Peptic Ulcers

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Peptic Ulcers

WHAT ARE PEPTIC ULCERS?

A peptic ulcer is an open sore or raw area on the lining of the stomach (gastric ulcers ), or on the upper part of the small intestine, which is called the duodenum ( duodenal ulcers ). They average between one-quarter and one-half inch in diameter. In the US, duodenal ulcers are three times more common than gastric ulcers.

Ulcers develop when digestive juices damage the lining of the stomach or duodenum. Digestive juices, most importantly hydrochloric acid and the enzyme pepsin, are produced by the stomach, intestines, and digestive gland. They break down and digest the starch, fat, and protein in food.

The stomach and duodenum, however, are composed mostly of protein so they can also be damaged by these acids and enzymes. To protect against these powerful substances the body has certain defense systems:

The mucous layer, which coats the stomach and duodenum, forms the first line of defense.
The body secretes bicarbonate into the mucous layer, which neutralizes the acid.
Hormone-like substances called prostaglandins help keep the blood vessels in the stomach dilated, ensuring good blood flow and protecting against injury. (Prostaglandins are also believed to stimulate bicarbonate and mucus production.)
If any of these defense mechanisms are disturbed and acid and pepsin are allowed to attack the stomach lining, ulcers can result.

The Digestive Juices and Ulcers

A common misbelief is that excess acid is solely responsible for producing ulcers. Hydrochloric acid secreted in the stomach does indeed play a part in the development of ulcers, but it is not the only culprit. Pepsin, the other major digestive fluid, is an enzyme that breaks down proteins, including, if exposed, the digestive tract's own tissues. Acid output in patients with duodenal ulcers does tend to be higher than normal, but in patients with gastric ulcers, acid production is usually normal or lower than normal. (Abnormally large amounts of gastric secretion occur in rare situations, primarily Zollinger-Ellison syndrome, a genetic condition in which gastrin, a potent acid, is secreted by tumors located in the pancreas or duodenum.)

WHAT CAUSES PEPTIC ULCERS?

Helicobacter Pylori (H. Pylori)

Before the discovery of the bacterium Helicobacter (H.) pylori , the stomach was believed to be a sterile environment. Now, H. Pylori is known to be a major cause of peptic ulcers. The bacteria appears to trigger ulcers in the following way:

H. Pylori's corkscrew shape enables it to penetrate the mucous membrane of the stomach or duodenum so that it can attach itself to the lining.
It survives its highly acidic environment by producing urease, an enzyme that generates ammonia and neutralizes the acid.
H. Pylori then produces a number of toxins and factors that in certain individuals cause inflammation and damage to the lining, leading to ulcers.
It also produces changes in certain immune factors that allow it to persist for a person's lifetime.

The bacteria is also now considered to be a major cause of active chronic gastritis (inflammation of the stomach) and active chronic duodenitis (inflammation of the duodenum), and is strongly linked to stomach (gastric) cancer.

Early studies suggested that H. Pylori was present in 90% of people with duodenal ulcers and in about 80% of people with gastric ulcers. As more people are being tested and treated for the bacteria, however, the rate of H. Pylori associated ulcers is declining. For example, a 2001 study suggested that up to 52% of duodenal ulcers and 47% of gastric ulcers were not caused by H. Pylori . Instead, they tended to be associated with NSAID use, genetic factors, or, rarely, Crohn's disease or Zollinger-Ellison syndrome.

Factors that Trigger Ulcers in H. Pylori Carriers. It should also be noted that H. Pylori is found in about 25% of people who do not have peptic ulcers. The magnitude of H. Pylori infection, particularly in older people, may not always predict the presence or absence of peptic ulcers. Other variables, then, may need to be present to actually trigger ulcers. They may include the following:

Genetic Factors. Some people harbor genetic strains of H. Pylori that may make the bacteria more dangerous and increase the risk for ulcers in infected individuals. The most intensively investigated genetic factor is cytotoxin-associated gene A (CagA), which has been associated with both gastric and duodenal ulcers as will as with stomach cancer. Other genetic types that may also increase bacterial severity are called vacuolating cytotoxin (vacA) and antigen-binding adhesin (BabA) genotypes. Some of these genetic factors genes be more or less important for development of ulcers depending on ethnicity.
Immune Abnormalities. Some experts suggest that certain individuals have abnormalities in the immune response in the intestine which allows the bacteria to become injurious to the lining.
Lifestyle Factors. Although life style factors (eg, chronic stress, coffee-drinking, smoking) are long believed to be the primary cause of ulcers, they increase susceptibility to them in some H. Pylori carriers.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of ulcers. Up to 20 million people take prescription NSAIDs regularly and about 26 billion tablets of over-the-counter brands are sold each year in America. The most common NSAIDs are aspirin, ibuprofen (Advil), and naproxen (Aleve, Naprosyn), although many others are available. [ See Box .]

Ulcers form when the rate of damage inflicted by the NSAID exceeds the rate of repair conducted by the stomach. Their damaging effects may be two-fold:

Mildly Acidic. NSAIDs are mild acids and can cause some injury by direct exposure to the lining of the stomach. Their primary damaging effects, however, are from actions that block protective factors in the intestines.
COX-1 Enzymes Inhibitors. NSAIDs reduce pain and inflammation by blocking an enzyme called cyclooxygenase (COX), which is involved in the production of prostaglandins. The COX enzyme has two functions: COX-1 protects the mucus lining while COX-2 causes intestinal contractions and inflammation. Because most NSAIDs reduce both COX-1 and COX-2, they relieve pain, but they also impair an important defense system in the intestine. Blocking prostaglandins can damage the mucous layer, lower bicarbonate levels, and reduce blood flow in the intestine. Each of these actions can increase the risk for ulcers and gastrointestinal bleeding. Even if an NSAID is injected intravenously, the drug will still inhibit prostaglandins in the stomach and duodenum. (Newer NSAIDs are now available that block only COX-2.)

No NSAIDs, even over-the-counter brands, should be used for long-term pain relief except under physician direction. For example, an analysis of controlled trials reported that about 1% of patients taking aspirin over a 28 month period will experience gastrointestinal bleeding. A significant risk existed even at low doses or with the use of modified-release formulations. Of further concern was a 1998 study indicating that taking NSAIDs for only six months posed a risk for symptomatic ulcers that was greater than 1%. The risk for bleeding is continuous for as long as a patient is on these drugs and may even persist for about a year after taking them. Taking short courses of NSAIDs for temporary pain relief should not cause major problems because the stomach has time to recover and repair any damage that has occurred.

Ulcer Risk by Specific NSAIDs
Lowest Risk	Medium Risk (see note)	Highest Risk
Nabumetone (Relafen) Etodolac (Lodine) Salsalate Sulindac (Clinoril)	Aspirin Ibuprofen (Motrin, Advil, Nuprin, Rufen) Naproxen (Aleve, Naprosyn, Naprelan, Anaprox) Diclofenac (Voltaren) Tolmetin (Tolectin) NOTE: Drugs within the medium risk group vary in risk. For example, studies show that use of naproxen is twice as likely as ibuprofen to be associated with hospitalization from GI bleeding.	Flurbiprofen (Ansaid) Piroxicam (Feldene) Fenoprofen Indomethacin (Indocin) Meclofenamate (Meclomen) Oxaprozin Ketoprofen (Actron, Orudis KT) NOTE: Ketoprofen is often considered a medium-risk drug, but one study reported that taking the drug even one week at low doses causes significant GI injury.

Other Causes

The least common major cause of peptic ulcer disease is the Zollinger-Ellison syndrome (ZES). [ See Box. ]

Rarely, certain conditions may cause ulceration in the stomach or intestine, including:

radiation treatments,
bacterial or viral infections,
alcohol abuse,
physical injury, and
burns.

ZOLLINGER-ELLISON SYNDROME

What is ZES? The least common major cause of peptic ulcer disease is the Zollinger-Ellison syndrome (ZES). In this condition, gastrinomas (tumors in the pancreas and the duodenum) produce excessive amounts of gastrin, a hormone that stimulates gastric acid formation. These tumors are usually malignant, so proper and prompt management of the disease is essential.

Who Gets ZES? The incidence of ZES in the United States is estimated at one case per million people per year, and at 0.1% to 1% among patients with peptic ulcers. The mean age at onset is 45 to 50 years, and men are affected more often than women are.

How Is ZES Diagnosed? ZES should be suspected in patients with ulcers who are not infected with H. Pylori and have no history of NSAID use. Diarrhea may precede ulcer symptoms. Ulcers occurring in the second, third, or fourth portions of the duodenum or the jejunum (the middle section of the small intestine) are signs of the syndrome. Gastroesophageal reflux disease (backflow of the stomach's contents into the esophagus) is more prevalent and often more severe in patients with ZES, and can be complicated by ulcerations and strictures of the esophagus.

How Is ZES Treated? Peptic ulcers associated with ZES are typically persistent and difficult to treat. Treatment consists of removing the tumors and suppressing acid with proton pump inhibitors. (Previously, removing the stomach was the only option.)

WHAT ARE THE SYMPTOMS OF PEPTIC ULCERS?

Common Symptoms of Ulcers

The most common symptoms of peptic ulcers are known collectively as dyspepsia. Peptic ulcers can occur without dyspepsia or any gastrointestinal symptoms, especially when caused by NSAIDs.

Dyspepsia. Dyspepsia may be persistent or recurrent and can encompass a variety of problems in the upper abdomen, including the following:

Pain or discomfort. Pain can be either localized in one place or diffuse. It may be described as burning, gnawing, or aching in the upper abdomen, or as a stabbing pain penetrating through the width of the gut. Sometimes pain radiates to the back or to the chest behind the breastbone where it feels like heartburn.
Bloating.
Fullness.
Mild nausea. (Vomiting, in fact, may relieve symptoms.)
Regurgitation. (The sensation of acid backing up into the throat.)
Belching.

It should be noted that dyspepsia occurs in 20% to 40% of people who live in industrialized nations and most of these people do not have ulcers. Such symptoms may also occur with gastroesophageal reflux disease (the backflow of stomach acid into the esophagus), gastritis, or with stomach cancer.

Ulcer Symptoms Related to Meals. Other common symptoms may include hunger and a feeling of being empty. Symptoms, in fact, usually occur one to three hours after a meal. Eating a meal usually relieves the pain of a duodenal ulcer but does not relieve pain from gastric ulcers and may even worsen them.

Symptoms of Anemia. Because ulcers can cause chronic and hidden bleeding, patients may experience the symptoms of anemia, including fatigue and shortness of breath.

Emergency Symptoms

A sudden onset of severe symptoms may indicate intestinal obstruction, perforation, or hemorrhage, which are all emergency conditions. They may include one or more of the following:

Tarry, black or bloody stools.
Severe vomiting, which may include one or more of the following: blood or a substance with the appearance of coffee grounds (a sign of a serious hemorrhage) or entire stomach contents (sign of intestinal obstruction).
Severe abdominal pain with our without vomiting or evidence of blood.

Persons who experience any of these symptoms should go to the emergency room immediately.

HOW SERIOUS ARE PEPTIC ULCERS AND H. PYLORI?

Impaired Quality of Life

Most people with severe ulcers experience significant problems with pain and sleeplessness, which can have a dramatic and adverse impact on the quality of life.

Bleeding and Perforation

Although peptic ulcers are rarely lethal, the disease can be very serious if it progresses to the point of hemorrhage or perforation of the stomach or duodenum. Of the people who get ulcers, up to 15% will experience some degree of bleeding. Fortunately, the incidence is declining with the introduction of effective treatments, but it is still one of the most common medical emergencies. The mortality rate for bleeding peptic ulcers is about 10%. The risk for a poor outcome is highest in people who have had long-term bleeding, blood clotting disorders, low systolic blood pressure, mental instability, or the presence of another serious, unstable medical condition.

Severity of NSAID-Related Bleeding. NSAID-related ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) are more likely to bleed than those caused by the bacteria H. Pylori. This may be due to the fact that NSAID-caused ulcers are less easy to treat. NSAID-related bleeding and stomach problems may be responsible for 70,000 hospital admissions and between an estimated 10,000 and 20,000 deaths each year. Because there are usually no GI symptoms from NSAIDs until bleeding begins, physicians cannot predict which patients taking these drugs will develop bleeding. Elderly patients and those with serious conditions, such as congestive heart failure, are at greatest risk.

Intestinal Obstruction

Ulcers that form where the small intestine joins the stomach can swell and scar, resulting in a narrowing or closing of the intestinal opening. In such cases, a patient will vomit the entire contents of the stomach and emergency procedures are necessary.

Stomach Cancer and H. Pylori

Between 30% and 90% of stomach, or gastric, cancers are linked to H. Pylori , and people with stomach ulcers from the bacteria are at twice the risk for stomach cancer than those without such ulcers. (Those with duodenal ulcers have a lower or no risk.) Some evidence exists that the virulent H. Pylori genetic strain called CagA may be a particular risk factor for precancerous changes, although one 1999 study found no significant association between malignancy and CagA.

Atrophic Gastritis and Childhood Infection. If H. Pylori bacteria infects a child, by early adulthood the individual may develop a condition called atrophic gastritis . In developing countries where the rate of H. Pylori in children is very high, the risk of stomach cancer is six times higher than in America. There is some suggestion then, that atrophic gastritis may lead to stomach cancer, possibly in the following way:

With atrophic gastritis, the stomach loses patches of glands that secrete protein and acid.
Acid protects against carcinogens (substances that cause cancerous changes in cells).
New cells replace those destroyed but these new cells do not produce enough acid to protect against carcinogens.
Over time, then, cancer cells in the stomach may develop and proliferate.
There is still no clear evidence, however, that atrophic gastritis is a direct cause of stomach cancer. Other factors, particularly diets low in fresh fruits and vegetables, might also influence the increased risk for stomach cancer reported in developing countries.

Cancer Risks in Adult-Onset Infection. Onset of H. Pylori infection in adulthood poses less of a risk, since the development of atrophic gastritis takes years and the patient is likely to die of other causes first. In the US, where H. Pylori infects older individuals, less than 1% of people with H. Pylori develop stomach cancer. There is some evidence, however, of an association between H. Pylori and a very high rate of stomach cancer in institutionalized patients, such as those with intellectual disabilities.

Heart Disease

Some research has reported a very high rate of H. Pylori infection in men with coronary artery disease, but more recent work has found no relationship between the bacteria and a risk for heart disease. Further research has been recommended.

Migraine Headaches

One study found an association between H. Pylori and migraine headaches in people who also have gastrointestinal problems. Eliminating the bacteria reduced the frequency and intensity of migraines in half of these patients.

WHO GETS PEPTIC ULCERS?

Peptic ulcer disease affects all age groups, but is rare in children. Men have twice the risk for ulcers as women do. The risk for duodenal ulcers tends to occur first at around age 25 and continues until age 75; gastric ulcers peak in people between the ages of 55 and 65.

Risk Factors for H. Pylori

The bacteria are nearly always acquired during childhood and persist throughout life if not treated. The prevalence in children ranges from under 10% to over 80%, with the lowest risks being in industrialized nations and the highest in developing countries. Regardless of nationalities, H. Pylori infection is almost universal among people who live in crowded, unsanitary conditions. (Rates are also high among people with diabetes.)

Ulcers themselves are very rare in children, even those infected with H. Pylori , and only a minority of infected adults actually develops ulcers. Other conditions, then, such genetic and immune factors, must be present to increase susceptibility and trigger the ulcers.

Risks for Transmission of the Bacteria. H. Pylori grows and colonizes only in the intestinal tracts of primates, and in no other animals. Still, little is yet known about its transmission.

It is most likely transmitted directly from person to person. It is possible that young adults and children with the bacteria may be infectious, but many experts do not believe adults can easily transmit H. Pylori to another adult.
One 1999 study concluded that it is potentially transmissible during gastrointestinal tract illness, particularly when vomiting occurs. The study detected H. Pylori in air samples collected after a person had vomited. The bacteria was alive for less than a minute, however, and did not spread very far, so experts doubted that its presence in the air had much effect.
The bacteria may be passed in stools. Since H. Pylori can live in water, but not apparently in food, then the bacteria may be spread by sewage-contaminated water.

Risk Factors for NSAID Ulcers

Between 15% and 25% of patients who have taken NSAIDs regularly will have evidence of one or more ulcers, but in most cases they are very small. According to a 2000 study, 3.8% of regular NSAID users develop serious gastrointestinal conditions. Given the widespread use of these drugs, the total number of people with serious problems may be considerable. One medical center reported that between 50% and 80% of people who were hospitalized for gastrointestinal problems were taking NSAIDs.

Any condition that requires relief from persistent pain using NSAIDs increases the risk for ulcers, including the following:

Chronic low back pain.
Fibromyalgia.
Repetitive stress injuries (such as carpal tunnel syndrome).
Any arthritic condition (although rheumatoid arthritis poses a higher risk than osteoarthritis).

In addition, certain people are at higher risk for those conditions, the damaging effects from NSAIDs, or both. They include the following:

Being elderly.
Having a history of peptic ulcers.
Alcohol abusers.

It is not yet known whether people who take NSAIDs and are infected with the H. Pylori bacteria face a significantly higher risk of ulceration than those with only one of these factors.

Factors that Increase Susceptibility to All Major Ulcers

Stress and Psychological Factors. Although stress is no longer considered to play a causal role in ulcers, studies still suggest that stress may predispose someone to ulcers or help sustain existing ulcers. Some experts, in fact, estimate that social and psychologic factors play a contributory role in 30% to 60% of peptic ulcer cases, whether they are caused by H. Pylori or NSAIDs. In any case, some experts believe that the anecdotal relationship between stress and ulcers is so strong that attention to psychological factors is still warranted.

Genetic Factors. Genetic factors may increase susceptibility to the effects of H. Pylori . As examples, duodenal ulcers unrelated to NSAIDs seem to be two to three times more likely in relatives of people with ulcers, and identical twins have similar risks for developing ulcers. Genetic abnormalities might result in high levels of acid production, weaknesses in the mucosal layer, or production of abnormal nonprotective mucus. Inherited ulcers, however, are far less common than ulcers caused by NSAIDs or those associated with lifestyle factors that may increase a person's vulnerability to the ulcer-producing effects of H. Pylori .

Coffee and Acidic Beverages. Coffee (both caffeinated and decaffeinated), soft drinks, and fruit juices with citric acid induce increased stomach acid production. Although no studies have proven that any of these drinks contribute to ulcers, consuming more than three cups of coffee per day may increase susceptibility to H. Pylori infection.

Smoking. Smoking increases acid secretion, reduces prostaglandin and bicarbonate production, and decreases mucosal blood flow. Results of studies on the actual effect of smoking on ulcers, however, are mixed. Some evidence suggests that smoking delays the healing of gastric and duodenal ulcers. One study reported that after ulcers healed, about half of nonsmokers relapsed after a year, but that all heavy smokers relapsed after three months. Other studies have found no increased risk for ulcers in smokers. In any case, smoking-associated ulcers do not seem to be affected by the presence of H. Pylori . This should not give smokers any comfort, however, given the other proven dangers from smoking.

Alcohol. Alcohol, too, has mixed reports. Some studies have shown that alcohol may actually protect against H. Pylori . Drinking alcohol may, however, intensify the risk of bleeding in those who also take NSAIDs. In any case, everyone should avoid excessive use of alcohol.

Blood Abnormalities. There seems to be an increased incidence of H. Pylori caused ulcers in people who have Type O blood. In elderly people, anemia may be a clue to the presence of an ulcer.

HOW IS DIAGNOSIS OF PEPTIC ULCERS CONFIRMED?

Initial Approach for Patients with Dyspepsia

Medical and Family History. The physician will ask for a thorough report of a patient's dyspepsia and other important symptoms, such as weight loss or fatigue, any present and past drug use (especially chronic use of NSAIDs), family members with ulcers, and drinking and smoking habits.

Trial of Acid-Blocking Medication. Before proceeding to expensive and possibly needless testing in patients who are suffering a first attack of symptoms, physicians often recommend a four-week course of acid-suppressing medication. In such cases, the ulcer may heal. If symptoms persist, then further testing is needed.

Tests for Gastrointestinal (GI) Bleeding. The physician should administer a rectal exam and have other tests for GI bleeding performed, including a complete blood count and a fecal occult blood test (FOBT), which is used to detect hidden blood. Blood in bowel movements is not always visible, in which case it is called occult blood.

Approach for Identifying H. Pylori

Although H. Pylori is now known to be a major cause of ulcers, clinicians still face many questions in their approach to making a diagnosis:

Which individuals should be tested for H. Pylori ? Expert guidelines recommend testing for H. Pylori only for certain individuals with dyspepsia. They include patients with the following conditions:

Strong indications for ulcers, such as weight loss, anemia, or indications of bleeding.
History of active ulcers.
Risk factors for stomach cancer or other complications from ulcers.

Which tests should be performed? Simple breath and blood tests can now detect H. Pylori with a fairly high degree of accuracy. Endoscopy, an invasive test, allows a biopsy of stomach tissue and is the most accurate test for the bacteria, however.
If tests show infection with H. Pylori, but no evidence of ulcers, should these patients be given antibiotics to eliminate the bacteria? The bacteria is very common, but it causes ulcers in only a minority of those infected.

Some experts argue that testing for H. Pylori may be beneficial even if symptoms are strongly associated with NSAID use, since the presence of the bacteria may significantly increase the existing risk for ulcers in such people.

Noninvasive Tests for H. Pylori

Breath Test. A simple test called the carbon isotope-urea breath test (UBT) is significantly reducing the need for invasive diagnostic testing. It involves the following steps:

To qualify for the test, a patient must be off all antibiotics and not have taken any bismuth containing agents (such as Pepto Bismol) or anti-heartburn agents known as proton pump inhibitors, such as omeprazole (Prilosec) or lansoprazole (Prevacid), for two weeks before the test.
The patient must not eat or drink for four to six hours before taking it.
The patient is asked to swallow a special fluid, pudding, or capsule containing urea that has been treated with carbon atoms. (Urea is a compound metabolized in mammals from nitrogen.)
H. Pylori (if present) converts the urea into carbon dioxide.
The patient exhales into a special device, which detects and records any urea contained in the exhaled carbon dioxide.

This test is proving to be very accurate for both initial detection of the bacteria and for checking recurrence after antibiotic treatment, which should be performed at least four weeks after therapy. Studies have found that the test can identify 95% of people who have H. Pylori .

Blood Tests. Blood tests are used to measure antibodies to H. Pylori , with results available in minutes. Diagnostic accuracy is reported at 80% and 90%. One such important test is called enzyme-linked immunosorbent assay (ELISA).

Other Noninvasive Tests. Other tests are under investigation including a saliva test. For example, using cells found in saliva or stools, the polymerase chain reaction (PCR) test makes multiple copies of a specific region of unknown (but suspicious) DNA, in order to produce enough DNA so that it can be tested to see if the DNA matches the H. Pylori .

Endoscopy (Gastroscopy)

Endoscopy of the stomach (called gastroscopy) with biopsy is the most accurate procedure for detecting the presence of peptic ulcers, stomach cancer, and for diagnosing H. Pylori , but it is invasive and expensive.

Appropriate Candidates for Gastroscopy. Gastroscopy is usually reserved for certain patients with dyspepsia, particularly those at higher risk for stomach cancer or who have symptoms of severe problems. They include the following:

Being over 45 ( when the risk for stomach cancer increases).
Having unexplained weight loss, gastrointestinal bleeding, vomiting, difficulty in swallowing, or anemia.

The Procedure. Gastroscopy may be performed either in a hospital or in a doctor's office, and typically involves the following.

The physician administers a local anesthetic using an oral spray and an intravenous sedative to suppress the gag reflex and to relax the patient.
The physician then places an endoscope (a thin, flexible plastic tube) into a patient's mouth and down the esophagus into the stomach.
A tiny camera in the endoscope allows the physician to see the surface of the esophagus (food pipe), stomach, and duodenum and to search for abnormalities.
The physician will take about ten small tissue samples (biopsies), which will be used to test for H. Pylori .

Some studies suggest that simply testing the gastric juices obtained using endoscopy can detect H. Pylori infection. The bacteria are likely to be present in over 90% of patients with high levels of urease, the enzyme produced by H. Pylori and which would be found in gastric juices.

Upper GI Series

The upper GI (gastrointestinal) series was the standard diagnostic method for peptic ulcers until the introduction of adequate tests for detecting H. Pylori . The patient drinks a solution containing barium. Then x-rays are taken, which may reveal inflammation, active ulcer craters, or deformities and scarring due to previous ulcers. Endoscopy is more accurate, although more invasive and expensive.

Other Laboratory Tests

Stool tests may show traces of blood that are not visible, and blood tests may reveal anemia in those who have bleeding ulcers. If Zollinger-Ellison syndrome is suspected, blood levels of gastrin should be measured.

WHAT ARE THE GUIDELINES FOR TREATING PEPTIC ULCERS CAUSED BY H. PYLORI?

Antibiotic regimens that eradicate H. Pylori can cure peptic ulcers and are now the standard agents used for ulcers in infected individuals. One computer analysis suggests that eliminating H. Pylori infection could significantly increase the lifespan of certain individuals with peptic ulcers, such as younger adults. Other agents, such as proton pump inhibitors or H2 blockers may also be useful for symptoms. [For details on these agents see What Are the Specific Drugs Used in Treating Peptic Ulcers? ]

Antibiotic Regimens

The standard treatments for H. Pylori include regimens that contain two antibiotics and a proton pump inhibitor, usually omeprazole (Prilosec), which suppresses acid production. Cure rates after antibiotic treatments range from 70% to 90%.

A typical regimen contains three drugs for treating H. Pylori and consists of the following:

Proton Pump Inhibitor. Omeprazole (Prilosec) is the standard proton pump inhibitor. Others, which include lansoprazole (Prevacid) and rabeprazole (Aciphex), are important for all peptic ulcers and are a critical component in antibiotic regimens. They reduce the acidity in the intestinal tract, thereby increasing the effectiveness of the bacteria-fighting drugs used in regimens to treat H. Pylori ulcers.
Two antibiotics. Standard antibiotics are clarithromycin (Biaxin) and amoxicillin.

This regimen is typically taken for at least 14 days. Many studies in 1999 and 2000, however, are suggesting that it may be effective after only seven days.

Other regimens being used or investigated include the following:

Some may substitute metronidazole (Flagyl) for clarithromycin or amoxicillin. ( H. Pylori resistance to metronidazole is increasing, however.)
A less costly three-drug regimen uses omeprazole, bismuth (Pepto-Bismol), and tetracycline. It may be a good alternative, although it is less effective; side effects can be very distressing, and many patients cannot tolerate it.
Two-drug regimens are being developed. Some use omeprazole and one antibiotic and others may use two antibiotics. One regimen uses Biaxin and a newly developed drug that combines ranitidine with bismuth citrate (Tritec). So far, they are slightly less effective than taking three drugs and are not recommended.
Quadruple (four-drug) combinations are proving to be very effective. Some contain two antibiotics, bismouth, and a proton pump inhibitor. Of particular interest is Helicide (a new triple-drug capsule containing bismuth, metronidazole, and tetracycline), which is taken in combination with omeprazole. Clinical trials have been promising, showing similar results to the standard triple-drug regimen of omeprazole, clarithromycin, and amoxicillin, even against metronidazole-resistant H. Pylori strains.

Compliance with standard antibiotic regimens have been poor for the following reasons:

The triple-drug regimens are complicated and require many pills. Helicide or two-drug combinations may help offset this problem.
Side effects from the H. Pylori regimens occur in up to 30% of patients. Gastrointestinal problems are very common, and cases of severe diarrhea have occurred during treatment.

Follow-up and Recurrence

Follow-Up. In most cases, patients experience symptom relief after treatment. It should be noted, however, that symptom relief after treatment does not always indicate success, nor does persistence of dyspepsia necessarily mean that treatment has failed. Follow-up testing for the bacteria should be conducted no sooner than four weeks after therapy. Test results before that time may not be accurate.

Recurrence. Studies are indicating that, at least in developed countries, once the bacteria are eliminated, recurrence rates are low. Reinfection with the bacteria is possible, however, particularly in areas where the incidence of H. Pylori is very high and sanitary conditions are poor.

Candidates for Antibiotic Therapy

Patients with Ulcers and H. Pylori Infection. Antibiotics are clearly indicated for patients who clearly have both ulcers and H. Pylori infection. In spite of the well-founded evidence that antibiotics can cure ulcers caused by H. Pylori. European and American studies in 1999 and 2000 continue to suggest that many physicians are still only treating symptoms and not treating ulcers with the antibiotics that might cure them.

Patients with Non-Ulcer Dyspepsia and H. Pylori Infection. There is considerable debate about whether to treat patients with dyspepsia who are infected with H. Pylori but who have no signs of ulcers:

Arguments Against Antibiotics for Non-Ulcer Dysppesia. There is no strong evidence that antibiotic treatments offer any symptom relief compared to acid-suppressing agents such as omeprazole. Two well-conducted studies, for example, reported that eradicating H. Pylori in patients with non-ulcer dyspepsia was no more effective than placebo in reducing symptoms. Furthermore, many physicians are concerned that treating infected patients when there is no clear evidence of ulcers will lead to unnecessary prescriptions and increase the risk for the development of bacteria that are resistant to antibiotics. Th growing evidence that eliminating H. Pylori from the intestinal tract increases the risk for gastroesophageal reflux disease is also of concern in this matter.
Arguments in Favor of Antibiotics for Non-Ulcer Dyspepsia. On the other hand, a major 2000 analysis reported a small but definite benefit in antibiotics for patients with dyspepsia who are infected with H. Pylori . Some experts believe that eliminating H. Pylori in patients with dyspepsia prevents ulcers and lowers the risk of stomach cancer. Some studies indicate that when infected patients with non-ulcer dyspepsia are treated only with omeprazole, acid secretion is reduced to such an extent that the intestinal tract may become susceptible to infections and precancerous changes. More research is needed.

Long-Term Effects from the Elimination of H. Pylori

Studies are now focusing on long-term effects of the elimination of H. Pylori.

Weight Gain. Weight gain may be a problem in some cases.

Gastroesophageal Reflux Esophagitis. Of some concern are studies indicating that H. Pylori may actually protect against gastroesophageal reflux disease (GERD) by reducing stomach acid. (GERD is inflammation in the esophagus and the most common cause of heartburn.) Furthermore, curing ulcers by eliminating the bacteria might actually produce GERD in some people. One study, for example, observed that patients with cured infections of H. Pylori were twice as likely to develop GERD as those who remained infected. Other studies have not been as conclusive, however, and some suggest that the higher incidence in GERD in patients treated for peptic ulcers is likely to be due to other factors. In any case, the association between H. Pylori and GERD does not appear to include any higher risk for more serious related complications of GERD, specifically Barrett's esophagus, a precancerous condition.

Effects on Other Gastrointestinal Infections. Some evidence exists that H. Pylori protects against other gastrointestinal infections in children, particularly those that cause diarrhea. If true, then treating infected children for H. Pylori s hould be undertaken very cautiously and only with evidence that the bacteria is causing harm.

Other Agents Used for H. Pylori Ulcers

Proton Pump Inhibitors. Proton pump inhibitors include omeprazole (Prilosec), lansoprazole (Prevacid), and rabeprazole (Aciphex). They are used in combination with antibiotics, but they may also be useful on their own. One study reported that in people whose ulcers were not cured by H. Pylori therapy, lansoprazole temporarily healed them and they remained in remission for more than a year.

H₂Blockers. H ₂ blockers, such as famotidine (Pepcid AC), cimetidine (Tagamet), and ranitidine (Zantac), used to be the mainstays of all ulcer treatments. They reduce acid secretion in the stomach, which gives the ulcer the opportunity to heal. Although they effectively heal up to 95% of ulcers after eight weeks, they do not permanently heal ulcers and recurrence is common. Elderly patients with ulcers caused by H. Pylori who cannot tolerate the side effects of antibiotic therapy may still benefit from H ₂ blockers. These agents are also helpful for people with non-ulcer dyspepsia.

Vaccines. Strains of H. Pylori are emerging that are resistant to many common antibiotics, which lends some urgency to the development of alternative treatments. An oral vaccine (Helivax) is showing promise in producing an immune response against H. Pylori and is now in clinical trials.

HOW ARE NSAID-INDUCED ULCERS PREVENTED AND TREATED?

Healing Existing NSAID-Induced Ulcers

If NSAID-induced ulcers are identified, the following steps have been suggested:

Switching to alternative pain relievers is the first step in preventing or healing ulcers caused by NSAIDs. If people cannot change drugs, then they should used the lowest NSAID dose possible. In addition, agents are available that may help prevent ulcers in people who need to take NSAIDs.
For healing the ulcers themselves, a number of agents are available. Treatment takes about two to six weeks. Proton pump inhibitors are the most effective drugs. Sucralfate or the H ₂ blockers may also be beneficial. Sucralfate may also help with dyspepsia caused by NSAIDs, but this agent plays no role in prevention. (It should be noted that misoprostol can prevent but not heal ulcers.)

Alternatives Pain Relievers

COX-2 Inhibitors. Celecoxib (Celebrex), rofecoxib (Vioxx), and meloxicam (Mobic) are known as COX-2 (cyclooxygenase-2) inhibitors, the so-called super-aspirins.

Benefits. These agents may prove to be as effective and less harmful to the GI tract than NSAIDs. Importantly, studies are reporting a lower incidence of ulcers and other toxic side effects in patients taking the COX-2 inhibitors than in those taking NSAIDs. The drugs were all equally effective in relieving pain. (One study compared celecoxib with the NSAIDs ibuprofen or diclofenac and the other compared rofecoxib with the NSAID naproxen.) One 1999 study even found the rate of GI problems with celecoxib was equal to that in people who do not take NSAIDs at all. COX-2 inhibitors are currently more expensive than traditional NSAIDs, however, and some insurers do not pay for them.

Theoretically, they may even have properties that produce less adverse effects on cartilage than NSAIDs may have.

Some early evidence also suggests they may be protective against colon cancer and possibly even Alzheimer's disease.

Possible Negative Effects. In spite of their promise, some researchers theorize that inhibiting COX-2 may have some negative side effects over the long term:

Although COX-2 inhibitors are very likely to have a lower risk for ulcers and GI bleeding than standard NSAIDs, studies have been mixed on whether patients taking COX-2 inhibitors have the same gastrointestinal symptoms (eg, diarrhea, abdominal discomfort) as standard NSAIDs. Vioxx may pose a higher risk for symptoms than Celebrex. (Other side effects found with short-term use include headache and dizziness.)
One 2000 study observed that the COX-2 inhibitors had some adverse effects on kidney function, particularly in elderly people, that were similar to the effects of standard NSAIDs. This effect can also trigger fluid build up and high blood pressure. (Celebrex may have fewer of these effects than Vioxx.)
Patients taking anticoagulant drugs may experience a higher risk for bleeding with the use of these agents.
Studies are reporting a higher incidence of heart attacks in patients taking Vioxx and possibly Celebrex than in those taking the standard NSAID, naproxen. Some evidence suggests that both COX-2 inhibitors may increase the risk for blood clots. Experts also suggest that heart patients with chronic pain may be substituting COX-2 inhibitors for heart-protective NSAIDs (such as aspirin, ibuprofen, or possibly naproxen). Patients with heart disease who are taking low-dose aspirin should continue it even while they are taking COX-2 inhibitors.
A few cases of psychiatric side effects (hallucinations), fluid build up, high blood pressure, and excess potassium in the blood have been observed with higher doses of celecoxib or rofecoxib.
They may have negative effects on pregnancy and fertility.
No one who has allergic reactions, hives, or asthma from sulfa drugs, aspirin, or other NSAIDs, should take a COX-2 inhibitor.
The use of COX-2 inhibitors can interfere with many other drugs taken concurrently, including many taken for heart disease and high blood pressure. Patients should discuss all other medications with their physician.

More research is needed to confirm or refute any possible hazard.

Arthrotec. Arthrotec is a combination of misoprostol [ see below ] and the NSAID diclofenac that may reduce the risk for gastrointestinal bleeding. One study found that patients taking Arthrotec had 65% to 80% fewer ulcers than those who took NSAIDs alone.

Acetaminophen. Acetaminophen (Tylenol, Anacin-3, Panadal, Phenaphen, Valadol, and other brands) is the most common alternative to NSAIDs. An estimated 20% to 30% of patients achieve satisfactory results with acetaminophen, which can be used alone or in combination with nonsteroidal anti-inflammatory drugs (NSAIDs). One acetaminophen product, Tylenol Extended Relief, is a controlled-release medication that needs to be taken only every eight hours and can help people achieve uninterrupted sleep without additional sleeping aids. Acetaminophen has its own risks, however. One study reported that up to 5,000 cases of kidney failure every year may be attributed to heavy use of acetaminophen and that taking just one pill a day for a year can double the risk of kidney disease. Patients who take high doses of this drug for long periods are at risk for liver damage, particularly if they drink alcohol and do not eat regularly.

Ulcer-Preventing Drugs for People Who Must Take Long-Term NSAIDs

Proton pump inhibitors and possibly other agents offer protection against the damage done by NSAIDs. In some cases, protective medications may need to be taken throughout life. [For specific details on these agents, see What Are the Specific Drugs Used in Treating Peptic Ulcers? ]

Proton Pump Inhibitors. Proton pump inhibitors are the most effective agents for preventing both duodenal and gastric ulcers in NSAID users, even in patients infected with H. Pylori. They are the first choice for preventing ulcers in high-risk individuals, and have been demonstrated to reduce NSAID-ulcer rates by as much as 80% compared with no treatment.

The brands include omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), and pantoprozole. One study compared omeprazole and misoprostol, another agent used for preventing NSAID-induced ulcers [ see below ]. The two drugs were about equally effective in the short term, but after eight weeks of maintenance therapy, omeprazole was superior and provided the following three advantages:

Omeprazole can actually heal ulcers (misoprostol does not).
Omeprazole is more effective with duodenal ulcers than misoprostol.
Patients with a history of peptic ulcer disease tolerate omeprazole better than they do misoprostol.

Misoprostol. Misoprostol is a prostaglandin, the protective substance blocked by NSAID use. It protects against the major intestinal toxicity of NSAIDs. It is used to prevent NSAID-induced ulcers, both duodenal and gastric, but is not useful in healing existing ulcers.

H2 Blockers. High-dose H2 blockers have been effective in preventing duodenal ulcers, but not gastric ulcers in patients taking NSAIDs. These drugs include famotidine (Pepcid AC), ranitidine (Zantac), cimetidine (Tagamet), and nizatidine (Axid). To date, famotidine is the most potent H2 blocker and the only one that is effective for NSAID-induced ulcers. Studies have suggested that it helps both prevent NSAID-induced ulcers and heal existing early ones. It is not known whether the drug is effective in people whose ulcers have developed to the point that they are causing symptoms. There are some concerns, however:

Patients with even moderate kidney insufficiency may be at risk for adverse effects on the central nervous system after taking famotidine. Patients with any kidney problems should check with their physicians before taking it.
Any H2 blocker can mask the symptoms of ulcers in people who take NSAIDs. With long-term NSAID use, some experts only recommend acid-blocking drugs for patients who are at risk for ulcers. This includes patients that have a history of ulcers, are over 70, or are also taking corticosteroids.

Nitrovasolidators. A gents that release nitric oxide, such as nitroglycerin, may reduce the risk of gastrointestinal bleeding from NSAIDs. These medications, called nitrovasodilators, increase blood flow in the intestinal mucuous lining, but they also prevent damage to the lining. A form of aspirin that releases nitric oxide is under investigation.

Antibiotics and H. Pylori-Infected NSAID Users

Considerable debate is underway on whether antibiotic treatments offer any treatment or protective benefits for long-term NSAID users who are infected with and H. Pylori . Studies report the following:

There is some evidence that people taking NSAIDs and who are infected with H. Pylori are at greater risk for ulcers than individuals who have these conditions independently. Furthermore, some small studies suggest that the use of antibiotics may cut their risk for ulcers by half. Some experts, then, suggest preventive antibiotics when there is evidence of H. Pylori , and some also recommend testing for the bacteria in long-term users.
Other studies have found no association between H. Pylori and any additional risk for ulcers in patients who take NSAIDs. In fact, one analysis of studies even indicated that H. Pylori infection may have a protective effect against NSAID-induced gastric ulcers (but not duodenal ulcers). Furthermore, antibiotics do not appear to be useful for patients with existing NSAID-induced ulcers who are also infected with H. Pylori . A 2001 study, for example, concluded that using antibiotics to eradicate H. Pylori in infected patients with bleeding ulcers caused by NSAIDs (not the bacteria) was equal or less effective than the use of omeprazole, a proton pump inhibitor [ see above ].

More research is needed. At this time experts do not recommend testing NSAID users routinely for H. Pylori.

WHAT ARE THE SPECIFIC DRUGS USED IN TREATING PEPTIC ULCERS?

The following drugs are sometimes used in the treatments of peptic ulcers caused by either NSAIDs or H. Pylori . They are described in alphabetical order.

Antacids

Many antacids are available without prescription and are the first drugs recommended to relieve heartburn and mild dyspepsia. They play no major role in either prevention or healing of ulcers, but help in the following ways:

All of the many brands available rely on various combinations of three basic compounds, magnesium, calcium, or aluminum, that neutralize the acid in the stomach.
They may also defend the stomach by increasing bicarbonate and mucus secretion.

It is generally believed that liquid antacids work faster and are more potent than tablets, although some evidence suggests that both forms work equally well.

Basic Salts Used in Antacids. There are three basic salts used in various antacids:

Magnesium. Magnesium compounds are available in the form of magnesium carbonate, magnesium trisilicate, and, most commonly, magnesium hydroxide (Milk of Magnesia). The major side effect of these magnesium compounds is diarrhea.
Calcium. Calcium carbonate (Tums, Titralac, and Alka-2) is a potent and rapid-acting antacid. It can cause constipation. There have been rare cases of hypercalcemia (elevated levels of calcium in the blood) in people taking calcium carbonate for long periods of time. This can lead to kidney failure and is very dangerous. None of the other antacids have this side effect.
Aluminum. The most common side effect of antacids containing aluminum compounds (Amphogel, Alternagel) is constipation. Maalox and Mylanta are combinations of aluminum and magnesium, which balance the side effects of diarrhea and constipation. People who take large amounts of antacids that contain aluminum may also be at risk for calcium loss and osteoporosis. Long-term use also increases the risk for kidney stones. People who have recently experienced GI bleeding should not use aluminum compounds if possible.

Interactions with Other Drugs. Antacids can interact with a number of drugs in the intestines and reduce their absorption. Conversely, some antacids increase the potency of certain drugs. The interactions can be avoided by taking these other drugs one hour before or three hours after the antacid.

Drug Interactions with Antacids
Drugs that are less absorbed with antacids	Drugs that are made more potent with antacids (such as Maalox and Mylanta)
tetracycline ciprofloxacin (Cipro) propranolol (Inderal) captopril (Capoten) ranitidine (Zantac) famotidine (Pepcid AC)	valproic acid sulfonylureas quinidine levodopa

Antibiotics

H. Pylori is highly sensitive to certain antibiotics, particularly amoxicillin or an antibiotic class known as a macrolide. Either agent serves effectively as a second antibiotic in a three-drug regimen. Others being used are tetracycline, metronidazole, and cirpofloxacin.

Amoxicillin is the most common form of penicillin. It is inexpensive, but many people are allergic to it.
Clarithromycin (Biaxin) is a macrolide and is the most expensive of the antibiotics used against H. Pylori . It is also very effective, but there is growing bacterial resistance to this drug. Researchers fear that this rate will increase as usage against H. Pylori rises.
Tetracycline is effective, but tetracyclines have unique side effects among antibiotics, including skin reactions to sunlight, possible burning in the throat, and tooth discoloration. Pregnant women cannot take it.
Ciprofloxacin (Cipro), known as a fluoroquinolone, is also sometimes used in regimens.
Metronidazole (Flagyl) was the mainstay in initial combination regimens for H. Pylori. There has been a growing bacterial resistance to the drug, however (about 25% of H. Pylori bacteria).

Side Effects of Antibiotics

The most common side effects of nearly all antibiotics are gastrointestinal problems, including cramps, nausea, vomiting, and diarrhea.
Allergic reactions can also occur with all antibiotics but are most common with medications derived from penicillin or sulfa. These reactions can range from mild skin rashes to rare but severe, even life-threatening anaphylactic shock.
Some drugs, including certain over-the-counter medications, interact with antibiotics; patients should report to the physician all medications they are taking.
They double the risk for vaginal infections in women.

Bismuth

Compounds that contain bismuth are often used in the three-drug antibiotic regimens. They destroy the cell walls of the H. Pylori bacteria. The only bismuth compound available in the US has been bismuth subsalicylate (Pepto-Bismol), although a drug combination of the H ₂blocker ranitidine and bismuth citrate (Tritec) has been released. High doses can cause vomiting and depression of the central nervous system, but the doses given for ulcer patients rarely cause side effects.

H2 Blockers

H₂ blockers impede or antagonize the actions of histamine, a chemical found in the body that encourages acid secretion in the stomach. H2 blockers were the standard treatment for peptic ulcers until the development of antibiotic regimens against H. Pylori . These drugs cannot cure ulcers, but in certain cases they are useful. They are effective only for duodenal ulcers, however, and have little effect on stomach (gastric) ulcers. Four H ₂ blockers are currently available over the counter in the US: famotidine (Pepcid AC), cimetidine (Tagamet), ranitidine (Zantac), and nizatidine (Axid). All have good safety profiles and few side effects. Each is discussed below. H ₂ blockers can interact with other drugs, so the physician should be made aware of any other drugs a patient is taking.

Famotidine. Famotidine (Pepcid AC) is the most potent H2 blocker. The most common side effect of famotidine is headache, which occurs in 4.7% of people who take it. Famotidine is virtually free of drug interactions.
Cimetidine. Cimetidine (Tagamet) has few side effects; approximately 1% of people taking cimetidine will experience mild temporary diarrhea, dizziness, rash, or headache. Cimetidine interacts with a number of commonly used medications, such as phenytoin, theophylline, and warfarin. Long term use of excessive doses (more than 3 grams a day) may cause impotence or breast enlargement in men; these problems resolve after the drug is discontinued.
Ranitidine. Ranitidine (Zantac) interacts with very few drugs. In a recent study, ranitidine provided more pain relief and healed ulcers more quickly than cimetidine in people under 60 years old, but there was no difference in older patients. A common side effect associated with ranitidine is headache, which occurs in about 3% of the people who take it.
Nizatidine. Nizatidine (Axid) is a new H2 blocker. It is nearly free of side effects and drug interactions.

Long-Term Concerns. Serious complications have been reported, including the following:

Liver damage. (This is more likely with ranitidine than other H2 blockers, but is rare in any event.)
Complications in the kidney. Adverse effects on the central nervous system in patients with even moderate renal (kidney) insufficiency have been reported with famotidine. Patients with any kidney problems should check with their physicians before taking it.
Increased risk for pneumonia in hospitalized patients.
Ulcer complications (perforation, bleeding). Some experts are concerned that the use of acid-blocking drugs may actually increase the risk for serious complications from ulcers by masking their symptoms.

Misoprostol

Misoprostol (Cytotec) increases prostaglandin levels in the stomach lining, which protects against the major intestinal toxicity of NSAIDs.

Actions Against Ulcers. Misoprostol can reduce formation of ulcers in the upper small intestine by two-thirds and in the stomach by three quarters. It does not neutralize or reduce acid, so although the drug is helpful for preventing NSAID-induced ulcers, it is not useful in healing existing ulcers.

Side Effects.

Diarrhea and other gastrointestinal problems are severe enough to cause 20% of patients to stop taking the drug. Taking misoprostol after meals should minimize these effects; one study indicated that taking the drug two or three times a day instead of the standard regimen of four times may prove to be just as effective and cause fewer side effects.
Misoprostol can induce abortion or cause birth defects and should not be taken by pregnant women. If pregnancy occurs during treatment, the drug should be discontinued at once and the physician contacted immediately.

Proton Pump Inhibitors (Gastric Acid Pump Inhibitors)

Actions Against Ulcers. Proton pump inhibitors are the drugs of choice for managing patients with peptic ulcers from any cause. They suppress the production of stomach acid. These agents work by inhibiting the molecule in the stomach glands that is responsible for acid secretion, which is called the gastric acid pump.

They can be used as part of a triple-drug regimen for H. Pylori or used alone for preventing and healing NSAID-related ulcers. They are even useful in the treatment of ulcers caused by Zollinger-Ellison syndrome. (Of note, certain individuals carry a gene that regulates an enzyme called CYP2C19 that reduces the effectiveness of proton pump inihibitors. This gene may be present in between 18% and 20% of Asians, who may not respond as well to these agents.)

Standard Brands. The standard agents are omeprazole (Prilosec) and lansoprazole (Prevacid). Newer ones, such as pantoprozole and rabeprazole (Aciphex), may be more potent but it is not clear yet if they are any more effective than the older agents. Pantoprozole can be administered intravenously and may be useful for patients who cannot take oral medications.

Adverse Effects. Proton pump inhibitors may pose the following concerns:

Side effects are uncommon but may include headache, diarrhea, constipation, nausea, and itching.

Proton pump inhibitors should be avoided by pregnant women and nursing mothers, although recent studies suggest that they do not pose an increased risk of birth defects.
They may interact with certain drugs, such as antiseizure agents (eg, phenytoin), anti-anxiety drugs (eg, diazepam), and blood thinners (such as warfarin).
The long-term use of proton pump inhibitors by people with H. Pylori may reduce acid secretion theoretically enough to cause atrophic gastritis (chronic inflammation of the stomach). This condition in turn, is a risk factor for stomach cancer. To date, however, there have been no reports of an increased risk of stomach cancer with long-term use of either omeprazole or lansoprazole.

Sucralfate

Sucralfate (Carafate) seems to work by adhering to the ulcer crater and protecting it from further damage by stomach acid and pepsin. It also promotes the defensive processes of the stomach. Sucralfate has an ulcer healing rate similar to that of H2 blockers. Other than constipation, which occurs in 2.2% of patients, the drug has few side effects. Sucralfate does interact with a wide variety of drugs, including warfarin, phenytoin, and tetracycline.

HOW ARE BLEEDING ULCERS TREATED?

Diagnosis and General Treatment

Bleeding stops spontaneously in about 70% to 80% of people with bleeding ulcers. For massive bleeding, fluid replacement is essential and blood transfusions may be required. Diagnosis is confirmed using endoscopy, which involves passing tubes into the stomach. Physicians are able to detect signs of bleeding that include active spurting or oozing of blood from arteries, swollen but nonbleeding blood vessels, and nearby blood clots. Depending on the intensity of the bleeding, patients can be released from the hospital within a day or kept up to three days after endoscopy. Patients who have the H. Pylori bacteria, even if NSAIDs caused the bleeding, should be treated with antibiotic therapy to eradicate the bacteria. People on NSAIDs should discontinue them if possible.

Surgical Treatment

Those who show signs of continued or recurrent bleeding require immediate emergency treatment. About 30% of patients who come to the hospital for bleeding ulcers require endoscopy or other surgical procedures.

Endoscopy. Endoscopy is the procedure most often used for treating bleeding ulcers, although not everyone is a candidate, and some patients require more invasive surgery [ see Major Surgery below ]. Endoscopic treatment of bleeding generally involves the following:

The surgeon uses a probe passing through an endoscopic tube to apply electricity or heat to coagulate the blood and stop the bleeding.
An injection of epinephrine (commonly known as adrenaline) directly into the ulcer increases the effectiveness of endoscopic treatments. Epinephrine plus a combination of blood clotting factors termed fibrin glue may prove to be even more effective.

Between 15% and 20% of patients who have endoscopy experience a recurrence of bleeding. (In one study, bleeding recurred in only 8.7% of patients treated with epinephrine plus endoscopy; it should be noted that the procedure was performed by highly experienced physicians.) Those at highest risk for bleeding recurrence are patients with the following conditions:

Large or deep ulcers.
Severe clotting abnormalities.
Very low blood pressure.
Bleeding that started after a patient was hospitalized.
Other serious medical conditions.

Recurring bleeding may require major surgery, although repeat endoscopy performed by experienced doctors is proving to be effective. In one study repeat endoscopy successfully stopped further bleeding in 73% of patients; the others required surgery.

Major Surgery. Major surgery is now generally performed only when endoscopy is not appropriate. Surgery is not effective for upper GI ulceration caused by chronic NSAID use. There are a number of surgical procedures.

Vagotomy cuts the vagus nerve and interrupts messages from the brain that stimulate acid secretion to the stomach. This surgery may impair stomach emptying; a recent variation that cuts only parts of the nerve may reduce this complication.
Antrectomy removes the lower part of the stomach, which manufactures the hormone responsible for stimulation of digestive juices.
Pyloroplasty enlarges the opening into the small intestine so that stomach contents can pass into it more easily.

Antrectomy and pyloroplasty are usually performed with vagotomy.

Additional Treatments

A number of medications may be helpful:

Triple therapy, including antibiotics, to eradicate H. Pylori immediately after endoscopy in infected patients can be very beneficial.
Intravenous administration of the proton pump inhibitor omeprazole is often used after endoscopy or other surgeries to prevent recurrent bleeding. In one survey of studies, it reduced the risk of further bleeding by 22% to 44%.
Somatostatin (a hormone used to prevent bleeding in cirrhosis) is also useful for reducing persistent peptic ulcer bleeding or the risk of recurrence.

Somatostatin or a proton pump inhibitor may also be useful for initial bleeding episodes if endoscopy is unsuccessful, inappropriate, or unavailable.

WHAT LIFESTYLE CHANGES ARE RECOMMENDED FOR PEPTIC ULCERS AND DYSPEPSIA?

Diet

It was common in the past to restrict people suffering from peptic ulcers to frequent intake of small amounts of bland foods and milk. Exhaustive research conducted since then has shown that a bland diet is not effective in reducing the incidence or recurrence of ulcers, and that frequent small meals throughout the day are no more effective than consumption of three meals per day. Large amounts of food should still be avoided because stretching or swelling of the stomach can result in painful symptoms.

Fruits and Vegetables. The good news is that a diet rich in fiber may cut the risk of developing ulcers in half and speed healing of existing ones. Fiber found in fruits and vegetables is particularly protective; vitamin A contained in many of these foods may increase the benefit. In one study, apples and yams appeared to be especially helpful. Apples, celery, cranberries, onions, red wine, and green and black tea are also high in natural chemicals known as flavonoids, which appear to inhibit H. Pylori growth and have many other health benefits. In fact cranberry juice specifically may have properties that help prevent H. Pylori from infecting the intestinal lining.

Milk. Milk actually encourages the production of acid in the stomach, although moderate amounts (two to three cups a day) can be drunk without harm.

Coffee and Carbonated Beverages. Coffee may increase susceptibility to H. Pylori . Cutting down on coffee (both decaf and caffeinated) and carbonated beverages may help reduce stomach acid.

Spices and Peppers. Studies conducted on spices and peppers have yielded conflicting results. The rule of thumb is to use these substances moderately, and to avoid them if they irritate the stomach.

Garlic. Some studies suggest that high amounts of garlic may have some protective properties against stomach cancer, although a recent study concluded that it offered no benefits against H. Pylori itself and, in high amounts, causes considerable gastrointestinal distress.

Vitamins. Although no vitamins have been shown to protect against ulcers, H. Pylori appears to impair absorption of vitamin C, which may play a role in the higher risk of stomach cancer.

Exercise

Some evidence exists that exercise may help reduce the risk for ulcers in some people. In one 2000 study, exercise was associated with a lower risk for duodenal (but not gastric) ulcers in men. In this study, exercise appeared to have no effect on ulcer development in women.

Stress Relief

Stress relief programs have not been shown to promote ulcer healing, but they may have other health benefits.

Herbal Remedies

One well-conducted 1999 study indicated that an herbal preparation (Iberogast) combined with extracts from a bitter candy reduced dyspepsia in 82% of subjects compared to 39% who had taken a placebo. Other herbal remedies are marketed for dyspepsia but few have been seriously studied. No one should take any untested medication, even so-called natural ones, without consulting a physician.

WHERE ELSE CAN INFORMATION ABOUT PEPTIC ULCERS BE OBTAINED?

National Digestive Diseases Information Clearinghouse, Two Information Way, Bethesda, MD 20892-3570. Call (301-654-3810) or on the Internet (http://www.niddk.nih.gov/). Offers patient information and educational materials.

American Gastroenterological Association, American Digestive Health Foundation, 7910 Woodmont Avenue, 7th Floor, Bethesda, MD 20814. Call (301-654-2055 or toll-free 800-NO-ULCER) or on the Internet (http://www.gastro.org).

American Society for Gastrointestinal Endoscopy, 13 Elm Street, Manchester, MA 01944-1314. Call (978-526-8330), fax (978-526-4018) on the Internet (http://www.asge.org/)

American College of Gastroenterology, 4900 B South 31 St., Arlington, VA 22206-1656. Call (703-820-7400) or (http://www.acg.gi.org/)

Helicobacter Pylori Foundation, P.O. Box 7965, Charlottesville, VA 22906-7965. On the Internet (http://www.helico.com/). Includes FAQ's, links, and on-line discussion.

Centers for Disease Control and Prevention. Call toll-free (1-800-311-3435) or on the Internet (http://www.cdc.gov). Their web site contains an excellent, searchable database of articles.