Contents

Indigestion (Dyspepsia, Upset Stomach) ...................................................................................................... 3 What is dyspepsia (indigestion)? .......................................................................................................... 3 What are the symptoms of dyspepsia (indigestion)? ........................................................................... 5 What causes dyspepsia (indigestion)? .................................................................................................. 6 What is the course of dyspepsia (indigestion)? .................................................................................... 8 What are the complications of dyspepsia (indigestion)?...................................................................... 8 How is dyspepsia diagnosed (indigestion)? .......................................................................................... 8 Exclusion of other diseases ................................................................................................................... 9 Specific tests of gastrointestinal function ........................................................................................... 11 How is dyspepsia (indigestion) treated? ............................................................................................. 13 What is a reasonable approach to the diagnosis and treatment of dyspepsia (indigestion)? ........... 17 What is in the future for dyspepsia (indigestion)? ............................................................................. 19 Peptic Ulcer Disease.................................................................................................................................... 23 Background ............................................................................................................................................. 23 Anatomy .................................................................................................................................................. 24 Pathphysiology ........................................................................................................................................ 24 Etiology ................................................................................................................................................... 25 H pylori infection................................................................................................................................. 26 Drugs ................................................................................................................................................... 26 Lifestyle factors ................................................................................................................................... 27 Severe physiologic stress .................................................................................................................... 27 Hypersecretory states (uncommon) ................................................................................................... 27 Physiologic factors .............................................................................................................................. 28 Genetics .............................................................................................................................................. 28 Additional etiologic factors ................................................................................................................. 28 Prognosis ................................................................................................................................................ 29 Patient Education .................................................................................................................................. 30 History.................................................................................................................................................... 30 Physical Examination ........................................................................................................................... 31

Diagnostic Considerations .................................................................................................................... 31 Differentials ........................................................................................................................................... 32

Indigestion (Dyspepsia, Upset Stomach)

What is dyspepsia (indigestion)? Dyspepsia is one of the most common ailments of the bowel (intestines), affecting an estimated 20% of persons in the United States. Perhaps only 10% of those affected actually seek medical attention for their dyspepsia. Dyspepsia is not a particularly good term for the ailment since it implies that there is "dyspepsia" or abnormal digestion of food, and this most probably is not the case. In fact, another common name for dyspepsia is indigestion, which, for the same reason, is no better than the term dyspepsia! Doctors frequently refer to the condition as non-ulcer dyspepsia. Dyspepsia (indigestion) is best described as a functional disease. (Sometimes, it is called functional dyspepsia.) The concept of functional disease is particularly useful when discussing diseases of the gastrointestinal tract. The concept applies to the muscular organs of the gastrointestinal tractesophagus, stomach, small intestine, gallbladder, and colon. What is meant by the term, functional, is that either the muscles of the organs or the nerves that control the organs are not working normally, and, as a result, the organs do not function normally. The nerves that control the organs include not only the nerves that lie within the muscles of the organs but also the nerves of the spinal cord and brain. Some gastrointestinal diseases can be seen and diagnosed with the naked eye, such as ulcers of the stomach. Thus, ulcers can be seen at surgery, on x-rays, and and by endoscopy. Other diseases cannot be seen with the naked eye but can be seen and diagnosed under the microscope. For example, gastritis (inflammation of the stomach) is diagnosed by microscopic examination of biopsies of the stomach. In contrast, gastrointestinal functional diseases cannot be seen with the naked eye or with the microscope. In some instances, the abnormal function can be demonstrated by tests (for example, gastric emptying studies or antro-duodenal motility studies). However, the tests often are complex, are not widely available, and do not reliably detect the functional abnormalities. Accordingly, and by default, functional gastrointestinal diseases are those that involve abnormal function of gastrointestinal organs in which the abnormalities cannot be seen in the organs with either the naked eye or the microscope. Occasionally, diseases that are thought to be functional are ultimately found to be associated with abnormalities that can be seen. Then, the disease moves out of the functional category. An example of this would be Helicobacter pylori (H. pylori) infection of the stomach. Some patients with mild upper gastrointestinal symptoms who were thought to have abnormal function of the stomach or intestines have been found to have stomachs infected with H. pylori. This infection can be diagnosed under the microscope by identifying the bacterium. When patients are treated with antibiotics, the H. pylori and symptoms disappear. Thus, recognition of infections with Helicobacter pylori has removed some patients' systems from the functional disease category. The distinction between functional disease and non-functional disease may, in fact, be blurry. Thus, even functional diseases probably have associated biochemical or molecular abnormalities that ultimately will be able to be measured. For example, functional diseases of the stomach and intestines may be shown ultimately to be associated with reduced or increased levels of normal chemicals within the gastrointestinal organs, the spinal cord, or the brain. Should a disease that is demonstrated to be due to a reduced or increased chemical still be considered a functional disease? I think not. In this theoretical situation, we can't see the abnormality with the naked eye or the microscope, but we can

measure it. If we can measure an associated or causative abnormality, the disease probably should no longer be considered functional. Despite the shortcomings of the term, functional, the concept of a functional abnormality is useful for approaching many of the symptoms originating from the muscular organs of the gastrointestinal tract. To repeat, this concept applies to those symptoms for which there are no associated abnormalities that can be seen with the naked eye or the microscope. While dyspepsia is a major functional disease(s), it is important to mention several other functional diseases. A second major functional disease is the irritable bowel syndrome, or IBS. The symptoms of IBS are thought to originate primarily from the small intestine and/or colon. The symptoms of IBS include abdominal pain that is accompanied by alterations in bowel movements (defecation), primarily constipation or diarrhea. In fact, dyspepsia and IBS may be overlapping diseases since up to half of patients with IBS also have symptoms of dyspepsia. A third distinct functional disorder is non-cardiac chest pain. This pain may mimic heart pain (angina), but it is unassociated with heart disease. In fact, non-cardiac chest pain is thought to result from a functional abnormality of the esophagus. Functional disorders of the gastrointestinal tract often are categorized by the organ of involvement. Thus, there are functional disorders of the esophagus, stomach, small intestine, colon, and gallbladder. The amount of research that has been done with functional disorders is greatest in the esophagus and stomach (for example, non-cardiac chest pain, dyspepsia), perhaps because these organs are easiest to reach and study. Research into functional disorders affecting the small intestine and colon (IBS) is more difficult to conduct and there is less agreement among the research studies. This probably is a reflection of the complexity of the activities of the small intestine and colon and the difficulty in studying these activities. Functional diseases of the gallbladder (referred to as biliary dyskinesia), like those of the small intestine and colon, also are more difficult to study, and at present they are less well-defined. Each of the functional diseases is associated with its own set of characteristic symptoms.

What are the symptoms of dyspepsia (indigestion)? We usually think of symptoms of dyspepsia as originating from the upper gastrointestinal tract, primarily the stomach and first part of the small intestine. These symptoms include:

upper abdominal pain (above the navel), belching, nausea (with or without vomiting), abdominal bloating (the sensation of abdominal fullness without objective distention), early satiety (the sensation of fullness after a very small amount of food), and,

possibly, abdominal distention (swelling as opposed to bloating).

The symptoms most often are provoked by eating, which is a time when many different gastrointestinal functions are called upon to work in concert. This tendency to occur after meals is what gave rise to the notion that dyspepsia might be caused by an abnormality in the digestion of food. It is appropriate to discuss belching in detail since it is a commonly misunderstood symptom associated with dyspepsia. The ability to belch is almost universal. Belching, also known as burping or eructating, is the act of expelling gas from the stomach out through the mouth. The usual cause of belching is a distended (inflated) stomach that is caused by swallowed air or gas. The distention of the stomach causes abdominal discomfort, and the belching expels the air and relieves the discomfort. The common reasons for swallowing large amounts of air (aerophagia) or gas are gulping food or drink too rapidly, anxiety, and carbonated beverages. People often are unaware that they are swallowing air. Moreover, if there is not excess air in the stomach, the act of belching actually may cause more air to be swallowed. "Burping" infants during bottle or breastfeeding is important in order to expel air in the stomach that has been swallowed with the formula or milk. Excessive air in the stomach is not the only cause of belching. For some people, belching becomes a habit and does not reflect the amount of air in their stomachs. For others, belching is a response to any type of abdominal discomfort and not just to discomfort due to increased gas. Everyone knows that when they have mild abdominal discomfort, belching often relieves the problem. This is because excessive air in the stomach is often the cause of mild abdominal discomfort. As a result, people belch whenever mild abdominal discomfort is felt-whatever the cause. If the problem causing the discomfort is not excessive air in the stomach, then belching does not provide relief. As mentioned previously, it even may make the situation worse by increasing air in the stomach. When belching does not ease the discomfort, the belching should be taken as a sign that something may be wrong within the abdomen and that the cause of the discomfort should be sought. Belching by itself, however, does not help the physician determine what may be wrong because belching can occur in virtually any abdominal disease or condition that causes discomfort.

What causes dyspepsia (indigestion)? It's not surprising that many gastrointestinal diseases have been associated with dyspepsia. However, many non-gastrointestinal diseases also have been associated with dyspepsia. Examples of the latter include diabetes, thyroid disease, hyperparathyroidism (overactive parathyroid glands), and severe kidney disease. It is not clear, however, how these non-gastrointestinal diseases might cause dyspepsia. A second important cause of dyspepsia is drugs. It turns out that many drugs are frequently associated with dyspepsia, for example, nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen), antibiotics, and estrogens). In fact, most drugs are reported to cause dyspepsia in at least some patients. As discussed previously, most dyspepsia (not due to non-gastrointestinal diseases or drugs) is believed to be due to abnormal function (dysfunction) of the muscles of the organs of the gastrointestinal tract or the nerves controlling the organs. The nervous control of the gastrointestinal tract, however, is complex. A system of nerves runs the entire length of the gastrointestinal tract from the esophagus to the anus in the muscular walls of the organs. These nerves communicate with other nerves that travel to and from 6

the spinal cord. Nerves within the spinal cord, in turn, travel to and from the brain. (The gastrointestinal tract is exceeded in the numbers of nerves it contains only by the spinal cord and brain.) Thus, abnormal function of the nervous system in dyspepsia might occur in a gastrointestinal muscular organ, the spinal cord, or the brain. The nervous system controlling the gastrointestinal organs, as with most other organs, contains both sensory and motor nerves. The sensory nerves continuously sense what is happening (activity) within the organ and relay this information to nerves in the organ's wall. From there, information can be relayed to the spinal cord and brain. The information is received and processed in the organ's wall, the spinal cord, or the brain. Then, based on this sensory input and the way the input is processed, commands (responses) are sent to the organ over the motor nerves. Two of the most common motor responses in the intestine are contraction or relaxation of the muscle of the organ and secretion of fluid and/or mucus into the organ. As already mentioned, abnormal function of the nerves of the gastrointestinal organs, at least theoretically, might occur in the organ, spinal cord, or brain. Moreover, the abnormalities might occur in the sensory nerves, the motor nerves, or at processing centers in the intestine, spinal cord, or brain. Some researchers argue that the cause of functional diseases is abnormalities in the function of sensory nerves. For example, normal activities, such as stretching of the small intestine by food, may give rise to sensory signals that are sent to the spinal cord and brain, where they are perceived as painful. Other researchers argue that the cause of functional diseases is abnormalities in the function of motor nerves. For example, abnormal commands through the motor nerves might produce painful spasm (contraction) of the muscles. Still others argue that abnormally functioning processing centers are responsible for functional diseases because they misinterpret normal sensations or send abnormal commands to the organ. In fact, some functional diseases may be due to sensory dysfunction, motor dysfunction, or both sensory and motor dysfunction. Others may be due to abnormalities within the processing centers. An important concept that is relevant to these several potential mechanisms (causes) of functional diseases is the concept of "visceral hypersensitivity". This concept states that diseases affecting the gastrointestinal organs (viscera) "sensitize" (alter the responsiveness of) the sensory nerves or the processing centers to sensations coming from the organ. According to this theory, a disease such as colitis (inflammation of the colon) can cause permanent changes in the sensitivity of the nerves or processing centers of the colon. As a result of this prior inflammation, normal stimuli are perceived (felt) as abnormal (for example, as being painful). Thus, a normal colonic contraction may be painful. It is not clear what prior diseases might lead to hypersensitivity in people, although infectious diseases (bacterial or viral) of the gastrointestinal tract are mentioned most often. Visceral hypersensitivity has been demonstrated clearly in animals and people. Its role in the common functional diseases, however, is unclear. Another potential cause of dyspepsia is bacterial overgrowth of the small intestine (small intestinal bacterial overgrowth), although the frequency with which this condition causes dyspepsia has not been determined, and there is little research in the area. The relationship between overgrowth and dyspepsia needs to be persued, however, since many of the symptoms of dyspepsia are also symptoms of bacterial overgrowth. Overgrowth can be diagnosed by hydrogen breath testing and is treated primarily with antibiotics.

Other diseases and conditions can aggravate functional diseases, including dyspepsia. Anxiety and/or depression are probably the most commonly-recognized exacerbating factors for patients with functional diseases. Another aggravating factor is the menstrual cycle. During their periods, women often note that their functional symptoms are worse. This corresponds to the time during which the female hormones, estrogen and progesterone, are at their highest levels. Furthermore, it has been observed that treating women who have dyspepsia with leuprolide (Lupron), an injectable drug that shuts off the body's production of estrogen and progesterone, is effective at reducing symptoms of dyspepsia in premenopausal women. These observations support a role for hormones in the intensification of functional symptoms.

What is the course of dyspepsia (indigestion)? Dyspepsia is a chronic disease that usually lasts years, if not a lifetime. It does, however, display periodicity, which means that the symptoms may be more frequent or severe for days, weeks, or months and then less frequent or severe for days, weeks, or months. The reasons for these fluctuations are unknown. Because of the fluctuations, it is important to judge the effects of treatment over many weeks or months to be certain that any improvement is due to treatment and not simply to a natural fluctuation in the frequency or severity of the disease.

What are the complications of dyspepsia (indigestion)? The complications of functional diseases of the gastrointestinal tract are relatively limited. Since symptoms are most often provoked by eating, patients who alter their diets and reduce their intake of calories may lose weight. However, loss of weight is unusual in functional diseases. In fact, loss of weight should suggest the presence of non-functional diseases. Symptoms that awaken patients from sleep also are more likely to be due to non-functional than functional disease. Most commonly, functional diseases interfere with patients' comfort and daily activities. Persons who develop nausea or pain after eating may skip breakfast or lunch. Patients also commonly associate symptoms with specific foods (for example, milk, fat, vegetables). Whether or not the associations are real, these patients will restrict their diets accordingly. Milk is the most common food that is eliminated, often unnecessarily, and this can lead to inadequate intake of calcium and osteoporosis. The interference with daily activities also can lead to problems with interpersonal relationships, especially with spouses. Most patients with functional disease live with their symptoms and infrequently visit physicians for diagnosis and treatment.

How is dyspepsia diagnosed (indigestion)? Dyspepsia is diagnosed primarily on the basis of typical symptoms and the exclusion of non-functional gastrointestinal diseases (including acid-related diseases), non-gastrointestinal diseases, and psychiatric illness. There are tests for identifying abnormal gastrointestinal function directly, but they are limited in their ability to do so. 8

Exclusion of other diseases Exclusion of non-functional gastrointestinal disease As always, a detailed history from the patient and a physical examination frequently will suggest the cause of dyspepsia. Routine screening blood tests often are performed looking for clues to unsuspected diseases. Examinations of stool also are a part of the evaluation since they may reveal infection, signs of inflammation, or blood and direct further diagnostic testing. Sensitive stool testing (antigen/antibody) for Giardia lamblia would be reasonable because this parasitic infection is common and can be acute or chronic. Some physicians do blood testing for celiac disease (sprue), but the value of doing this is unclear. (Moreover, if an EGD is planned, biopsies of the duodenum usually will make the diagnosis of celiac disease.) If bacterial overgrowth of the small intestine is being considered, breath hydrogen testing can be considered. There are many tests to exclude non-functional gastrointestinal diseases. The primary issue, however, is to decide which tests are reasonable to perform. Since each case is individual, different tests may be reasonable for different patients. Nevertheless, certain basic tests are often performed to exclude nonfunctional gastrointestinal disease. These tests identify anatomic (structural) and histological (microscopic) diseases of the esophagus, stomach, and intestines. Both x-rays and endoscopies can identify anatomic diseases. Only endoscopies, however, can diagnose histological diseases because biopsies (samples of tissue) can be taken during the procedure. The x-ray tests include:

The esophagram and video-fluoroscopic swallowing study for examining the esophagus The upper gastrointestinal series for examining the stomach and duodenum The small bowel series for examining the small intestine The barium enema for examining the colon and terminal ileum. The computerized tomography (CT) scan for examining the small intestine

The endoscopic tests include:

Upper gastrointestinal endoscopy (esophago-gastro-duodenoscopy or EGD) to examine the esophagus, stomach and duodenum Colonoscopy to examine the colon and terminal ileum Endoscopy also is available to examine the small intestine, but this type of endoscopy is complex, not widely available, and of unproven value in dyspepsia.

For examination of the small intestine, there is also a capsule containing a tiny camera and transmitter that can be swallowed (capsule endoscopy). As the capsule travels through the intestines, it transmits pictures of the inside of the intestines to an external recorder for later review. The capsule is not widely available and its value, particularly in dyspepsia, has not yet been proven. 9

X-rays are easier to perform and less costly than endoscopies. The skills necessary to perform gastrointestinal x-rays, however, are becoming rare among radiologists because they are doing them less often. Therefore, the quality of the x-rays often is not as high as it used to be, and, as a result, CT scans of the small intestine are replacing small intestinal x-rays. As noted previously, endoscopies have an advantage over x-rays since at the time of endoscopies, biopsies can be taken to diagnose or exclude histological diseases, something that x-rays cannot do. Exclusion of acid-related gastrointestinal diseases Because they are so common, the most important non-functional gastrointestinal diseases to exclude are acid-related diseases that cause inflammation and ulceration of the esophagus, stomach, and duodenum. Infection of the stomach with Helicobacter pylori, an infection that is closely associated with some acid-related diseases, is included in this group. It is not clear, however, how often Helicobacter pylori causes dyspepsia. Moreover, the only way of excluding this bacterium as a cause of dyspepsia in a particular patient is by eliminating the infection (if it is present) with appropriate antibiotics. If dyspepsia is substantially improved by eradication, it is likely that the bacterium was responsible. Helicobacter pylori infection can also be diagnosed (or excluded) by blood tests, biopsy of the stomach, urea breath test, or a stool test. Endoscopy is a good way of diagnosing or excluding acid-related inflammation. If no signs of inflammation are present, acid-related diseases are unlikely. Nevertheless, some patients without signs of inflammation respond to potent and prolonged suppression of acid, suggesting that acid is causing their dyspepsia. Therefore, many physicians will use potent suppression of acid in dyspepsia as a means to both treat and diagnose. Thus, if dyspepsia improves substantially (more than 50% to 75%) with suppression of acid, they consider it likely that acid is responsible for the dyspepsia. For this purpose, it is important to use potent acid suppression with proton pump inhibitors (PPIs), such as:

omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix) or esomeprazole (Nexium).

Treatment often is given at higher than recommended doses for 12 weeks or more before a decision is made about the effect of treatment on the symptoms. (A short course for just a few days or weeks is not enough.) If the symptoms of dyspepsia do not improve, it even may be reasonable to check the amount of acid produced by the stomach (and also the reflux of acid into the esophagus) by 24 hour ph monitoring to be certain that the acid-suppressing drugs are effectively suppressing acid. (Up to 10% of patients are resistant to the effects of even the PPIs.) Exclusion of non-gastrointestinal disease Patients with dyspepsia often undergo abdominal ultrasonography (US), computerized tomography (CT or CAT scans), or magnetic resonance imaging (MRI). These tests are used primarily to diagnose non10

intestinal diseases. (Although the tests also are capable of diagnosing intestinal diseases, their value for this purpose is limited. X-ray and endoscopy are better.) It is important to realize that US, CT, and MRI are powerful tests and may uncover abnormalities that are unrelated to dyspepsia. The most common example of this is the finding of gallstones that, in fact, are causing no symptoms. (Up to 50% of gallstones cause no symptoms.) This can cause a problem if the gallstones are assumed to be causing the dyspepsia. Surgical removal of the gallbladder with its gallstones (cholecystectomy) is unlikely to relieve the dyspepsia. (Cholecystectomy would be expected to relieve only the characteristic symptoms that gallstones can cause.) Additional tests to exclude non-gastrointestinal diseases may be appropriate in certain specific situations, although certainly not in most patients. Exclusion of psychiatric disease The possibility of psychiatric (psychological or psychosomatic) illness often arises in patients with dyspepsia because the symptoms are subjective and no objective abnormalities can be identified. Psychiatric illness may complicate dyspepsia, but it is unclear if psychiatric illness causes dyspepsia. If there is a possibility of psychiatric illness, a psychiatric evaluation is appropriate.

Specific tests of gastrointestinal function Esophageal motility study Functional disorders of the esophagus can be identified with esophageal motility studies (manometry). For these studies, a pressure-sensing tube is swallowed and positioned within the esophagus. Contractions of the esophageal muscle normally cause increases in pressure within the esophagus that can be monitored by the catheter during and between swallows of water. Among the abnormalities that can be seen are abnormally high or abnormally low pressures during swallow-associated contractions and/or during spontaneous contractions unassociated with swallows. Gastric emptying study and electrogastrogram Slow emptying of the stomach is a common functional abnormality that can lead to bloating, nausea, and vomiting. Rapid emptying of the stomach is relatively uncommon and can lead to abdominal pain and diarrhea. Both of these abnormalities--slow and rapid emptying--can be identified by a gastric emptying study. The most common type of emptying study is a nuclear medicine study. In this test, patients drink or eat food labeled with radioactive material. A Geiger counter-like device then is placed over the abdomen and the speed with which the radioactive drink or food empties from the stomach is monitored. The electrogastrogram (EGG) is like the electrocardiogram (ECG) for the heart. Electrodes that are taped to the upper abdomen monitor the electrical activity generated by the muscle of the stomach. Abnormalities of the electrical rhythm of the stomach frequently are associated with dyspeptic symptoms, particularly nausea and vomiting. Barostatic study 11

A barostat is an instrument that is used to measure pressure and determine the compliance (flexibility) of a gastrointestinal organ. Compliance is a term that describes the effect that internal stretching has on the organ. The greater the compliance of an organ, the less there is tension (pressure) generated when the organ is stretched from within. Compliance is important to the normal function of gastrointestinal organs. For example, as food fills the stomach during a meal, the muscles of the stomach must relax (comply) to accommodate the increasing volume of food. If the stomach does not relax properly, the pressure in the stomach increases abnormally. It is believed that abnormally high pressures within the stomach (due to reduced compliance) can lead to symptoms such as early satiety (the feeling of abdominal fullness or pain after only a small amount of food has been ingested). The barostat includes a balloon that is placed within a gastrointestinal organ through the mouth or anus. As the balloon is progressively blown up and stretches the organ, the pressure within the organ is measured by the barostat. In this way, abnormal compliance can be identified. Barostats can be placed in the esophagus, stomach, small intestine or colon. Barostatic studies, however, probably should be considered experimental. In fact, barostats and expertise in their use are available in only a limited number of centers. Small intestinal transit study Small intestinal transit studies measure the speed with which food travels through the small intestine. In the most common type of transit study, a test meal that has been labeled with a radioactive material is ingested. A Geiger-counter-like device is placed over the abdomen and is used to follow the radioactive material through the small intestine and into the colon. Rapid transit is associated with abdominal pain and diarrhea. Slow transit also may be associated with abdominal pain. Although transit studies are not difficult to conduct, they are not frequently used because experience with their use is not wide-spread. They probably should be considered experimental. Antro-duodenal motility study Antro-duodenal motility studies measure the pressures that are generated by the contractions of the muscles of the antrum (outlet) of the stomach and the duodenum. For these studies, a pressure-sensing tube is swallowed or passed through the nose and positioned in the distal (outlet) part of the stomach (the antrum) and the first part of the small intestine (the duodenum). Pressures are measured with the stomach empty and after a test meal. Abnormally high or low pressures as well as uncoordinated contractions can be identified. These abnormalities are believed to be associated with symptoms of dyspepsia. Antro-duodenal motility studies and expertise in their use are not widely available. Gallbladder emptying studies Gallbladder emptying studies determine how well the gallbladder empties. Between meals, the gallbladder stores bile that is produced by the liver. After meals, the muscles of the gallbladder contract and squeeze out (empty) most of the bile into the intestine. In the intestine, the bile assists with the digestion of food.

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For a gallbladder emptying study, a radioactive material is injected intravenously. The radioactive material is removed from the blood by the liver and accumulates with the bile in the gallbladder. The gallbladder then is stimulated to contract with either a meal or an intravenous injection of a hormone, called cholecystokinin. A Geiger-counter-like device is placed over the abdomen and the speed with which the radioactivity leaves the gallbladder and enters the intestine is monitored. Emptying studies of the gallbladder are widely available since this technology is used for several purposes other than measurement of gallbladder emptying. It has been suggested that abnormally slow emptying of the gallbladder may be associated with abdominal pain. Unfortunately, however, the studies that support the association between slow gallbladder emptying and symptoms are weak. Moreover, many people have abnormally slow emptying of the gallbladder but no symptoms. For these reasons, abnormal emptying studies of the gallbladder have not been widely accepted for diagnosing functional disorders of the gallbladder. The lack of a clear association between dyspepsia and abnormalities of gallbladder emptying is important since it means that patients with abnormal emptying may not be improved by removal of their gallbladders.

How is dyspepsia (indigestion) treated? The treatment of dyspepsia is a difficult and unsatisfying topic because so few drugs have been studied and have shown to be effective. Moreover, the drugs that have been shown to be useful have not been substantially effective. This difficult situation exists for many reasons, as follows:

Life-threatening illnesses (for example, cancer, heart disease, and high blood pressure) are the illnesses that capture the public's interest and, more importantly, research funding. Dyspepsia is not a life-threatening illness and has received little research funding. Because of the lack of research, an understanding of the physiologic processes (mechanisms) that are responsible for dyspepsia has been slow to develop. Effective drugs cannot be developed until there is an understanding of these mechanisms. Research in dyspepsia is difficult. Dyspepsia is defined by subjective symptoms (such as pain) rather than objective signs (for example, the presence of an ulcer). Subjective symptoms are more unreliable than objective signs in identifying homogenous groups of patients. As a result, groups of patients with dyspepsia who are undergoing treatment are likely to contain some patients who do not have dyspepsia, which may dilute (negatively affect) the results of the treatment. Moreover, the results of treatment must be evaluated on the basis of subjective responses (such as improvement of pain). In addition to being more unreliable, subjective responses are more difficult to measure than objective responses (for example, healing of an ulcer). Different subtypes of dyspepsia (for example, abdominal pain and abdominal bloating) are likely to be caused by different physiologic processes (mechanisms). It also is possible, however, that the same subtype of dyspepsia may be caused by different mechanisms in different people. What's more, any drug is likely to affect only one mechanism. Therefore, it is unlikely that any one medication can be effective in all-even most-patients with dyspepsia, even patients with similar symptoms. This inconsistent effectiveness makes the testing of drugs particularly

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difficult. Indeed, it can easily result in drug trials that demonstrate no efficacy (usefulness) when, in fact, the drug is helping a subgroup of patients.

Subjective symptoms are particularly prone to responding to placebos (inactive drugs). In fact, in most studies, 20% to 40% of patients with dyspepsia will improve if they receive inactive drugs. Now, all clinical trials of drugs for dyspepsia require a placebo-treated group for comparison with the drug-treated group. The large placebo response means that these clinical trials must utilize large numbers of patients to detect meaningful (significant) differences in improvement between the placebo and drug groups. Therefore, these trials are expensive to conduct.

The lack of understanding of the physiologic processes (mechanisms) that cause dyspepsia has meant that treatment usually cannot be directed at the mechanisms. Instead, treatment usually is directed at the symptoms. For example, nausea is treated with medications that suppress nausea but do not affect the cause of the nausea. On the other hand, the psychotropic drugs (antidepressants) and psychological treatments (such as cognitive behavioral therapy) treat hypothetical causes of dyspepsia (for example, abnormal function of sensory nerves and the psyche) rather than the symptoms. Treatment for dyspepsia often is similar to that for irritable bowel syndrome (IBS) even though the causes of IBS and dyspepsia are likely to be different. Education It is important to educate patients with dyspepsia about their illness, particularly by reassuring them that the illness is not a serious threat to their physical health (though it may be to their emotional health). Patients need to understand the mechanisms (causes) for the symptoms. Most importantly, they need to understand the medical approach to the problem and the reasons for each test or treatment. Education prepares patients for a potentially prolonged course of diagnosis and trials of treatment. Education also may prevent patients from falling prey to the charlatans who offer unproven and possibly dangerous treatments for dyspepsia. Many symptoms are tolerable if patients' anxieties about the seriousness of their symptoms can be relieved. It also helps patients deal with symptoms when they feel that everything that should be done to diagnose and treat, in fact, is being done. The truth is that psychologically healthy people can tolerate a good deal of discomfort and continue to lead happy and productive lives. Diet Dietary factors have not been well-studied in the treatment of dyspepsia. Nevertheless, patients often associate their symptoms with specific foods (such as salads and fats). Although specific foods might worsen the symptoms of dyspepsia, it is clear that they are not the cause of dyspepsia. The common placebo response in functional disorders such as dyspepsia also may explain the improvement of symptoms in some people with the elimination of specific foods. Dietary fiber often is recommended for patients with IBS, but fiber has not been studied in the treatment of dyspepsia. Nevertheless, it probably is reasonable to treat patients with dyspepsia with fiber if they also have constipation. Intolerance to lactose (the sugar in milk) often is blamed for dyspepsia. Since dyspepsia and lactose intolerance both are common, the two conditions may coexist. In this situation, restricting lactose will 14

improve the symptoms of lactose intolerance, but will not affect the symptoms of dyspepsia. Lactose intolerance is easily determined by testing the effects of lactose (hydrogen breath testing) or trying a strict lactose elimination diet. If lactose is determined to be responsible for some or all of the symptoms, elimination of lactose-containing foods is appropriate. Unfortunately, many patients stop drinking milk or eating milk-containing foods without good evidence that it improves their symptoms. This often is detrimental to their intake of calcium which may contribute to osteoporosis. One of the food substances most commonly associated with the symptoms of dyspepsia is fat. The scientific evidence that fat causes dyspepsia is weak. Most of the support is anecdotal (not based on carefully done, scientific studies). Nevertheless, fat is one of the most potent influences on gastrointestinal function. (It tends to slow down the gastrointestinal muscles while it causes the muscles of the gallbladder to contract.) Therefore, it is possible that fat may worsen dyspepsia even though it doesn't cause it. Moreover, reducing the ingestion of fat might relieve symptoms. A strict low fat diet can be accomplished fairly easily and is worth trying. Additionally, there are other health-related reasons for reducing dietary fat. Another dietary factor, fructose and fructose-related sugars, has been suggested as a cause of dyspepsia since many people do not fully digest and absorb them before they reach the distal intestine. It is diagnosed with a hydrogen breath test using fructose and treated with elimination of fructosecontaining foods from the diet. Unfortunately, fructose and its related sugars are widespread among fruits and vegetables and are found in high concentrations in many food products sweetened with corn syrup. Thus, an elimination diet is more difficult to maintain. Psychotropic drugs Patients with functional disorders, including dyspepsia, are frequently found to be suffering from depression and/or anxiety. It is unclear, however, if the depression and anxiety are the cause or result of the functional disorders or are unrelated to these disorders. (Depression and anxiety are common and, therefore, their occurrence together with functional disorders may be coincidental.) Several clinical trials have shown that antidepressants are effective in IBS in relieving abdominal pain. Antidepressants also have been shown to be effective in unexplained (non-cardiac) chest pain, a condition thought to represent a dysfunction of the esophagus. Antidepressants have not been studied adequately in other types of functional disorders, including dyspepsia. It probably is reasonable to treat patients with dyspepsia with psychotropic drugs if they have moderate or severe depression or anxiety. The antidepressants work in dyspepsia and in functional esophageal pain at relatively low doses that have little or no effect on depression. It is believed, therefore, that these drugs work not by combating depression, but in different ways (through different mechanisms). For example, these drugs have been shown to adjust (modulate) the activity of the nerves and to have analgesic (pain-relieving) effects as well. Commonly used psychotropic drugs include the tricyclic antidepressants, desipramine (Norpramine) and trimipramine (Surmontil). Although studies are encouraging, it is not yet clear whether the newer class of antidepressants, the serotonin-reuptake inhibitors such as fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil), are effective in functional disorders, including dyspepsia. Psychological treatments 15

Psychological treatments include cognitive-behavioral therapy, hypnosis, psychodynamic or interpersonal psychotherapy, and relaxation/stress management. Few studies of psychological treatments have been conducted in dyspepsia, although more studies have been done in IBS. Thus, there is little scientific evidence that they are effective in dyspepsia, although there is some evidence that they are effective in IBS. Promotility drugs One of the leading theories for the cause of dyspepsia is abnormalities in the way gastrointestinal muscles function. The function of muscles may be abnormally increased, abnormally decreased, or it may by uncoordinated. There are medications, called smooth muscle relaxants, that can reduce the activity of the muscles and other drugs that can increase the activity of the muscles, called the promotility drugs. Many of the symptoms of dyspepsia can be explained on the basis of reduced activity of the gastrointestinal muscles that results in slowed transport (transit) of food through the stomach and intestine. (It is clear, as discussed previously, that there are other causes of these symptoms in addition to slowed transit.) Such symptoms include nausea, vomiting, and abdominal bloating. When transit is severely affected, abdominal distention (swelling) also may occur and can result in abdominal pain. (Early satiety is unlikely to be a function of slowed transit because it occurs too early for slowed transit to have consequences.) Theoretically, drugs that speed up the transit of food should, in at least some patients, relieve symptoms of dyspepsia that are due to slow transit. The number of promotility drugs that are available for use clinically is limited. Studies of their effectiveness in dyspepsia are even more limited. The most studied drug is cisapride (Propulsid), a promotility drug that was withdrawn from the market because of serious cardiac side effects. The few studies with cisapride for dyspepsia were inconsistent in their results. Some studies demonstrated benefits whereas others showed no benefit. Cisapride was effective in patients with severe emptying problems of the stomach (gastroparesis) or severely slowed transit of food through the small intestine (chronic intestinal pseudo-obstruction). These two diseases may or may not be related to dyspepsia. Another promotility drug that is available is erythromycin, an antibiotic that stimulates gastrointestinal smooth muscle as one of its side effects. Erythromycin is used to stimulate smooth muscles of the gastrointestinal tract at doses that are lower than those used for treating infections. There are no studies of erythromycin in dyspepsia, but erythromycin is effective in gastroparesis and probably also in chronic intestinal pseudo-obstruction. Metoclopramide (Reglan) is another promotility drug that is available. It has not been studied, however, in dyspepsia. Moreover, it is associated with some troubling side effects. Therefore, it may not be a good drug to undergo further testing in dyspepsia. Domperidone (Motilium) is a promotility drug that is available in the U.S., but requires a special permit from the US Food and Drug administration. As a result, it is not very commonly prescribed. It is an effective drug with minimal side effects. Smooth muscle relaxants

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The most widely studied drugs for the treatment of abdominal pain in functional disorders are a group of drugs called smooth-muscle relaxants. The gastrointestinal tract is primarily composed of a type of muscle called smooth muscle. (By contrast, skeletal muscles such as the biceps are composed of a type of muscle called striated muscle.) Smooth muscle relaxant drugs reduce the strength of contraction of the smooth muscles but do not affect the contraction of other types of muscles. They are used in functional disorders, particularly IBS, with the assumption (not proven) that strong or prolonged contractions of smooth muscles in the intestinespasms-are the cause of the pain in functional disorders. There are even smooth muscle relaxants that are placed under the tongue, as is nitroglycerin for angina, so that they may be absorbed rapidly. There are not enough studies of smooth muscle relaxants in dyspepsia to conclude that they are effective at reducing pain. Since their side effects are few, these drugs probably are worth trying. As with all drugs that are given to control symptoms, patients should carefully evaluate whether or not the smooth muscle relaxant they are using is effective at controlling the symptoms. If it is not clearly effective, the option of discontinuing the relaxant should be discussed with a physician. Commonly used smooth muscle relaxants are hyoscyamine (Levsin, Anaspaz, Cystospaz, Donnamar) and methscopolamine (Pamine, Pamine Forte). Other drugs combine smooth muscle relaxants with a sedative chlordiazepoxide hydrochloride and clidinium bromide (Donnatal, Librax), but there is no evidence that the addition of sedatives adds to the effectiveness of the treatment.

What is a reasonable approach to the diagnosis and treatment of dyspepsia (indigestion)? The initial approach to dyspepsia, whether it be treatment or testing, depends on the patient's age, symptoms and the duration of the symptoms. If the patient is younger than 50 years of age and serious disease, particularly cancer, is not likely, testing is less important. If the symptoms are typical for dyspepsia and have been present for many years without change, then there is less need for testing, or at least extensive testing, to exclude other gastrointestinal and non-gastrointestinal diseases. On the other hand, if the symptoms are of recent onset (weeks or months), progressively worsening, severe, or associated with "warning" signs, then early, more extensive testing is appropriate. Warning signs include loss of weight, nighttime awakening, blood in the stool or the material that is vomited (vomitus), and signs of inflammation, such as fever or abdominal tenderness. Testing also is appropriate if, in addition to symptoms of dyspepsia, there are other prominent symptoms that are not commonly associated with dyspepsia. If there are symptoms that suggest conditions other than dyspepsia, tests that are specific for these diseases should be done first. The reason is that if these other tests disclose other diseases, it may not be necessary to do additional testing. Examples of such symptoms and possible testing include:

Vomiting: upper gastrointestinal endoscopy to diagnose inflammatory or obstructing diseases; gastric emptying studies and/or electrogastrography to diagnose impaired emptying of the stomach.

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Abdominal distention with or without increased flatulence: upper gastrointestinal and small intestinal x-rays to diagnose obstructing diseases; hydrogen breath testing to diagnose bacterial overgrowth of the small intestine.

For a patient with typical symptoms of dyspepsia who requires testing to exclude other diseases, a standard screening panel of blood tests would reasonably be included. These tests might reveal clues to non-gastrointestinal diseases. Sensitive stool testing (antigen/antibody) for Giardia lamblia would be reasonable because this parasitic infection is common and can be acute or chronic. Some physicians do blood testing for celiac disease (sprue), but the value of doing this is unclear. Moreover, if an EGD is planned, biopsies of the duodenum usually will make the diagnosis of celiac disease. A plain x-ray of the abdomen might be done during an episode of abdominal pain (to look for intestinal blockage or obstruction). Testing for lactose intolerance or a trial of a strict lactose-free diet should be considered. The physician's clinical judgment should determine the extent to which initial testing is appropriate. Once testing has been done to an extent that is appropriate for the clinical situation, it is reasonable to first try a therapeutic trial of stomach acid suppression to see if symptoms improve. Such a trial probably should involve a PPI (proton pump inhibitor) for 8 to 12 weeks. If there is no clear response of symptoms, the options then are to discontinue the PPI or confirm its effectiveness in suppressing acid with 24 hour acid testing. If there is a clear and substantial decrease in symptoms with the PPI, then decisions need to be made about continuing acid suppression and which drugs to use. Another therapeutic approach is to test for Helicobacter pylori infection of the stomach (with blood, breath or stool tests) and to treat patients with infection to eradicate the infection. It may be necessary to retest patients after treatment to prove that treatment has effectively eradicated the infection, particularly if dyspeptic symptoms persist after treatment. If treatment with a PPI has satisfactorily suppressed acid according to acid testing (or acid suppression has not been measured) and yet the symptoms have not improved, it is reasonable to conduct further testing as described above. Esophago-gastro-duodenoscopy, or EGD, (and, possibly, colonoscopy) would be the next consideration, probably with multiple biopsies of the stomach and duodenum (and colon if colonoscopy is done). Finally, small intestinal x-rays and an ultrasound examination of the gallbladder might be done. An abdominal ultrasound examination, CT scan, or MRI scan can exclude nongastrointestinal diseases. Once appropriate testing has been completed, empiric trials of other drugs (for example, smooth muscle relaxants, psychotropic drugs, and promotility drugs) can be done. (An empiric trial of a drug is a trial that is not based on an understanding of the exact cause of the symptoms) If all of the appropriate testing reveals no disease that could be causing the symptoms and the dyspeptic symptoms have not responded to empiric treatments, other, more specialized tests should be considered. These tests include hydrogen breath testing to diagnose bacterial overgrowth of the small intestine, gastric emptying studies, EGG, small intestinal transit studies, and antro-duodenal motility and barostatic studies. These specialized studies probably should be done at centers that have experience and expertise in diagnosing and treating functional diseases.

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What is in the future for dyspepsia (indigestion)? The future of dyspepsia will depend on our increasing knowledge of the processes (mechanisms) that cause dyspepsia. Acquiring this knowledge, in turn, depends on research funding. Because of the difficulties in conducting research in dyspepsia, this knowledge will not come quickly. Until we have an understanding of the mechanisms of dyspepsia, newer treatments will be based on our developing a better understanding of the normal control of gastrointestinal function, which is proceeding more rapidly. Specifically, there is intense interest in intestinal neurotransmitters, which are chemicals that the nerves of the intestine use to communicate with each other. The interactions of these neurotransmitters are responsible for adjusting (modulating) the functions of the intestines, such as contraction of muscles and secretion of fluid and mucus. 5-hydroxytriptamine (5-HT or serotonin) is a neurotransmitter that stimulates several different receptors on nerves in the intestine. Examples of experimental drugs that affect intestinal neurotransmission are sumatriptan (Imitrex) and buspirone (Buspar). These drugs are believed to reduce the responsiveness (sensitivity) of the sensory nerves to what's happening in the intestine by attaching to a particular 5-HT receptor, the 5-HT1 receptor. The 5-HT1 receptor drugs, however, have received only minimal study so far and their role in the treatment of dyspepsia, if any, is unknown.

Information: Dyspepsia This section describes dyspepsia and its causes, and how to diagnose and treat it. This page has been divided into the following categories: What is dyspepsia? What are the symptoms of dyspepsia? What causes dyspepsia? How is dyspepsia diagnosed? What is the treatment for dyspepsia?

What is dyspepsia? Latin for "bad digestion", dyspepsia can be quite severe and even debilitating for some. Dyspepsia has been defined as "pain or discomfort centred in the upper abdomen" but people with dyspepsia may have more than one symptom. People whose predominant symptom is heartburn (i.e. reflux or acid regurgitation, often described as a "sensation of burning in the upper chest") are usually considered to have gastroesophageal reflux disease (GERD). However, 'reflux' symptoms can also occur along with symptoms caused by peptic ulcer disease, abnormal motility (contractions of the esophagus, stomach or intestines that move food through the digestive tract) or 'non-ulcer dyspepsia'. Because of this, the Canadian Dyspepsia (CanDys) Working Group has recently published a new, more comprehensive definition which describes dyspepsia as "a symptom complex of
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epigastric (upper abdominal) pain or discomfort thought to originate in the upper gastrointestinal tract, and it may include any of the following symptoms: heartburn, acid regurgitation, excessive burping/belching, increased abdominal bloating, nausea, a feeling of abnormal or slow digestion, or early satiety." For dyspepsia to be considered a chronic condition, symptoms must be present at least 25% of the time over a period of at least three months. Dyspepsia is thought of as a group of symptoms rather than a disorder or disease, and it often occurs without any organic disease. Dyspepsia is very common and is estimated to affect roughly of the population in Western Europe and North America. In Canada, a recent study showed 29% of the population has substantial symptoms of dyspepsia. Dyspepsia is more common in developing nations since Helicobacter pylori (H. pylori) infection, which can result in ulcers and symptoms of dyspepsia, is more prevalent. Back to top What are the symptoms of dyspepsia? Because dyspepsia is a group of symptoms, rather than a disease, dyspepsia tends to vary from person to person and may be characterized by the following symptoms:

Pain or discomfort centred in the upper abdomen Bloating Pain or burning radiating from the chest up through the throat (heartburn) Nausea Vomiting Excessive gas or belching Feeling full too soon when eating (early satiety)

Symptoms of dyspepsia can be a sign of a more serious condition. Notify your doctor if you experience:

Weight loss of more than 10 pounds (3 kilograms) or appetite loss. Black tarry stools or blood in vomit. Severe pain in the upper right abdomen. Discomfort unrelated to eating. Indigestion accompanied by shortness of breath, sweating or pain radiating to the jaw, neck or arm

Back to top What causes dyspepsia? Structural causes

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When there is a structural cause, that is, when a condition like peptic ulcer disease or biliary tract disease (gallstones) is present, symptoms of dyspepsia can ensue. Peptic ulcer disease and poor motility (the wave-like action that moves food through the digestive tract) are other disorders which can result in symptoms associated with dyspepsia. Functional (non-ulcer) dyspepsia The symptoms of functional dyspepsia, also called non-ulcer dyspepsia, can be quite severe and chronic. Unlike peptic ulcer disease where ulcers are usually found in the stomach or duodenum, examination reveals no signs of any organic abnormality in functional dyspepsia. Functional dyspepsia may result from poor nerve and muscle function. Symptoms such as gas and abdominal pain come back again and again but there are no signs of disease or damage. Emotional stress may trigger or worsen symptoms. Because the symptoms of functional dyspepsia (without signs of organic disease upon examination) resemble those other organic diseases, such as peptic ulcer disease or gastroparesis (the inability of the stomach to empty properly), functional dyspepsia has been subdivided into ulcer-like, dysmotility-like or unspecified dyspepsia. Those who experience ulcer-like functional dyspepsia tend to have symptoms similar to those who have peptic ulcer disease - heartburn and abdominal pain. Those who experience dysmotility-like functional dyspepsia tend to experience symptoms similar to those who have gastroparesis - abdominal pain, bloating, excessive gas, nausea, and vomiting. Back to top How is dyspepsia diagnosed? Because the symptoms of dyspepsia may be the result of serious conditions like ulcers, gallstones or other problems like improper stomach emptying or aerophagia (excessive swallowing or air), these causes must be ruled out as the source of the problem. Different tests are used to test for the various causes of dyspepsia. X-ray tests A barium meal and upper GI series are both x-ray examinations and involve drinking barium, a contrast solution which allows the esophagus, stomach and intestines to show up against your other internal organs. Endoscopy Endoscopy involves swallowing a thin flexible tube with a video camera on the end. In upper endoscopy, your doctor can visualize the duodenum, the stomach, and the esophagus, and can
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take small biopsy (tissue) samples to diagnose disease that may only be detected under a microscope. Gastric emptying study A gastric emptying test can be used to determine how well or slowly the stomach can empty its contents. Back to top What is the treatment for dyspepsia? Again, the treatment will depend on what is causing the symptoms. If an H. pylori infection is the cause, your doctor will prescribe a combination antibiotic and acid-reducing medication to clear the infection. If gallstones are resulting in symptoms of dyspepsia, there are surgical and non-surgical treatments available. The symptoms associated with functional dyspepsia may be alleviated by certain lifestyle changes. The following are a list of the foods, activities, and medications that may aggravate symptoms. Check with your doctor to find out which changes would most likely benefit you. Foods Fatty or greasy foods Fatty meats: bacon, hot dogs Chocolate Caffeine (cola, coffee) Peppermint or spearmint Alcohol Spicy foods Citrus juices: orange, tomato Acidic fruits, vegetables: apples, tomatoes, peppers Carbonated beverages Activities Bending over Lying down after eating Eating large meals Obesity Pregnancy Wearing tight clothing Smoking Medications ASA (aspirin) NSAIDs: Non-steroidal antiinflammatory drugs Some heart medications Some drugs for anxiety or insomnia Oral contraceptives Vitamin C Iron supplements Potassium supplements Antibiotics

Ways to improve symptoms of dysmotility (poor stomach emptying) include: eating smaller, well-balanced meals and more frequent meals, not lying down for 2-3 hours after a meal, avoiding foods which aggravate symptoms, being a healthy weight, avoid constrictive clothing, elevating the head of your bed, stop smoking.

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Peptic Ulcer Disease

Background
Gastric and duodenal ulcers usually cannot be differentiated based on history alone, although some findings may be suggestive (see Diagnosis). Epigastric pain is the most common symptom of both gastric and duodenal ulcers. It is characterized by a gnawing or burning sensation and occurs after mealsclassically, shortly after meals with gastric ulcer and 2-3 hours afterward with duodenal ulcer. In uncomplicated peptic ulcer disease (PUD), the clinical findings are few and nonspecific. Alarm features" that warrant prompt gastroenterology referral[1] include bleeding, anemia, early satiety, unexplained weight loss, progressive dysphagia or odynophagia, recurrent vomiting, and family history of GI cancer. Patients with perforated PUD usually present with a sudden onset of severe, sharp abdominal pain. (See Clinical Presentation.) In most patients with uncomplicated PUD, routine laboratory tests usually are not helpful; instead, documentation of PUD depends on radiographic and endoscopic confirmation. Testing for H pylori infection is essential in all patients with peptic ulcers. Rapid urease tests are considered the endoscopic diagnostic test of choice. Of noninvasive tests, fecal antigen testing is more accurate than antibody testing and is less expensive than urea breath tests. A fasting serum gastrin level should be obtained in certain cases to screen for Zollinger-Ellison syndrome. (See Workup.) Upper GI endoscopy is the preferred diagnostic test in the evaluation of patients with suspected PUD. Endoscopy provides an opportunity to visualize the ulcer, to determine the presence and degree of active bleeding, and to attempt hemostasis by direct measures, if required. Perform endoscopy early in patients older than 45-50 years and in patients with associated so-called alarm features. Most patients with PUD are treated successfully with cure of H pylori infection and/or avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs), along with the appropriate use of antisecretory therapy. In the United States, the recommended primary therapy for H pylori infection is proton pump inhibitor (PPI)based triple therapy.[1] These regimens result in a cure of infection and ulcer healing in approximately 85-90% of cases.[2] Ulcers can recur in the absence of successful H pylori eradication. (See Treatment and Management.) In patients with NSAID-associated peptic ulcers, discontinuation of NSAIDs is paramount, if it is clinically feasible. For patients who must continue with their NSAIDs, proton pump inhibitor (PPI) maintenance is recommended to prevent recurrences even after eradication of H pylori.[3, 4] Prophylactic regimens that have been shown to dramatically reduce the risk of NSAID-induced gastric and duodenal ulcers include the use of a prostaglandin analog or a PPI. Maintenance therapy with antisecretory medications (eg, H2 blockers, PPIs) for 1 year is indicated in high-risk patients. (See Medication.)

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The indications for urgent surgery include failure to achieve hemostasis endoscopically, recurrent bleeding despite endoscopic attempts at achieving hemostasis (many advocate surgery after 2 failed endoscopic attempts), and perforation. Patients with gastric ulcers are also at risk of developing gastric malignancy.

Anatomy
Because many surgical procedures for peptic ulcer disease (PUD) entail some type of vagotomy, a discussion concerning the vagal innervation of the abdominal viscera is appropriate (see image below). The left (anterior) and the right (posterior) branches of the vagus nerve descend along either side of the distal esophagus. As they enter the lower thoracic cavity, they can communicate with each other through several cross-branches that comprise the esophageal plexus. However, below this plexus, the 2 vagal trunks again become separate and distinct before the anterior trunk branches to form the hepatic, pyloric, and anterior gastric (also termed the anterior nerve of Latarjet) branches. The posterior trunk branches to form the posterior gastric branch (also termed the posterior nerve of Latarjet) and the celiac branch. The parietal cell mass of the stomach is segmentally innervated by the terminal branches from each of the anterior and posterior gastric branches. These terminal branches are divided during a highly selective vagotomy. The gallbladder is innervated from efferent branches of the hepatic division of the anterior trunk. Consequently, transection of the anterior vagus trunk (performed during truncal vagotomy) can result in a dilated gallbladder with inhibited contractility and subsequent cholelithiasis. The celiac branch of the posterior vagus innervates the entire midgut (with the exception of the gallbladder). Thus, division of the posterior trunk during truncal vagotomy may contribute to postoperative ileus.

Vagal innervation of stomach.

Pathphysiology
Peptic ulcers are defects in the gastric or duodenal mucosa that extend through the muscularis mucosa. The epithelial cells of the stomach and duodenum secrete mucus in response to irritation of the epithelial lining and as a result of cholinergic stimulation. The superficial portion of the gastric and duodenal mucosa exists in the form of a gel layer, which is impermeable to acid and pepsin. Other gastric and duodenal cells secrete bicarbonate, which aids in buffering acid that
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lies near the mucosa. Prostaglandins of the E type (PGE) have an important protective role, because PGE increases the production of both bicarbonate and the mucous layer. In the event of acid and pepsin entering the epithelial cells, additional mechanisms are in place to reduce injury. Within the epithelial cells, ion pumps in the basolateral cell membrane help to regulate intracellular pH by removing excess hydrogen ions. Through the process of restitution, healthy cells migrate to the site of injury. Mucosal blood flow removes acid that diffuses through the injured mucosa and provides bicarbonate to the surface epithelial cells. Under normal conditions, a physiologic balance exists between gastric acid secretion and gastroduodenal mucosal defense. Mucosal injury and, thus, peptic ulcer occur when the balance between the aggressive factors and the defensive mechanisms is disrupted. Aggressive factors, such as NSAIDs, H pylori infection, alcohol, bile salts, acid, and pepsin, can alter the mucosal defense by allowing back diffusion of hydrogen ions and subsequent epithelial cell injury. The defensive mechanisms include tight intercellular junctions, mucus, mucosal blood flow, cellular restitution, and epithelial renewal. The gram-negative spirochete H pylori was first linked to gastritis in 1983. Since then, further study of H pylori has revealed that it is a major part of the triad, which includes acid and pepsin, that contributes to primary peptic ulcer disease. The unique microbiologic characteristics of this organism, such as urease production, allows it to alkalinize its microenvironment and survive for years in the hostile acidic environment of the stomach, where it causes mucosal inflammation and, in some individuals, worsens the severity of peptic ulcer disease. When H pylori colonizes the gastric mucosa, inflammation usually results. The causal association between H pylori gastritis and duodenal ulceration is now well established in the adult and pediatric literature. In patients infected with H pylori, high levels of gastrin and pepsinogen and reduced levels of somatostatin have been measured. In infected patients, exposure of the duodenum to acid is increased. Virulence factors produced by H pylori, including urease, catalase, vacuolating cytotoxin, and lipopolysaccharide, are well described. Most patients with duodenal ulcers have impaired duodenal bicarbonate secretion, which has also proven to be caused by H pylori because its eradication reverses the defect[5] . The combination of increased gastric acid secretion and reduced duodenal bicarbonate secretion lowers the pH in the duodenum, which promotes the development of gastric metaplasia (ie, the presence of gastric epithelium in the first portion of the duodenum). H pylori infection in areas of gastric metaplasia induces duodenitis and enhances the susceptibility to acid injury, thereby predisposing to duodenal ulcers. Duodenal colonization by H pylori was found to be a highly significant predictor of subsequent development of duodenal ulcers in one study that followed 181 patients with endoscopy-negative, nonulcer dyspepsia[6] .

Etiology
Peptic ulcer disease (PUD) may be due to any of the following:

H pylori infection 25

Drugs Lifestyle factors Severe physiologic stress Hypersecretory states (uncommon) Genetic factors

H pylori infection

H pylori infection and NSAID use account for most cases of PUD. The rate of H pylori infection for duodenal ulcers in the United States is less than 75% for patients who do not use NSAIDs. Excluding patients who used NSAIDs, 61% of duodenal ulcers and 63% of gastric ulcers were positive for H pylori in one study. These rates were lower in whites than in nonwhites. Prevalence of H pylori infection in complicated ulcers (ie, bleeding, perforation) is significantly lower than that found in uncomplicated ulcer disease.
Drugs

NSAID use is a common cause of PUD. These drugs disrupt the mucosal permeability barrier, rendering the mucosa vulnerable to injury. As many as 30% of adults taking NSAIDs have GI adverse effects. Factors associated with an increased risk of duodenal ulcers in the setting of NSAID use include history of previous peptic ulcer disease, advanced age, female sex, high doses or combinations of NSAIDs, long-term NSAID use, concomitant use of anticoagulants, and severe comorbid illnesses. A long-term prospective study found that patients with arthritis who were older than 65 years who regularly took low-dose aspirin were at an increased risk for dyspepsia severe enough to necessitate the discontinuation of NSAIDs.[7] This suggests that better management of NSAID use should be discussed with older patients in order to reduce NSAID-associated upper GI events. Although the idea was initially controversial, most evidence now supports the assertion that H pylori and NSAIDs are synergistic with respect to the development of peptic ulcer disease. A meta-analysis found that H pylori eradication in NSAID-naive users before the initiation of NSAIDs was associated with a decrease in peptic ulcers[8] . Although the prevalence of NSAID gastropathy in children is unknown, it seems to be increasing, especially in children with chronic arthritis treated with NSAIDs. Case reports have demonstrated gastric ulceration from low-dose ibuprofen in children, even after just 1 or 2 doses[9] . Corticosteroids alone do not increase the risk for PUD; however, they can potentiate ulcer risk in patients who use NSAIDs concurrently. The risk of upper GI tract bleeding may be increased in users of the diuretic spironolactone[10] or serotonin reuptake inhibitors with moderate to high affinity for serotonin transporter[11] .

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Lifestyle factors

Evidence that tobacco use is a risk factor for duodenal ulcers is not conclusive. Support for a pathogenic role for smoking comes from the finding that smoking may accelerate gastric emptying and decrease pancreatic bicarbonate production. However, studies have produced contradictory findings. In one prospective study of more than 47,000 men with duodenal ulcers, smoking did not emerge as a risk factor.[12] However, smoking in the setting of H pylori infection may increase the risk of relapse of PUD.[13] Smoking is harmful to the gastroduodenal mucosa, and H pylori infiltration is denser in the gastric antrum of smokers.[14] Ethanol is known to cause gastric mucosal irritation and nonspecific gastritis. Evidence that consumption of alcohol is a risk factor for duodenal ulcer is inconclusive. A prospective study of more than 47,000 men with duodenal ulcer did not find an association between alcohol intake and duodenal ulcer.[12] Little evidence suggests that caffeine intake is associated with an increased risk of duodenal ulcers.
Severe physiologic stress

Stressful conditions that may cause PUD include burns, CNS trauma, surgery, and severe medical illness. Serious systemic illness, sepsis, hypotension, respiratory failure, and multiple traumatic injuries increase the risk for secondary (stress) ulceration. Cushing ulcers are associated with a brain tumor or injury and typically are single, deep ulcers that are prone to perforation. They are associated with high gastric acid output and are located in the duodenum or stomach. Extensive burns are associated with Curling ulcers. Stress ulceration and upper-GI hemorrhage are complications that are increasingly encountered in critically ill children in the intensive care setting. Severe illness and a decreased gastric pH are related to an increased risk of gastric ulceration and hemorrhage.
Hypersecretory states (uncommon)

The following are among hypersecretory states that may, uncommonly, cause PUD:

Gastrinoma (Zollinger-Ellison syndrome) or multiple endocrine neoplasia type I (MEN-I) Antral G cell hyperplasia Systemic mastocytosis Basophilic leukemias Cystic fibrosis Short bowel syndrome Hyperparathyroidism

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Physiologic factors

In up to one third of patients with duodenal ulcers, basal acid output (BAO) and maximal acid output (MAO) are increased. In one study, increased BAO was associated with an odds ratio [OR] of up to 3.5, and increased MAO was associated with an OR of up to 7 for the development of duodenal ulcers. Individuals at especially high risk are those with a BAO greater than 15 mEq/h. The increased BAO may reflect the fact that in a significant proportion of patients with duodenal ulcers, the parietal cell mass is increased to nearly twice that of the reference range.[15] In addition to the increased gastric and duodenal acidity observed in some patients with duodenal ulcers, accelerated gastric emptying is often present. This acceleration leads to a high acid load delivered to the first part of the duodenum, where 95% of all duodenal ulcers are located. Acidification of the duodenum leads to gastric metaplasia, which indicates replacement of duodenal villous cells with cells that share morphologic and secretory characteristics of gastric epithelium. Gastric metaplasia may create an environment that is well suited to colonization by H pylori.
Genetics

More than 20% of patients have a family history of duodenal ulcers, compared with only 5-10% in the control groups. In addition, weak associations have been observed between duodenal ulcers and blood type O. Furthermore, patients who do not secrete ABO antigens in their saliva and gastric juices are known to be at higher risk. The reason for these apparent genetic associations is unclear. A rare genetic association exists between familial hyperpepsinogenemia type I (a genetic phenotype leading to enhanced secretion of pepsin) and duodenal ulcers. However, H pylori can increase pepsin secretion, and a retrospective analysis of the sera of one family studied before the discovery of H pylori revealed that their high pepsin levels were more likely related to H pylori infection.
Additional etiologic factors

Any of the following may be associated with PUD:

Hepatic cirrhosis Chronic obstructive pulmonary disease Allergic gastritis and eosinophilic gastritis Cytomegalovirus infection Graft versus host disease Uremic gastropathy Henoch-Schnlein gastritis Corrosive gastropathy Celiac disease Bile gastropathy Autoimmune disease 28

Crohn disease Other granulomatous gastritides (eg, sarcoidosis, histiocytosis X, tuberculosis) Phlegmonous gastritis and emphysematous gastritis Other infections, including Epstein-Barr virus, HIV, Helicobacter heilmannii, herpes simplex, influenza, syphilis, Candida albicans,histoplasmosis, mucormycosis, and anisakiasis Chemotherapeutic agents, such as 5-fluorouracil (5-FU), methotrexate (MTX), and cyclophosphamide Local radiation resulting in mucosal damage, which may lead to the development of duodenal ulcers Use of crack cocaine, which causes localized vasoconstriction, resulting in reduced blood flow and possibly leading to mucosal damage

Prognosis
When the underlying cause is addressed, the prognosis is excellent. Most patients are treated successfully with eradication of H pylori infection, avoidance of NSAIDs, and the appropriate use of antisecretory therapy. Eradication of H pylori infection changes the natural history of the disease, with a decrease in the ulcer recurrence rate from 60-90% to approximately 10-20%. However, this is a higher recurrence rate than previously reported, suggesting an increased number of ulcers not caused by H pylori infection. With regard to NSAID-related ulcers, the incidence of perforation is approximately 0.3% per patient year, and the incidence of obstruction is approximately 0.1% per patient year. Combining both duodenal ulcers and gastric ulcers, the rate of any complication in all age groups combined is approximately 1-2% per ulcer per year. The mortality rate for PUD, which has decreased modestly in the last few decades, is approximately 1 death per 100,000 cases. If one considers all patients with duodenal ulcers, the mortality rate due to ulcer hemorrhage is approximately 5%. Over the last 20 years, the mortality rate in the setting of ulcer hemorrhage has not changed appreciably despite the advent of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). However, evidence from meta-analyses and other studies has shown a decreased mortality rate from bleeding peptic ulcers when intravenous PPIs are used after successful endoscopic therapy.[17, 18,
19, 20]

Emergency operations for peptic ulcer perforation carry a mortality risk of 6-30%.[21] Factors associated with higher mortality in this setting include the following:

Shock at the time of admission Renal insufficiency Delaying the initiation of surgery for more than 12 hours after presentation Concurrent medical illness (eg, cardiovascular disease, diabetes mellitus Age older than 70 years Cirrhosis Immunocompromised state

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Location of ulcer (mortality associated with perforated gastric ulcer is twice that associated with perforated duodenal ulcer.)

Patient Education
Patients should be warned of known or potentially injurious drugs and agents. Some examples are as follows:

NSAIDs Aspirin Alcohol Tobacco Caffeine (eg, coffee, tea, colas)

Obesity has been shown to have an association with peptic ulcer disease (PUD), and patients should be counseled regarding benefits of weight loss. Stress reduction counseling might be helpful in individual cases but is not needed routinely.

History
Obtaining a medical history, especially for peptic ulcer disease, H pylori infection, ingestion of NSAIDs, or smoking, is essential in making the correct diagnosis. Gastric and duodenal ulcers usually cannot be differentiated based on history alone, although some findings may be suggestive. Epigastric pain is the most common symptom of both gastric and duodenal ulcers. It is characterized by a gnawing or burning sensation and occurs after mealsclassically, shortly after meals with gastric ulcer and 2-3 hours afterward with duodenal ulcer. Food or antacids relieve the pain of duodenal ulcers but provide minimal relief of gastric ulcer pain. Duodenal ulcer pain often awakens the patient at night. About 50-80% of patients with duodenal ulcers experience nightly pain, as opposed to only 30-40% of patients with gastric ulcers and 2040% of patients with nonulcer dyspepsia (NUD). Pain typically follows a daily pattern specific to the patient. Pain with radiation to the back is suggestive of a posterior penetrating gastric ulcer complicated by pancreatitis. Patients who develop gastric outlet obstruction as a result of a chronic, untreated duodenal ulcer usually report a history of fullness and bloating associated with nausea and emesis that occurs several hours after food intake. A common misconception is that adults with gastric outlet obstruction present with nausea and emesis immediately after a meal. Other possible manifestations include the following:

Dyspepsia, including belching, bloating, distention, and fatty food intolerance Heartburn
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Chest discomfort Hematemesis or melena resulting from gastrointestinal bleeding. Melena may be intermittent over several days or multiple episodes in a single day. Rarely, a briskly bleeding ulcer can present as hematochezia. Symptoms consistent with anemia (eg, fatigue, dyspnea) may be present Sudden onset of symptoms may indicate perforation. NSAID-induced gastritis or ulcers may be silent, especially in elderly patients. Only 20-25% of patients with symptoms suggestive of peptic ulceration are found on investigation to have a peptic ulcer.

Alarm features that warrant prompt gastroenterology referral[1] include the following:

Bleeding or anemia Early satiety Unexplained weight loss Progressive dysphagia or odynophagia Recurrent vomiting Family history of GI cancer

Physical Examination
In uncomplicated PUD, the clinical findings are few and nonspecific and include the following:

Epigastric tenderness (usually mild) Right upper quadrant tenderness may suggest a biliary etiology or, less frequently, PUD. Guaiac-positive stool resulting from occult blood loss Melena resulting from acute or subacute gastrointestinal bleeding Succussion splash resulting from partial or complete gastric outlet obstruction

Patients with perforated PUD usually present with a sudden onset of severe, sharp abdominal pain. Most patients describe generalized pain; a few present with severe epigastric pain. As even slight movement can tremendously worsen their pain, these patients assume a fetal position. Abdominal examination usually discloses generalized tenderness, rebound tenderness, guarding, and rigidity. However, the degree of peritoneal findings is strongly influenced by a number of factors, including the size of perforation, amount of bacterial and gastric contents contaminating the abdominal cavity, time between perforation and presentation, and spontaneous sealing of perforation. These patients may also demonstrate signs and symptoms of septic shock, such as tachycardia, hypotension, and anuria. Not surprisingly, these indicators of shock may be absent in elderly or immunocompromised patients or in those with diabetes. Patients should be asked if retching and vomiting occurred before the onset of pain.

Diagnostic Considerations
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Nonulcer dyspepsia (NUD) or functional dyspepsia Functional dyspepsia is a diagnosis of exclusion made in patients with chronic persistent epigastric pain in whom a thorough evaluation shows no organic disease. Patients may primarily have epigastric pain, which is referred to as ulcerlike dyspepsia, or they may have symptoms of postprandial bloating, which is referred to as motility-like dyspepsia. Crohn disease Crohn ulceration can involve any part of the GI tract from the buccal mucosa to the rectum. Isolated Crohn ulceration of the stomach is rare, although it may cause duodenal or ileal ulcerations. Zollinger-Ellison syndrome Zollinger-Ellison syndrome (ZES) is a rare disorder that can cause gastric or duodenal ulcers (usually multiple) from excessive acid secretion. Consider ZES if a patient has severe peptic ulceration, kidney stones, watery diarrhea, or malabsorption. ZES can also be associated with multiple endocrine neoplasia type I, which occurs earlier than isolated ZES. Patients with ZES usually have fasting serum gastrin levels of more than 200 pg/mL and basal gastric acid hypersecretion of more than 15 mEq/h. Proton pump inhibitor (PPI) therapy should be discontinued at least 2 weeks before the gastrin level is measured.

Differentials

Acute Coronary Syndrome Aneurysm, Abdominal Cholangitis Cholecystitis Cholecystitis and Biliary Colic in Emergency Medicine Cholelithiasis Diverticular Disease Esophageal Perforation, Rupture and Tears Esophagitis Gastritis, Acute Gastritis, Chronic Gastroenteritis Gastroesophageal Reflux Disease Inflammatory Bowel Disease Viral Hepatitis

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