Surprise Cause of Gastritis Revolutionizes Ulcer Treatment
by Ricki Lewis, Ph.D.

     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 Dr.
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 stem 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:
fl    All patients examined who are infected with the bacteria have
evidence at the tissue level of gastritis (inflammation), but most
are asymptomatic.
fl    Clearing up the infection cures the gastric inflammation.
fl    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.

Diagnosis
     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.

Treatment
     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." 

Ricki Lewis is a geneticist and writes college biology textbooks.

Can the Ulcer Bacterium Also Cause Cancer?
     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. 

--R.L.