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Peptic ulcers

Highlights

New Research:

Overview:

Risk Factors Include:

Introduction

A peptic ulcer is an open sore or raw area that tends to develop in one of two places:

In the U.S., duodenal ulcers are 3 times more common than gastric ulcers.

A peptic ulcer is an open sore or raw area in the lining of the stomach (gastric) or the upper part of the small intestine (duodenal).

Ulcers average between one-quarter and one-half inch in diameter. They develop when digestive juices produced in the stomach, intestines, and digestive glands damage the lining of the stomach or duodenum.

The two important digestive juices components are hydrochloric acid and the enzyme pepsin. Both substances are critical in the breakdown and digestion of starches, fats, and proteins in food. They play different roles in ulcers:


Click the icon to see an image of the stomach.

Fortunately, the body has a defense system to protect the stomach and intestine against these two powerful substances:

Disrupting any of these defense mechanisms makes the stomach and intestine lining susceptible to the actions of acid and pepsin, increasing the risk for ulcers.

Causes

In 1982 two Australian scientists identified H. pylori as the main cause of stomach ulcers. They showed that inflammation of the stomach, and stomach ulcers, result from an infection of the stomach caused by the H. pylori bacteria. This discovery was so important that the researchers were awarded the Nobel Prize in Medicine in 2005. The bacteria appear to trigger ulcers in the following way:

Even if ulcers do not develop, the bacterium is now considered to be a major cause of active chronic inflammation in the stomach (gastritis) and in the upper part of the small intestine (duodenitis).

H. pylori is also strongly linked to stomach cancer and possibly other non-intestinal problems.

Factors that Trigger Ulcers in H. pylori Carriers. Only around 10 to 15% of people infected with H. pylori develop peptic ulcer disease. The magnitude of H. pylori infection, particularly in older people, may not always predict the presence or absence of peptic ulcers. Other variables must to be present to actually trigger ulcers. These may include:

When H. pylori was first identified as the major cause of peptic ulcers, it was found 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 has declined. Currently, H. pylori is found in about 50% of people with peptic ulcer disease.

Some researchers now believe that duodenal ulcers are not caused by H. pylori, but that the presence of the bacteria simply delays healing. This fact, they say, may explain why up to half of cases of acute duodenal perforation show no evidence of H. pylori, and why duodenal ulcers can recur even after H. pylori has been eradicated.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Long-term use of NSAIDs is the second most common cause of ulcers, and the rate of NSAID-caused ulcers is increasing. About 20 million people take prescription NSAIDs regularly, and more than 25 billion tablets of over-the-counter brands are sold each year in the U.S. alone. The most common NSAIDs are aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve, Naprosyn), although many others are available. Patients with NSAID-caused ulcers should stop taking these drugs.

There is no doubt NSAIDs increase the risk of ulcers and gastrointestinal (GI) bleeding. The risk of bleeding is continuous for as long as a patient takes these drugs and may persist for about one year after stopping. 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.

Specific NSAIDs pose greater or lesser risks for ulcers and bleeding. No NSAIDs, however, even over-the-counter brands, should be used long-term except under a doctor's supervision.

Other Causes

Certain drugs other than NSAIDs may aggravate ulcers (an example is warfarin [Coumadin], an anticoagulant that increases the risk of bleeding). Other drugs include oral corticosteroids, some chemotherapy agents, spironolactone, and niacin.

Risk of GI perforation was seen in phase 3 clinical trials of bevacizumab, the first anti-vascular endothelial growth factor agent (VEGF) approved by the FDA. This drug has been shown to increase survival and stop the progression of metastatic colorectal cancer when used in combination with chemotherapy. While the benefits of bevacizumab outweigh the risks, GI perforation is very serious. If it occurs, the drug must be discontinued.

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

Zollinger-Ellison Syndrome (ZES)

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

Cause of peptic ulcers
Another cause of peptic ulcer, although far less common than H. pylori or NSAIDs, is Zollinger-Ellison syndrome. A large amount of excess acid is produced in response to the overproduction of the hormone gastrin, which in turn is caused by tumors on the pancreas or duodenum. These tumors are usually malignant, must be removed and acid production suppressed to relieve the recurrence of the ulcers.

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

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 in the jejunum (the middle section of the small intestine) are signs of ZES. Gastroesophageal reflux disease (GERD) 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 an intravenous proton-pump inhibitor (Protonix). Previously, removing the stomach was the only option.

Symptoms

Dyspepsia. The most common symptoms of peptic ulcer are known collectively as dyspepsia. Peptic ulcers can occur without dyspepsia or any other gastrointestinal symptom, especially when caused by NSAIDs. Dyspepsia may be persistent or recurrent and can encompass a variety of symptoms in the upper abdomen, including:

Many patients with the above symptoms do not have peptic ulcer disease or any other diagnosed condition. In that case, they have what is called functional dyspepsia.

Ulcer Pain. There are some symptoms that are more strongly suggestive of gastric ulcers, although not everyone with these symptoms has an ulcer. The pain of ulcers can be either localized in one place, or it can be diffuse (all over the abdomen). The pain is described as a burning, gnawing, or aching in the upper abdomen, or as a stabbing pain penetrating through the gut. The symptoms may vary depending on the location of the ulcer:

Ulcer pain may be particularly confusing or disconcerting when it radiates to the back or to the chest behind the breastbone. In such cases it can be confused with other conditions such as a heart attack.

Because ulcers can cause 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, all of which are emergencies. Symptoms may include:

Anyone who experiences any of these symptoms should go to the emergency room immediately.

Ulcer emergencies
Peptic ulcers may lead to emergency situations. Severe abdominal pain with or without evidence of bleeding may indicate a perforation of the ulcer through the stomach or duodenum. Vomiting of a substance that resembles coffee grounds or the presence of black tarry stools may indicate serious bleeding.

Complications

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

Bleeding and hemorrhage

Peptic ulcers caused by H. pylori or NSAIDs can be very serious if they cause hemorrhage or perforate the stomach or duodenum. Up to 15% of people with ulcers experience some degree of bleeding, which can be life-threatening. 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, the patient will vomit the entire contents of the stomach, and emergency treatment is necessary.

Complications of peptic ulcers cause an estimated 6,500 deaths each year. These figures, however, do not reflect the high number of deaths associated with NSAID use. Ulcers caused by NSAIDs are more likely to bleed than those caused by H. pylori. NSAID-related bleeding and stomach problems may be responsible for as many as 107,000 hospital admissions and 16,500 deaths each year.

Because there are often no GI symptoms from NSAID ulcers until bleeding begins, doctors cannot predict which patients taking these drugs will develop bleeding. The risk for a poor outcome is highest in people who have had long-term bleeding from NSAIDs, blood clotting disorders, low systolic blood pressure, mental instability, or the presence of another serious, unstable medical condition. Populations at greatest risk are the elderly and those with other serious conditions, such as heart problems.

Stomach Cancer and Other Conditions Associated with H. pylori

H. pylori is strongly associated with certain cancers. Some studies have also linked it to a number of non-gastrointestinal illnesses as well, although the evidence is inconsistent.

Stomach Cancers. Stomach cancer, also called gastric cancer, is the second most common type of cancer worldwide. In developing countries where the rate of H. pylori is very high, the risk of stomach cancer is 6 times higher than in the U.S. Evidence now suggest that H. pylori may be as carcinogenic to the stomach as cigarette smoke is to the lungs.

Eradication of H. pylori may reduce the risk of stomach cancer, but not eliminate it. A continued risk is associated with the degree of damage to the mucous membranes sustained before H. pylori treatment started. The damage can be measured during an endoscopy.

Infection with H. pylori promotes a precancerous condition called atrophic gastritis. The process most likely starts in childhood. It may lead to cancer through the following steps:

Onset of H. pylori infection in adulthood poses a lower risk, since the development of atrophic gastritis takes years, and an adult is likely to die of other causes first. Other factors, such as specific strains of H. pylori and a person's diet, might also influence the degree of risk for stomach cancer. For example, a diet high in salt and low in fresh fruits and vegetables has been associated with a greater risk. Some evidence suggests that the virulent H. pylori strain carrying the cytotoxin-associated gene A (CagA) may also be a particular risk factor for precancerous changes.

Interestingly, people with duodenal ulcers caused by H. pylori appear to have a lower risk of stomach cancer, although scientists do not know why. It may be that different H. pylori strains affect the duodenum and the stomach. Or, the high levels of acid found in the duodenum may help prevent the spread of the bacteria to critical areas of the stomach.

Other Diseases. H. pylori has also been weakly associated with other nonintestinal disorders, including migraine, Raynaud's disease (marked by cold extremities), and some skin disorders, such as chronic hives.

Risk Factors

About 25 million people in the U.S. are expected to develop peptic ulcers at some point in their lives. Peptic ulcer disease affects all age groups, but is rare in children. Men have twice the risk of ulcers as women. The risk of duodenal ulcers tends to rise beginning around age 25 and continues until age 75; gastric ulcers peak at age 55 - 65.

Peptic ulcers are less common than they once were. Research suggests that ulcer rates have even declined in areas with widespread H. pylori infection. The increased use of proton-pump inhibitor (PPI) drugs may be responsible for this trend.

Risk Factors for H. pylori

H. pylori grows and colonizes only in the intestinal tracts of primates. The bacteria are most likely transmitted directly from person to person. Still, little is yet known about its transmission.

Who Is Infected with H. pylori? About half the world's adults are infected with H. pylori. The bacteria are nearly always acquired during childhood and persist throughout life, if not treated. The prevalence in children ranges from less than 10% to more than 80%, with the highest infection rates (3 - 10%) in developing countries and the lowest (0.5%) in industrialized nations, where rates continue to decline. Even in industrialized countries, however, infection rates in regions with crowded, unsanitary conditions are equal to those in developing countries.

How Does the Bacteria Pass from Person to Person? It is not entirely clear how the bacteria are transmitted. Suggested but not clearly proven methods of transmission include: intimate contact, GI tract illness, particularly when vomiting occurs, contact with oral secretions. The bacteria may also be passed in stools. Since H. pylori can live in water, but apparently not in food, the bacteria may also be transmitted through sewage-contaminated water.

Who Is at Risk for Ulcers from H. pylori? Although H. pylori infection is common, ulcers in children are very rare, and only a minority of infected adults develops ulcers. Some known risk factors include smoking, alcohol use, having a relative with peptic ulcers, being male, and the presence of the cytotoxin-associated gene A (CagA). Experts are unable to determine, however, any single factor or group of factors that can determine which infected patients are most likely to develop ulcers.

Risk Factors for NSAID-Induced Ulcers

Between 15 - 25% of patients who have taken NSAIDs regularly will have evidence of one or more ulcers, but in most cases these ulcers are very small. Given the widespread use of NSAIDs, however, the potential total number of people who can develop serious problems may be very large. Long-term NSAID use can damage the stomach and, possibly, the small intestine.

In April 2005, the FDA asked manufacturers of prescription NSAIDs to include with their products the same boxed warning used for the COX-2 inhibitor celecoxib (Celebrex). This boxed warning emphasizes the increased risk for cardiovascular events and GI bleeding in people taking these drugs. (Pharmaceutical companies are trying to develop new COX-2 inhibitors without these dangerous side effects. Early safety studies of the novel COX-2 inhibitor known as CS-706 showed its effect on gastric mucosa to be the same as placebo.)

The FDA also requested manufacturers of over-the-counter NSAIDs to revise their labels to include more specific language concerning potential cardiovascular and GI risks. Due to its proven heart benefits, aspirin was excluded from these labeling revisions.

Frequent Users

NSAIDs. Anyone who uses NSAIDs regularly is at risk for gastrointestinal problems. Even low-dose aspirin (81 mg) may pose some risk, although the risk is lower than with standard doses. In one 4-year study, 4.5% of regular NSAID users were hospitalized for GI bleeding. The highest risk, however, was found in people who require long-term use of very high-dose NSAIDs, notably patients with rheumatoid arthritis. Other people who take high doses of NSAIDs include those with chronic low back pain, fibromyalgia, and chronic stress.

The use of Cox 2 inhibitors may result in a decrease in uncomplicated ulcers, but more serious events, such as bleeding or perforation, do not seem to be reduced by the use of these medications

Contributing Factors. Certain factors add to the risk for ulcers in NSAID-users:

Other Risk Factors for Ulcers from Either H. pylori or NSAIDs

Stress and Psychological Factors. Although stress is no longer considered a cause of ulcers, studies still suggest that stress may predispose a person to ulcers or prevent existing ulcers from healing. Some even believe that the anecdotal relationship between stress and ulcers is so strong that treatment of psychological factors is warranted in people with ulcers.

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. Other studies have found no increased risk for ulcers in smokers. In any case, any impact of smoking on ulcers does not seem to be affected by the presence of H. pylori.

Tobacco and vascular disease
Tobacco use and exposure may cause an acceleration of coronary artery disease and peptic ulcer disease. It is also linked to reproductive disturbances, esophageal reflux, hypertension, fetal illness and death, and delayed wound healing.

Diagnosis

Peptic ulcers are always suspected in patients with persistent dyspepsia (bloating, belching, and abdominal pain). Dyspepsia, however, occurs in 20 - 40% of people who live in industrialized nations, and only about 15 - 25% of these people actually have ulcers. A number of steps are needed to make an accurate diagnosis of ulcers.

Medical and Family History

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

Ruling out Other Disorders

In addition to peptic ulcers, a number of conditions, notably gastroesophageal reflux disease and irritable bowel syndrome, cause dyspepsia. Often, however, no cause can be determined. In such cases, the symptoms are referred to collectively as functional dyspepsia.

Peptic ulcer symptoms, particularly abdominal pain and chest pain, may resemble those of other conditions, such as gallstones or heart attack. Certain features may help to distinguish these different conditions. However, symptoms often overlap, and it is impossible to make a diagnosis based on symptoms alone. A number of tests are needed.

The following disorders may be confused with peptic ulcers:

Dyspepsia may also occur with gastritis, stomach cancer, or as a side effect of certain drugs, including NSAIDs, antibiotics, iron, corticosteroids, theophylline, and calcium blockers.

Noninvasive Tests for Gastrointestinal (GI) Bleeding

When ulcers are suspected, the doctor will order tests to detect bleeding. These may include a rectal exam, a complete blood count, and a fecal occult blood test (FOBT). The FOBT tests for hidden (occult) blood in stools. Typically, the patient is asked to supply up to 6 stool specimens in a specially prepared package. A small quantity of feces is smeared on treated paper, which reacts to hydrogen peroxide. If blood is present, the paper turns blue.

Traditional radiology tests have not yet proven valuable for diagnosing ulcers.

Noninvasive Screening Tests for H. pylori

Simple blood, breath, and stool tests can now detect H. pylori with a fairly high degree of accuracy. It is not entirely clear, however, which individuals should be screened for H. pylori.

Candidates for Screening. Some doctors currently test for H. pylori only in individuals with dyspepsia who also have high-risk conditions, such as:

Smokers and those who experience regular and persistent pain on an empty stomach may also be good candidates for screening tests. Some doctors argue that testing for H. pylori may be beneficial for patients with dyspepsia who are regular NSAID users. In fact, given the possible risk for stomach cancer in H. pylori- infected people with dyspepsia, some experts now recommend that any patient with dyspepsia lasting longer than 4 weeks should have a blood test for H. pylori. This is a subject of considerable debate, however.

Tests for diagnosing H. pylori. The following tests are used to diagnose H. pylori infection. Testing may also be done after treatment to ensure the bacteria are fully eradicated.

It should be noted that such tests are not as accurate as endoscopy, an invasive procedure, which is needed to confirm a diagnosis of H. pylori. The breath and stool tests, however, can be particularly useful after treatment to determine if a patient has been cured.

If symptoms persist, endoscopy is usually performed. Though it is an invasive procedure, it is the only procedure in which a biopsy of stomach tissue can be taken, making it the most accurate test.

Experts debate whether endoscopy should be performed on all patients who do not respond to initial medication, since it does not appear to add any useful information on treatment choices, unless there is evidence or suspicion of bleeding or serious complications.

Endoscopy

Endoscopy is a procedure used to evaluate the esophagus, stomach, and duodenum using an endoscope -- a long, thin tube equipped with a tiny video camera. When combined with a biopsy, endoscopy is the most accurate procedure for detecting the presence of peptic ulcers, bleeding, and stomach cancer, or for confirming the presence of H. pylori.

Appropriate Candidates for Endoscopy. Because endoscopy is invasive and expensive, it is unsuitable for screening everyone with dyspepsia. Most individuals with these symptoms are managed effectively without endoscopy. Endoscopy is usually reserved for patients with dyspepsia who also have risk factors for ulcers, stomach cancer, or both. Such risk factors include the following:

There is some debate whether patients under 45 with persistent dyspepsia and no alarm symptoms should have an endoscopy.

The Procedure. Endoscopy may be performed in a hospital, doctor's office, or outpatient surgery center, and typically involves the following:

Gastroscopy procedure
In endoscopy, the doctor places a long, thin, flexible tube (called an endoscope) down the patient's throat and into the stomach and duodenum. A camera and light on the tip of the endoscope enables the doctor to check for abnormalities. Tiny samples may be taken to check for H. pylori bacteria, a cause of many peptic ulcers. If a bleeding ulcer is found, it may be sealed with a burning tool (cauterized) during the procedure.

Note: Some evidence suggests that patients who take PPIs should stop taking the medication 2 weeks before an endoscopy, since it may mask ulcers.

Upper GI Series

An upper GI series was the standard diagnostic method for peptic ulcers until the introduction of adequate tests for detecting H. pylori. In an upper GI series, the patient drinks a solution containing barium. X-rays are then taken, which may reveal inflammation, active ulcer craters, or deformities and scarring due to previous ulcers. Endoscopy is more accurate, although it is more invasive and expensive.

GI bleeding - series

Click the icon to see an illustrated series detailing treatment of GI bleeding.

Other Laboratory Tests

Stool tests may show traces of blood that are not visible to the naked eye, 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.

Treatment

Deciding which treatment is best for patients with symptoms of dyspepsia or peptic ulcer disease depends on a number of factors. An endoscopy to identify any ulcers, and to perform the most accurate test for H. pylori, probably gives the best guidance for treatment. However, dyspepsia is such a common reason for a doctor's visit that many people are treated initially based on symptoms and blood or breath H. pylori test results. This approach (called test and treat) is considered an appropriate option for most patients. Those with any evidence of bleeding, with other alarm symptoms, and who are older than 55 years of age should have an endoscopy performed first.

Approach to Patients Who Are Not Taking NSAIDs

If an endoscopy is performed soon after the patient first visits a doctor for their symptoms, treatment is based upon the results of the endoscopy:

As mentioned above, most patients without risk factors for more complications are treated without having an endoscopy first. The decision regarding which treatment to use is based on the types of symptoms these patients have, and the results of their H. pylori blood or breath tests.

Patients who are not infected with H. pylori are given a diagnosis of functional (non-ulcer) dyspepsia. These patients are most commonly given four to eight weeks of a proton pump inhibitor. If this dose not work, occasionally a doubling of the does will relieve symptoms. If there is still no relief of symptoms, patients may have an endoscopy performed. However, it is unlikely that an ulcer is present. Full resolution of symptoms may be difficult for this group of patients.

There is considerable debate about whether to test for H. pylori and treat infected patients who have dyspepsia but no clear evidence of ulcers.

Antibiotic and Combination Drug Regimens for the Treatment of H. pylori

Reported cure rates for H. pylori range from 70 - 90% after antibiotic treatment. The standard treatment regimen uses 2 antibiotics and a PPI:

This combination treatment typically lasts for at least 14 days. Many studies, however, suggest that a 7-day treatment may work just as well. See Medication section in this article.

Follow-Up. Follow-up testing for the bacteria should be done no sooner than 4 weeks after therapy is completed. Test results before that time may not be accurate.

In most cases, drug treatment relieves ulcer symptoms. However, symptom relief does not always indicate success, nor does persistence of dyspepsia necessarily mean that treatment has failed. Heartburn and other symptoms from GERD, for example, can worsen and require acid-suppressing medication.

Failure. Treatment fails in about 15% of patients, mostly when they do not follow their prescribed treatment. Compliance with standard antibiotic regimens may be poor for the following reasons:

Treatment may also fail if the patients harbor strains of H. pylori that are resistant to the antibiotics. When this happens, different drugs are tried.

Reinfection after Successful Treatment. Studies in developed countries indicate that once the bacteria are eliminated, recurrence rates are below 1% per year. Reinfection with the bacteria is possible, however, in areas where the incidence of H. pylori is very high and sanitary conditions are poor. In such regions, reinfection rates are 6 - 15%.

Treatment of NSAIDs-induced ulcers

If NSAID-caused ulcers or bleeding are identified, patients should:

Healing Existing Ulcers. A number of drugs are used to treat NSAID-caused ulcers. PPIs -- omeprazole (Prilosec), lansoprazole (Prevacid), or esomeprazole (Nexium) -- are used most often. Other drugs that may be useful include H2 blockers, such as famotidine (Pepcid AC), cimetidine (Tagamet), and ranitidine (Zantac). Sucralfate is another drug used to heal ulcers and reduce the stomach upset caused by NSAIDs.

A number of alternative medications may be tried for people with chronic pain, to minimize the risk of ulcers associated with NSAIDs.

Gastroenterology

Click the icon to see an animation on ulcer treatment.

Medications

The following drugs are sometimes used in the treatments of peptic ulcers caused by either NSAIDs or H. pylori.

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 the prevention or healing of ulcers, but help in the following ways:

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 antacids:

Interactions with Other Drugs. Antacids can reduce the absorption of a number of drugs. Conversely, some antacids increase the potency of certain drugs. The interactions can be avoided by taking these other drugs 1 hour before or 3 hours after taking the antacid.

Drug Interactions with Antacids (such as Maalox, Mylanta)

Drugs that are absorbed less well if taken with antacids

Drugs that are made more potent by antacids

Tetracycline

Ciprofloxacin (Cipro)

Propranolol (Inderal)

Captopril (Capoten)

Ranitidine (Zantac)

Famotidine (Pepcid AC)

Valproic acid

Sulfonylureas

Quinidine

Levodopa

Antibiotics

H. pylori is usually highly sensitive to certain antibiotics, particularly amoxicillin, and to antibiotics in the macrolide class, such as clarithromycin. Either class of antibiotics serves effectively as a second antibiotic in a three-drug regimen. Other antibiotics that are sometimes used include tetracycline, metronidazole, and ciprofloxacin.

Side Effects of Antibiotics.

Bismuth

Compounds that contain bismuth are often used in the three-drug treatment programs. They destroy the cell walls of H. pylori bacteria. The only bismuth compound available in the U.S. has been bismuth subsalicylate (Pepto-Bismol), although a drug combination of the H2 blocker 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.

Proton-Pump Inhibitors (PPIs)

Actions against ulcers. PPIs are the drugs of choice for managing patients with peptic ulcers, regardless of the cause. They suppress the production of stomach acid by blocking the gastric acid pump -- the molecule in the stomach glands that is responsible for acid secretion.

PPIs can be used either as part of a multidrug regimen for H. pylori or alone for preventing and healing NSAID-caused ulcers. They are also useful in treating ulcers caused by Zollinger-Ellison syndrome. They are considered to be more effective than H2 blockers (see below).

Some people carry a gene that reduces the effectiveness of PPIs. This gene is present in 18 - 20% of people of Asian descent.

Standard Brands. Most PPIs are available by prescription as oral drugs. There is no evidence that one brand of PPI works better than another. Brands approved for ulcer prevention and treatment include:

Possible Adverse Effects.

In theory, long-term use of PPIs by people with H. pylori may reduce acid secretion enough to cause atrophic gastritis (chronic inflammation of the stomach), a risk factor for stomach cancer. Long-term use of PPIs may also mask symptoms of stomach cancer and delay diagnosis. At this time, however, there have been no reports of an increase in the incidence of stomach cancer with long-term use of these drugs.

H2 Blockers

H2 blockers interfere with acid production by blocking histamine, a substance produced by the body that encourages acid secretion in the stomach. H2 blockers were the standard treatment for peptic ulcers until proton pump inhibitor and antibiotic regimens against H. pylori were developed. These drugs cannot cure ulcers, but they are useful in certain cases. They are effective only for duodenal ulcers, however.

Four H2 blockers are currently available over-the-counter in the U.S.: famotidine (Pepcid AC), cimetidine (Tagamet), ranitidine (Zantac), and nizatidine (Axid). All have good safety profiles and few side effects. There are some differences between these drugs:

The PPIs are more effective than the H2 blockers in healing ulcers in people who take NSAIDs. Treatment efficacy for PPIs runs between 65 and 100% versus 50 and 85% or H2 blockers, depending on which agents are being used

Nizatidine (Axid). Nizatidine is nearly free of side effects and drug interactions.

Long-Term Concerns. In most cases, these H2 blockers have good safety profiles and few side effects. Because H2 blockers can interact with other drugs, be sure to tell your doctor about any other drugs you are taking. There are also some concerns about possible long-term effects -- for example, that long-term acid suppression with these drugs may cause cancerous changes in the stomach in patients who also have untreated H. pylori infection. More research is needed. However, the following concerns are well documented:

FDA Warning for Famotidine (Pepcid AC)

Famotidine is excreted primarily by the kidney. This can pose a danger to people with kidney problems. Physicians are now being advised by the U.S. Food and Drug Administration (FDA) and Health Canada to reduce the dose and increase the time between doses in patients with kidney failure. Use of the drug in those with impaired kidney function can affect the central nervous system and may result in anxiety, depression, insomnia or drowsiness, and mental disturbances.

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 the risk of NSAID-induced ulcers in the upper small intestine by two-thirds and in the stomach by three-fourths. 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.

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, however, including warfarin, phenytoin, and tetracycline.

Surgery

When a patient comes to the hospital with bleeding ulcers, endoscopy is usually performed. This procedure is critical for the diagnosis, determination of treatment options, and treatment of bleeding ulcers.

In high-risk patients or those with evidence of bleeding, options include watchful waiting with medical treatments or surgery. The first critical steps for massive bleeding are to stabilize the patient and support vital functions with fluid replacement and possibly blood transfusions. People on NSAIDs should discontinue them, if possible.

Depending on the intensity of the bleeding, patients can be released from the hospital within a day or kept up to 3 days after endoscopy. Bleeding stops spontaneously in about 70 - 80% of patients, but about 30% of patients who come to the hospital for bleeding ulcers need surgery. Endoscopy is the surgical procedure most often used for treating bleeding ulcers and patients at high-risk for rebleeding. It is usually combined with medications, such as epinephrine and intravenous proton-pump inhibitors.

Between 10 - 20% of patients require more invasive procedures for bleeding, usually major abdominal surgery.

Endoscopy for Treating or Preventing Bleeding Ulcers

Endoscopy is important for both diagnosing and treating bleeding ulcers. The doctor first places a thin, flexible plastic tube called an endoscope into the patient's mouth and down the esophagus into the stomach.

Endoscopy for Diagnosing Bleeding Ulcers and Determining Risk of Rebleeding. With endoscopy, doctors are able to detect the signs of bleeding, such as active spurting or oozing of blood from arteries. Endoscopy can also detect specific features in the ulcers referred to as stigmata, which indicate a higher or lower risk of rebleeding.

Such features include the following:

Endoscopy as Treatment. Endoscopy is usually used to treat bleeding from visible vessels that are less than 2 mm in diameter. This approach also appears to be very effective in preventing rebleeding in patients whose ulcers are not bleeding, but who have high-risk features (swollen blood vessels or clots adhering to ulcers).

The following is a typical endoscopy procedure:

Endoscopy is effective in controlling bleeding in more than 85% of appropriate candidates. If rebleeding occurs, a repeat endoscopy is effective in about 75% of patients. Those who fail to respond require major abdominal surgery. The most serious complication from endoscopy is perforation of the stomach or intestinal wall,

Other Medical Considerations. Certain agents may be warranted after endoscopy:

Major Abdominal Surgery

Major abdominal surgery for bleeding ulcers is now generally performed only when endoscopy fails or is not appropriate. Certain emergencies may require surgical repair, such as when an ulcer perforates the wall of the stomach or intestine, causing sudden intense pain and life-threatening infection.

Surgical Approaches. The standard major surgical approach uses a wide abdominal incision and standard surgical instruments (called open surgery). Laparoscopic techniques employ small abdominal incisions and the insertion of tubes that contain miniature cameras and instruments. Laparoscopic techniques are increasingly being used for perforated ulcers. Surgery is not effective for upper GI ulceration caused by chronic NSAID use.

Major Surgical Procedures. There are a number of surgical procedures aimed at long-term relief of ulcer complications. These include:

Gastrectomy - series

Click the icon to see an illustrated series detailing a gastrectomy procedure.

Antrectomy and pyloroplasty are usually performed with vagotomy.

Lifestyle Changes

In the past, it was common practice to tell people suffering from peptic ulcers to consume small, frequent amounts of bland foods. Exhaustive research conducted since that time has shown that a bland diet is not effective in reducing the incidence or recurrence of ulcers, and that eating numerous small meals throughout the day is no more effective than eating three meals a day. Large amounts of food should still be avoided, because stretching 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 ulcers. Fiber found in fruits and vegetables is particularly protective; vitamin A contained in many of these foods may increase the benefit.

Milk. Milk actually encourages the production of acid in the stomach, although moderate amounts (2 - 3 cups a day) appear to do no harm. Certain probiotics, which are "good" bacteria added to yogurt and other fermented milk drinks, may also have gastric protective qualities.

Coffee and Carbonated Beverages. Coffee (both caffeinated and decaffeinated), soft drinks, and fruit juices with citric acid increase stomach acid production. Although no studies have proven that any of these drinks contribute to ulcers, consuming more than 3 cups of coffee per day may increase susceptibility to H. pylori infection.

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 and, in high amounts, can cause considerable GI distress.

Olive Oil. Studies from Spain have shown that phenolic compounds in virgin olive oil may have strong bactericidal activity against 8 strains of H. pylori, 3 of which are resistant to antibiotics.

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.

Stress Relief

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

Alternative Treatments

Melatonin is a hormone found in the brain that is normally associated with sleep. Researchers have observed that the GI tract is rich in melatonin, and that the hormone may have properties that help prevent ulcers, reduce acid secretion, and improve blood flow. It is not known whether this would benefit people with peptic ulcers, but it appears to warrant some research. In the U.S., melatonin is classified as a dietary supplement and not a drug, so its quality and effectiveness are uncontrolled. The U.S. is the only developed nation that does not regulate this agent.

Resources

References

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de Bortoli M, Leonardi G, Ciancia E, et al. Helicobacter pylori eradication: a randomized prospective study of triple therapy versus triple therapy plus lactoferrin and probiotics. Am J. Gastroenterol. 2007;102(5):951-956.

Gancz H, Jones KR, Merrell DS. Sodium Chloride Affects Helicobacter pylori Growth and Gene Expression. Journal of Bacteriology. 2008;190(11):4100-4105.

Kim JI, Cheung DY, Cho SH, et al. Oral proton pump inhibitors are as effective as endoscopic treatment for bleeding peptic ulcer: a prospective, randomized, controlled trial. Dig Dis Sci. 2007;52(12):3371-3376.

Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2007;369(9560):465-73.

Luo J, Nordenvall C, Nyren O, et al. The risk of pancreatic cancer in patients with gastric or duodenal ulcer disease. Int J Cancer. 2007;120(2):368-372.

Malagelada J-R, KuipersMartin EJ, Blaser J. Acid Peptic Disease: Clinical manifestations, Diagnosis, Treatment, and Prognosis. In: Goldman: Cecil Medicine, 23rd ed. Philadelphia, PA: WB Saunders, 2007.

Mercer DW, Robinson EK. Stomach. In: Townsend: Sabiston Textbook of Surgery, 18th ed. Philadelphia, PA: WB Saunders, 2007.

Moberly JB, Harris SI, Diff DS, et al. A randomized, double-blind, one-week study comparing the effects of a novel COX-2 inhibitor and naproxen on the gastric mucosa. Dig Dis Sci. 2007;52(2):442-450.

O'Brien DP, Romero-Gallo J, Schneider BG, et al. Regulation of the Helicobacter pylori cellular receptor decay-accelerating factor. J Biol Chem. 2008 Aug 29;283(35):23922-23930

Pietroiusti A, Forlini A, Magrini A, et al. Shift work increases the frequency of duodenal ulcer in H. pylori infected workers. Occup Environ Med. 2006;63(11):773-775.

Saif MW, Elfiky A, Salem RR. Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol. 2007;14(6):1860-1869.

Ramakrishnan K, Salinas RC. Peptic ulcer disease. Am Fam Physician. 2007;76(7):1005-1012.

Take S, Mizuno M, Ishiki K, et al. Baseline gastric mucosal atrophy is a risk factor associated with the development of gastric cancer after Helicobacter pylori eradication therapy in patients with peptic ulcer disease. J Gastroenterol. 2007;42(suppl 17):21-27.

Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med. 2007;146(8):556-563.

Verhamme K, Mosis G, Dieleman J, Stricker B, Sturkenboom M. Spironolactone and risk of upper gastrointestinal events: population-based case-control study. BMJ. 2006;333(7563):330. Epub 2006 Jul 13.

Yeomans ND, Svedberg LD, Naesdal J. Is ranitidine therapy sufficient for healing peptic ulcers associated with non-steroidal anti-inflammatory drug use? Int J Clin Pract. 2006;60(11):1401-407.

Review Date: 11/3/2008
Reviewed By: Reviewed by: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
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