and blood vessels.

A vat of churning acidic goop may not seem a hospitable place for a microbe, but the type that causes ulcers thrives in the low pH environment. "They have outgrowths called flagella that allow them to penetrate the mucus layer of the stomach, where the pH is more tolerable. Eradicating these bacteria is not simple," says Gallo-Torres. The antibiotic drug must be able to kill the bacteria, yet also resist breakdown in the acidic surroundings.

Researchers aren't certain how people acquire the bacteria. However, person-to-person transmission is believed to be the most likely route in developed countries. In developing countries, fecal-oral transmission may play a more important role, similar to the way a person contracts cholera and hepatitis A.

Early in the 20th century, the prescription for an ulcer was bed rest and a bland diet, in a hospital if the patient could afford it. Antacids were added to the treatment regimen when researchers learned that ulcer patients produce excess stomach acid. By 1971, the control site of acid secretion was identified--histamine (H2) receptors on the parietal cells.

When histamine binds such receptors, acid output increases. Four approved ulcer drugs--Zantac (ranitidine), Tagamet (cimetidine), Pepcid (famotidine), and Axid (nizatidine)--block H2 receptors, thwarting the signal to secrete acid. A second type of ulcer drug, called an acid- or proton-pump inhibitor, works at a different point in digestion, blocking parietal cells from releasing acid. Prilosec (omeprazole) is the only acid-pump inhibitor approved in the United States at this time.

The problem with existing drugs is that they only temporarily improve symptoms; the ulcer is likely to return. If bacteria causing some ulcers are eradicated, however, the likelihood of ulcer recurrence is much less because the problem is attacked at its source. But acceptance of the role of bacteria in the production of peptic ulcer disease has been slow.

Discovering the Infection Connection
In 1982, two young Australian physicians, Barry J. Marshall and J Robin Warren, isolated bacteria from patients with ulcers or gastritis (stomach inflammation). In a paper published in the medical journal Lancet in early 1983, they proposed that a spiral-shaped bacterium, later named Helicobacter pylori, causes gastritis and possibly ulcers. But few physicians accepted their work, so entrenched was the idea that ulcers stern from stress. So Marshall and Warren took drastic measures to prove their point--they swallowed some of the bacteria. And their digestive tracts soon became inflamed.

But most of the medical community felt this was not sufficient proof to definitively implicate the bacteria in causing ulcers. A medical dictionary published in 1986, for example, lists the causes of ulcers in order of importance as high acid, irritation, decreased blood supply to the digestive tract, decreased mucus, and last, with a question mark, infection.

"We had treated ulcers with anti-secretory compounds for so many years, it was hard to accept that a germ, a bacterium, would produce a disease like that. It took a while. Even academicians were not convinced. Gradually other people found the same thing," says Gallo-Torres.

The accumulating evidence became the basis of the February 1994 consensus development conference, which concluded: "Ulcer patients with Helicobacter pylori infection require treatment with anti-microbial agents in addition to anti-secretory drugs."

In a nutshell, the evidence for the link between bacteria and ulcers is that:

All patients examined who are infected with the bacteria have evidence at the tissue level of gastritis (inflammation), but most are asymptomatic.
Clearing up the infection cures the gastric inflammation.
Giving the bacteria to laboratory animals (and Warren and Marshall) causes gastritis.
However, even though nearly all people who are infected develop gastritis, not all develop ulcers. This suggests that other factors--such as heredity, diet, stress, and other environmental influences--may be important for the development of peptic ulcers. According to the consensus development report, "the strongest evidence for the pathogenic role of H. pylori in peptic ulcer disease is the marked decrease in recurrence rate of ulcers following the eradication of infection."

How common are bacterial ulcers? The consensus report estimates that "almost all" duodenal ulcers are attributable to H. pylori, as are about 80 percent of gastric ulcers, making the microbes a very major cause. A very small percentage of ulcer sufferers develop ulcers from using aspirin or a nonsteroidal anti-inflammatory drug (NSAID) such as Voltaren (diclofenac), Feldene (piroxicam), or Ansaid (flurbiprofen). Ibuprofen, also an NSAID, is less likely to cause gastric inflammation.

For ulcer patients, diagnosis and treatment are changing.

Several different tests detect H. pylori. "You can biopsy [take tissue samples of] gastric and duodenal mucosa, then culture bacteria and identify them. But this approach is not very sensitive because it depends upon where you biopsy," says Gallo-Torres.

To sample stomach or intestinal tissue, a physician snakes a lighted tube called an endoscope down through the throat. Less invasive techniques are available, too. Blood tests can detect IgG antibodies to H. pylori in a person's blood, representing the immune system's response to the microbe. These tests are cleared for marketing by FDA.

Other diagnostic tests in development, but not yet evaluated by FDA, are based on the ability of H. pylori to break down urea, human metabolic waste, with an enzyme called urease, which humans do not produce. Elevated levels of breakdown products of urea, detected in a person's breath after drinking chemically labeled urea, indicate H. pylori infection.

Quite a few helpful drugs are already on the market, though they are not approved for treating ulcers. FDA's role now is to wade through studies, old and new, to identify the best combinations of drugs, a process that was under way when this issue of FDA Consumer went to press. FDA is also considering new drugs to treat bacterial ulcers.

"We would really like to inform physicians quickly and also evaluate the data. There are many regimens proposed," says Gallo-Torres.

The consensus development conference examined several treatment plans. Its report said that there had been extensive studies of bismuth subsalicylate (better known as Pepto Bismol), an antiprotozoan drug, Flagyl (metronidazole), and either the antibiotic tetracycline (giving an overall 90 percent cure rate) or amoxicillin (with an overall 80 percent cure rate).

According to the consensus development report, there had been one study of another regimen, consisting of amoxicillin, metronidazole and ranitidine, that showed a 90 percent effective rate. However, all of these approaches require a patient to take several different pills several times a day. The committee reported that a two-drug alternative, consisting of amoxicillin, taken four times a day, and Prilosec (omeprazole), taken twice a day, offers 80 percent effectiveness. However, at press time FDA had not verified these regimens.

Clearly, doctors will have many choices. But at the time of the conference, only 1 to 2 percent of U.S. physicians were treating an ulcer as they would a bacterial infection, according to the conference report.

Concluded conference member Daniel K. Podolsky, M.D., of Massachusetts General Hospital, "These recommendations represent a sea change in how we approach this problem. From this time forward, I would consider use of these drugs to be essential ."

As data confirming the bacteria-ulcer link continue to pour in, medical researchers are already asking questions that will form the basis of future studies: What factors cause bacterial gastritis to develop into an ulcer? Do children have bacterial ulcers? Can the new treatments prevent complications, such as bleeding ulcers? Does H. pylori cause stomach cancer, and, if so, can we prevent it? (See accompanying article.)

Meanwhile, the future of current ulcer sufferers looks brighter than ever. Says consensus team member Ann L.B. Williams, M.D., of George Washington University Medical College, "We now have an opportunity to cure a disease that previously we had only been able to suppress or control."

DIAGRAM: Bacteria and Ulcers

Spiral-shaped Helicobacter pylori bacteria attach to the surface epithelial cells of the stomach lining after eating a hole in the mucus layer that normally protects the lining from gastric juice. Gastritis results and a peptic ulcer may develop.


By Ricki Lewis, Ph.D.

Ricki Lewis is a geneticist and writes college biology textbooks.

It's been known for several years that people with a form of stomach cancer called gastric carcinoma are very often infected with H. pylori, and there is evidence that the infection precedes the cancer. More recently, researchers linked the microbe to a second type of stomach cancer, called primary gastric lymphoma.

This second type of malignancy affects lymphoid tissue--antibody-producing cells in the stomach. However, such cells are not normally present in the stomach unless there is an infection.

In the May 5, 1994, issue of The New England Journal of Medicine, a multi-center team led by Julie Parsonnet, M.D., of Stanford University, reported that people with gastric lymphoma also have H. pylori infection, and that the infection precedes the cancer. In an accompanying editorial, Peter G. Isaacson, D.M., of University College London Medical School, suggests that the bacterial infection initiates a chain reaction leading to cancer. He suggests that first infection causes chronic gastritis; then, the inflammation causes stomach lining tissue to overgrow; and, ultimately, excess growth may blossom into cancer, given some as-yet unidentified environmental trigger or genetic susceptibility.

But, so far, the link between H. pylori and cancer is far more tenuous than that between the bacteria and gastritis or ulcers. Fewer than 1 percent of people infected with the microbe develop cancer, and some populations in which many people are infected have very low stomach cancer rates. These facts, researchers say, suggest that several factors are at play. Still, it will be interesting to see if antibiotic/anti-secretory treatment can reduce incidence of these already rare cancers.

The consensus development conference convened to study H. pylori in February 1994 concluded, "if there is any causal relationship between H. pylori infection and gastric cancer, clearly other facts are also important." They recommend further study into whether eradicating the infection can prevent cancer.

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