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Sun 1 Jul 2007 12:00 AM

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Peptic ulcers and bacterial infections

Knowledge about the cause of peptic ulcers is increasing, enhancing doctors' ability to treat them.

Quiz your patients on the causes of peptic ulcers, and most are likely to point to stomach acid, spicy foods, alcohol, and coffee as the common culprits. They may be surprised when you inform them that actually food and drink have nothing to do with ulcers.

Up to 3% of Americans with HP go on to develop peptic ulcers in the stomach or duodenum.

In the last two decades, doctors have gained a lot more knowledge about the causes of peptic ulcers - knowledge that has helped improve the efficiency of both diagnosis and treatment.


Peptic ulcers have plagued men throughout the centuries, but the exact cause of the condition was uncertain. In 1940, Dr. A. Stone Freedberg of Harvard Medical School identified unusual curved bacteria in the stomachs of ulcer victims; he suspected that they might be responsible for ulcers but abandoned the research when his team was unable to grow the bacteria in the lab.

Doctors went on treating patients with diet modifications, antacids, and operations for the next 40 years. But in the early 1980s, two Australian physicians, Dr. Barry J. Marshall and Dr. J. Robin Warren, discovered how to culture the bacterium in the laboratory.

Next, they tried to infect experimental animals. It's a traditional step in microbiological research, but it failed because their bacterium, now called Helicobacter pylori (HP), can infect only humans.

Dr. Marshall responded to two years of scientific frustration by taking the dramatic step of drinking a vial of fluid laced with about a billion bacteria. A week later, he developed stomach symptoms; after another 10 days, a gastroscopy showed that his stomach tissue was acutely inflamed and teeming with HP. Fortunately, Dr. Marshall recovered fully and continued his research. And both men were alive and well on October 3, 2005, when their pioneering research was rewarded with the Nobel Prize in Physiology or Medicine.

Meet the ulcer bug

HP is the only bacterium that can survive - and thrive! - in the stomach. The bug has several properties that explain its unique adaptation.

First, it needs only a tiny amount of oxygen, about a fifth of the amount humans need. Second, its spiral shape allows it to burrow through the mucus that covers the stomach lining. Third, it has up to seven whiplike proteins that project from the end of the bug and propel it through the mucus. Fourth, it has special receptors that permit it to latch onto stomach cells once it makes its way through the mucus.

HP has another property that is the most important of all. It can split molecules of urea, a chemical that's present in human tissues and fluids. The process releases ammonia and carbon dioxide, which form a cloudlike mantle around the bacterium, protecting it from the stomach acid that kills ordinary bacteria.

This ability to split urea is a big plus for HP, but doctors have turned it to their own advantage by developing the urea breath test to diagnose the infection (see section overleaf: ‘Diagnosis').

Who gets HP?

According to the best estimate, about half the world's population is infected with HP, making it the most common bacterial infection of humans. Because the organism spreads only in food or water that has been contaminated by infected human faecal material, HP infection is most common in regions with crowded living conditions, poor hygiene, and inadequate sanitation. In developing countries, the prevalence approaches 80%, but only 30% of Americans carry the bug. Even in the United States, the rate varies with socioeconomic status and age; up to 50% of senior citizens have HP that they acquired in childhood, when life was harder, but only 20% of young adults harbour HP.

How HP harms

Unlike strep or staph, which are often carried on the skin or in the throat without causing inflammation, HP always triggers inflammation, in this case stomach inflammation, gastritis. The bacterium produces a variety of toxins that stimulate white blood cells to produce small proteins (cytokines) that perpetuate the inflammatory cycle. Strains of HP that contain a specific gene, cagA, are most virulent. However, not even this nasty strain ever spreads from the stomach lining to other parts of the body.

Although everyone who harbors HP has at least some degree of gastritis, the great majority have no symptoms and remain well. But in the course of a lifetime, up to 3% of Americans with HP go on to develop peptic ulcers in the stomach or duodenum (the portion of the intestines just beyond the stomach), and a much lower percentage develop stomach cancer or the low-grade stomach lymphoma known as MALT.

Smoking increases the risk of ulcers and cancers related to HP, and it also makes antibiotic treatment more difficult. Diets high in salt, smoked foods, and preserved foods boost the risk of cancer, but foods that provide vitamin C and other antioxidants appear to reduce the risk.
Since HP is so common, it's not surprising that doctors have tried to blame it for a variety of other conditions. After many years, HP infection can lead to atrophic gastritis, a condition in which the stomach lining becomes thin and does not produce enough acid to liberate vitamin B12 from food. More controversial is the possible link between HP and non-ulcer dyspepsia, the fancy name applied to patients who have ulcer-like symptoms (such as upper abdominal pain, early fullness, bloating, and nausea) without having ulcers.

At present, the weight of evidence suggests that treating HP does not alleviate the symptoms of non-ulcer dyspepsia, whereas treatment is extremely effective for true ulcer symptoms. Doctors agree that HP does not cause gastroesophageal reflux disease (GERD; "heartburn"); the controversy here relates to whether HP may actually protect against GERD by diminishing stomach acid.

The ‘gold standard’ test requires an endoscopy and stomach biopsy.

Some evidence has also linked HP to other disorders, ranging from iron deficiency anemia to skin and blood problems, low levels of HDL ("good") cholesterol, and atherosclerosis. More research is needed to determine if any of these associations are valid.


The easiest way to diagnose HP is with a blood test that can detect the antibodies that form in response to the infection. Despite its convenience, the blood test has two drawbacks. First, it cannot discriminate between an active infection that is causing disease and a simmering infection that is not producing symptoms.

Second, the blood test cannot tell if treatment has produced a cure, since antibodies linger in the blood long after HP has been eradicated. Still, if antibody levels are very high before treatment, they suggest active infection, while a sharp reduction after therapy suggests success.

Two other noninvasive tests allow doctors to diagnose active HP infection and test for cure with great precision. The newer test detects bacterial proteins in a stool specimen.

About 94% of patients with active HP infection have a positive stool test - and if treatment is successful, nearly all will have negative tests one to four weeks after therapy.

The old standby is a test that depends on HP's ability to split urea. The urea breath test is safe, accurate, and fairly quick - and since it detects only active bacteria, it can be used to test for cure.

Most patients who are suspected of having HP can be diagnosed with one of these three noninvasive tests. But the oldest test for HP is an invasive procedure that remains the gold standard. Indeed, endoscopy was used to document Dr. Marshall's self-induced infection in 1984. All patients who are at risk for stomach cancer should undergo endoscopy; alarming symptoms that call for endoscopy are listed in the box below .

Before an endoscopy, the patient is given a sedative and his throat sprayed with a local anesthetic. Next, doctors pass a fiberoptic tube through his mouth into his stomach. They inspect the stomach lining and perform biopsies. For rapid diagnosis, the tissue sample can be tested for the HP enzyme that splits urea.

Using a microscope and special stains, pathologists can look for the bacterium itself in the stomach tissue. Although it's usually not necessary for diagnosis, microbiologists can grow HP in the laboratory and test its susceptibility to various antibodies.

Other causes of ulcers

Forget stress and diet. There are only three proven causes of ulcers. HP is the most common. Another is very rare: Gastrinomas are tumors of the pancreas or duodenum that stimulate extreme overproduction of stomach acid and ulcers. The final cause is much more common. Nearly all ulcers that are not caused by HP are related to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and many others. All of these medications can cause inflammation, ulceration, or bleeding, especially in elderly people. Most experts believe that HP infection increases the risk of NSAID-induced ulcers, but some research suggests the opposite.

Get an infection, take an antibiotic, and enjoy a cure. That's the way it works for many bacteria - but not HP, which has the nasty ability to become resistant to antibiotics. Fortunately, doctors can outwit their adversary by using combination therapy. Many programs are available; all require two antibiotics plus one or two acid-neutralisng drugs. Here are some of the medications commonly recommended.

Amoxicillin (many brands). This penicillin derivative is more active than similar medications because it is secreted into the gastric fluid. It is usually prescribed for HP in a dose of 1,000 mg twice a day. Major side effects include rashes and diarrhoea.

Clarithromycin (Biaxin). This member of the erythromycin family is one of the most effective drugs for HP;0 a typical dose is 500 mg twice a day. Major side effects include an unpleasant taste, nausea, and diarrhoea. It's also rather expensive.

Metronidazole (Flagyl).Once uniformly effective against HP, emerging bacterial resistance has led many doctors to use it only for patients who cannot take amoxicillin.

A typical dose for HP is 500 mg twice a day. The major side effects include an abnormal taste sensation, nausea and loss of appetite, headache, and, less often, nerve irritation. No one should drink alcohol while taking metronidazole.

Tetracycline (many brands). Usually prescribed in a dose of 500 mg four times a day, tetracycline is most often used in combination with other drugs for patients who have failed first-line treatment. Its major side effects in men include rashes, a sensitivity to sunlight, and bouts of diarrhoea.

Omeprazole (Prilosec, generics). The first proton-pump inhibitor, omeprazole dramatically reduces stomach acid. It has no direct effect on HP, but it increases the efficacy of antibiotics. The usual dose for HP is 20 mg twice a day during antibiotic therapy. An occasional side effect of omeprazole is dizziness.

Many newer proton-pump inhibitors are available and can be substituted for omeprazole in appropriate doses.

Bismuth subsalicylate (Pepto-Bismol). Although not an antibiotic, bismuth is able to kill HP in the stomach. Always used with two antibiotics, the usual dose is two tablets four times a day. The only common side effect is dark-coloured stools.

Ranitidine bismuth citrate (Tritec). This newer drug combines ranitidine (Zantac), which has been used for years to reduce stomach acid, with bismuth, which has antibacterial activity. The drug cannot eradicate HP on its own. Most patients respond well when it is given in a dose of 400 mg twice a day along with other medications. Side effects are uncommon.

Many treatment regimens are available; they are safe and effective, but tend to be unpleasant and relatively expensive. Until recently, 10- and 14-day programs were standard, but many physicians now prefer 7-day programs. The most popular one administers amoxicillin, clarithromycin, and omeprazole for 7 to 14 days. A second plan substitutes metronidazole for amoxicillin but is otherwise similar. Another approach administers tetracycline, metronidazole, bismuth, and omeprazole for two weeks. And many other regimens have been advocated by experts in the United States and Europe.

Evidence suggests that HP has coexisted with humans for thousands of years, but doctors have known about it for a relatively brief time. Scientists have learned a lot more since the pioneering research of Dr. Marshall and Dr. Warren, but many questions remain unanswered.

At a glance: Warning symptoms

Doctors can use noninvasive blood, stool, or breath tests to diagnose HP infections. The ‘gold standard' test, however, requires an endoscopy and stomach biopsy. Most patients prefer noninvasive tests, but certain warning symptoms increase the likelihood of stomach cancer. As a result, patients with these red flags should undergo endoscopy without undue delay.

Here are some of the warning symptoms that call for aggressive diagnosis:

• Onset of symptoms after the age of 50

• Family history of gastric cancer

• Intestinal bleeding

• Abdominal mass

• Difficulty swallowing

• Persistent vomiting

• Unexplained weight loss

• Anemia

• Persistence or return of symptoms after treatment.

This article is provided courtesy of Harvard Medical International. © 2007 President and Fellows of Harvard College.

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