Dyspepsia

Author : Dr Uri Ladabaum Professor of Medicine Gastroenterology University of California, San Francisco

2008-07-19

Dyspepsia: The "Upset Stomach"

“Doctor, I have an upset stomach” -- What is “dyspepsia”?

The term “dyspepsia” is used in medical writing, but it is not used in everyday life, and patients do not come to a doctor saying “I have dyspepsia.” However, it is very common for people to express that they have “upset stomach,” “indigestion,” “acid stomach,” “acid indigestion,” “stomach pain,” “stomach burning,” or “stomach fullness.” These and similar terms reflect the experience of abdominal pain or discomfort, often worsened by eating. It is also common for people to complain of “heartburn,” which to some means upper abdominal burning alone, but for many it consists of a burning sensation in the chest.

A concise definition of dyspepsia is chronic or recurrent abdominal pain or discomfort in the upper abdomen.[1] Researchers debate the distinction between “pain” and “discomfort” but most recognize that some patients with “dyspepsia” do not have pain, yet they are bothered by other symptoms that can include an uncomfortable sensation in the upper abdomen, losing appetite after eating very little, and feeling full after eating.[2] Some patients may also experience nausea, an unpleasant sensation that they may soon need to vomit. The term “dyspepsia” is used to capture this group of digestive symptoms, which are believed to arise from the stomach and upper gut.[3]

It has been controversial whether “heartburn” should be considered separately from “dyspepsia” or whether it should be part of the “dyspepsia umbrella.” The practical reason for a distinction is that “heartburn” is more likely than “dyspepsia” to be explained by acid reflux (passage of stomach acid to the esophagus, which is the “swallowing tube” in the chest, between the mouth and stomach). The approach to patients with acid reflux, or gastroesophageal reflux disease (GERD), differs from the approach to patients with dyspepsia without prominent “heartburn.” For this reason, recent guidelines recommend that patients who have heartburn predominantly should be considered initially to have gastroesophageal reflux disease and should not be grouped with patients with dyspepsia.[2-4] However, it is recognized that some patients with “dyspepsia” do actually have gastroesophageal reflux disease without classic heartburn, and that some without demonstrable gastroesophageal reflux disease may experience heartburn as one of their symptoms.

“Doctor, I have pain in the abdomen” -- What is NOT “dyspepsia”?

Patients with the variety of symptoms described above may be said to have “dyspepsia,” but it is important to recognize patients with other patterns of symptoms that should not be confused with “dyspepsia.” Acute abdominal pain (pain that comes on suddenly and has not happened before) is not dyspepsia. Depending on the nature of the pain and other symptoms, acute abdominal pain may represent medical emergencies such as serious inflammation of the gallbladder or pancreas, intestinal blockage, loss of blood flow to the intestines, appendicitis, a gynecological emergency, a heart attack, or other serious diseases. Severe acute abdominal pain should be considered an emergency.

Gallstones can lead to recurrent attacks of upper abdominal pain, which may be severe and may be accompanied by nausea, back or shoulder pain, and sweating. People may often feel completely fine for weeks between such attacks. This symptom pattern should be distinguished from the pattern of more frequent – even daily – and generally milder symptoms that is implied by “dyspepsia.”

It is common for patients to experience abdominal pain and changes in their bowel function, such as diarrhea or constipation. These symptoms may have many causes, including an acute infection, metabolic problems, inflammatory bowel disease, celiac disease, and irritable bowel syndrome. This group of persons should be considered separately from those with dyspepsia.

How common is dyspepsia?

In Western countries, approximately 25% of people experience dyspepsia in any given year.[1] Many do not see a doctor, and self-medication is common, as attested to by the many products that are available over the counter for various digestive symptoms. For most persons with dyspepsia, it is a chronic problem, although the intensity and frequency can vary over the years. Approximately 1% of people may develop new dyspepsia every year, with a similar number becoming free of dyspepsia, so that the number of people with dyspepsia in the population remains stable.[1] Dyspepsia is a common reason for a medical visit, accounting for 2-5% of family practice consultations and a significant number of referrals to gastroenterologists.

“So I have dyspepsia. What is causing it?”

Before discussing how to approach patients with dyspepsia, including what tests or treatments should be considered, it is important to understand the possible causes of dyspepsia and how likely they are. Appreciating these possible causes lays the logical foundation for the currently recommended approaches to patients with dyspepsia.

In patients who have endoscopy (a “camera scope” exam of the upper esophagus, stomach, and upper small intestine, known as the duodenum) to try to determine the cause of dyspepsia, the types of abnormalities that can be uncovered include:

• Stomach or duodenal ulcer

• Gastroesophageal reflux disease with or without visible damage to the esophagus (esophagitis)

• Stomach cancer, which is the least common underlying disease in persons with dyspepsia, but fear of which may drive people to see a doctor

• No abnormality

Patients may find it remarkable, but over half of people with dyspepsia do not have any identifiable abnormalities on routine medical testing. This group of people is labeled as having “functional dyspepsia,” also known as “non-ulcer dyspepsia” or “idiopathic dyspepsia” (“idiopathic” means we do not know what causes it). Not finding an abnormality can be a source of both relief and frustration for patients and doctors, and the management of persons with functional dyspepsia can be challenging, as discussed below.

The likelihood of the various cause of dyspepsia differs between countries and even between specific locations within countries, and is affected by patient age and other factors. In North America, it is estimated that peptic ulcer disease accounts for 5-15% of cases of dyspepsia, gastroesophageal reflux disease for 15-30%, cancer for less than 1-2%, and functional dyspepsia for over 50%.[1] Older patients are more likely to have cancer than younger patients, but even in older patients cancer is an uncommon explanation for dyspepsia.

Two important factors to consider in diseases associated with dyspepsia

There are two very important factors to consider when developing management strategies for persons with dyspepsia. These are aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin, Advil) and naproxen (Aleve), and the bacterium Helicobacter pylori (H. pylori). Both are related in important ways to dyspepsia and its associated diseases.

Aspirin and NSAIDs may cause dyspepsia without causing ulcers. They may also cause gastrointestinal damage ranging from minor erosions (small areas of injury that are too small and superficial to be called an ulcer) to severe ulceration. Ulcers, in turn, may or may not cause dyspepsia. Serious complications of ulcers can include bleeding, bowel blockage or perforation, and sometimes patients do not have dyspepsia before these complications occur. These relationships between aspirin and NSAIDs and dyspepsia and its associated diseases highlight why it is important to establish whether dyspeptic patients are using aspirin and NSAIDs. This includes patients who have not yet had any testing, “investigated patients” (those who have had endoscopy) with proven ulcer disease, and also in those with no abnormality on upper endoscopy.

H. pylori is a bacterium that lives in the stomachs of hundreds of millions of people around the world.[5] It is more common in developing countries and in Asia, Africa and South America than in Western countries. There is a clear and strong association between H. pylori and peptic ulcer disease, H. pylori and stomach cancer, and H. pylori may also be important in a small proportion of persons with functional dyspepsia. In persons with ulcer disease due to H. pylori, cure of the infection almost eliminates the chance of developing an ulcer again, whereas failure to eradicate H. pylori is associated with a very high rate of recurrent peptic ulcer disease.[6] The vast majority of people with H. pylori do not develop ulcer disease or cancer, but H. pylori causes inflammation and other changes in the stomach lining that can eventually lead to stomach cancer in a small fraction of infected persons. These relationships between H. pylori and dyspepsia and its associated diseases form the basis for the current recommendations on how to approach persons with dyspepsia. 

Approach to the patient with “uninvestigated dyspepsia”

A person with dyspepsia who has not had medical testing (usually endoscopy) to try to determine a cause has “uninvestigated dyspepsia.” Many studies have tried to determine the optimal approach in these patients. Unfortunately, the clinical story alone does not allow doctors to make an accurate diagnosis without testing. Current recommendations on how to approach patients with uninvestigated dyspepsia are based on an appreciation of how common the different possible underlying diseases are, and on the available research studies.[1-3, 7, 8] Performing endoscopy up-front on all patients with dyspepsia would be the most direct route to determining a specific diagnosis, but this is not practical in the primary care setting, and it is not likely to be a viable strategy because it is too costly.

A reasonable stepwise approach begins with determining if a person complaining of dyspeptic symptoms is taking aspirin or NSAIDs. If so, and if these medications can be stopped readily, it is reasonable to stop them and observe to see if the dyspeptic symptoms go away. If the person has a strong reason to take low-dose aspirin, such as prevention of heart attack or stroke, or to take NSAIDs, such as treatment of arthritis pain that does not respond to acetaminophen (Tylenol), a reasonable approach is to take a proton pump inhibitor along with the aspirin or NSAID. Proton pump inhibitors are medications that decrease the amount of acid produced by the stomach, and these medications can improve the dyspepsia associated with aspirin or NSAIDs, as well as heal or prevent ulcers. The available proton pump inhibitors include omeprazole (Prilosec, now also available in the United States without prescription as Prilosec OTC), lansoprazole (Prevacid), rabeprazole (AcipHex), pantoprazole (Protonix) and esomeprazole (Nexium). It is advisable to take the lowest possible dose of aspirin and NSAIDs and to use these for the shortest possible time.

Older persons have a higher risk of cancer than younger persons, and for this reason guidelines recommend that older persons presenting with dyspepsia should undergo prompt endoscopy. The precise age cut-off is debated and depends on how likely cancer is in a given region and on the availability of health services, but prompt endoscopy is sensible in persons older than 45-55 years of age presenting with dyspepsia.[1-3]

Most persons with cancer of the upper digestive system have “alarm symptoms” such as difficulty swallowing, nausea and vomiting, weight loss, vomiting blood, or black stools (reflecting internal bleeding). Unfortunately, the presence of alarm symptoms does not seem to be very useful in identifying persons with cancer versus those without cancer.[9] Nonetheless, most experts agree that patients with dyspepsia and alarm symptoms should undergo prompt endoscopy.[2-4]

In younger persons (under 45-55 years of age) without alarm symptoms, the H. pylori “test-and-treat” strategy is recommended.[2-5, 8] These persons are unlikely to have cancer, a minority may have peptic ulcer disease or gastroesophageal reflux disease, and most would have a normal upper endoscopy. In the absence of aspirin or NSAID use, peptic ulcer disease would likely be due to H. pylori. Treatment of H. pylori can have several benefits:

• It treats peptic ulcer disease and nearly eliminates the risk of recurrent ulcer.[6]

• When H. pylori was first discovered, it was hoped that treating it might cure most persons with dyspepsia but without an ulcer. Unfortunately, this is not the case, but a small minority of these patients does seem to benefit. It is estimated that 10-25 persons with functional dyspepsia and H. pylori need to be treated in order to cure one.[10]

• It has the potential to decrease the risk of developing ulcers or stomach cancer later in life.

The currently recommended tests for H. pylori are a stool test (stool antigen test) or a breath test (urea breath test). If a test for H. pylori is positive, the recommended first-line treatment is triple therapy with a proton pump inhibitor combined with amoxicillin 1 gram, and clarithromycin 500 mg or metronidazole 500 mg, all taken twice a day for 10-14 days.[5] It is important to complete the entire treatment course as prescribed in order to increase the likelihood that H. pylori will be eradicated.

If H. pylori is very rare in a particular region, it may be most cost-effective to offer young persons with dyspepsia without alarm symptoms a trial of proton pump inhibitor treatment once a day for 4-8 weeks and then reassess. However, eradicating H. pylori could decrease future ulcer and cancer risk, and this opportunity is lost when a proton pump inhibitor trial is given instead of testing for H. pylori.

In Western countries, most patients with dyspepsia will test negative for H. pylori, leaving the question of how to manage this majority of patients. A trial of proton pump inhibitor treatment once a day for 4-8 weeks is recommended for several reasons:

• Gastroesophageal reflux disease is reasonably likely, and proton pump inhibitors are excellent treatment for this condition.

• Symptoms in functional dyspepsia may improve with proton pump inhibitor treatment.[11]

• Although ulcers are rare in the absence of H. pylori, aspirin, or NSAIDs, most ulcers heal with proton pump inhibitor treatment.

Regardless of what initial approach is followed, a substantial number of persons with dyspepsia will not feel better with the initial treatment or will experience a return of their symptoms. The options at this point are to re-test those who had eradication therapy for H. pylori and treat again with a different regimen if infection persists, to switch from H. pylori “test-and-treat” to proton pump inhibitor therapy or vice versa, or to move on to endoscopy. Ultimately, it is reasonable to perform endoscopy in persons who fail to improve after two attempts at therapy. Although it is unlikely that endoscopy will uncover any serious abnormality at this point, it is important to exclude cancer and it is possible that the reassurance from a normal endoscopy may help decrease the anxiety over possible serious disease. At the time of endoscopy, stomach biopsy should be performed, and H. pylori should be treated if it is found on biopsy.

What about an abdominal ultrasound?

Abdominal ultrasound is unlikely to be useful in patients with dyspepsia. As discussed above, it is important to distinguish patients who may have pain from gallstones from those with dyspepsia. Most people with gallstones do not have symptoms from them, and do not need to have their gallbladder removed. The problem with looking for gallstones in people with dyspepsia is that they may have gallstones by chance alone. Removal of the gallbladder in these patients will not help and carries a small but real risk of complications.

If a cause for dyspepsia is found, what are the treatments?

If endoscopy identifies an explanation for dyspepsia, then directed management will be possible. Stomach cancer can be treated depending on the type and extent. Gastroesophageal reflux disease can be treated with acid suppression. The most potent acid-suppressing medications are the proton pump inhibitors. Some patients with gastroesophageal reflux disease may do well with the less potent histamine receptor antagonists such as cimetidine (Tagamet), ranitidine (Zantac), nizatidine (Axid), or famotidine (Pepcid), but proton pump inhibitors are usually needed in those with esophagitis. Gastroesophageal reflux disease often requires long-term, ongoing treatment. Peptic ulcer disease can be managed by eradicating H. pylori and avoiding aspirin and NSAIDs. If aspirin or NSAIDs must be continued, treatment with a proton pump inhibitor will decrease but not eliminate the risk of ulcer recurrence.

What is functional dyspepsia?

The majority of patients with dyspepsia do not have an identifiable abnormality at endoscopy, and they are diagnosed with functional dyspepsia. Functional dyspepsia is one of the common “functional gastrointestinal disorders,” which are conditions in which patients have symptoms but standard medical testing is normal.[3] Beginning in the 1980’s, leading researchers in the field of functional gastrointestinal disorders have engaged in the “Rome process” (named after the city where the major meetings for this group have taken place), which addresses multiple issues related to the study of the functional gastrointestinal disorders. A major task of the Rome process is to define symptom-based diagnostic criteria for these disorders.

The Rome III pragmatic definition of functional dyspepsia, proposed in 2006, is “the presence of symptoms thought to originate in the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms.”[3] The Rome III diagnostic criteria for functional dyspepsia are:[3]

1. One or more of:           
            a. Bothersome postprandial (after eating) fullness
            b. Early satiation (early loss of appetite during a meal)
            c. Epigastric (mid-upper abdominal) pain
            d. Epigastric burning

AND

2. No evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms

* Criteria fulfilled for the last three months with symptom onset at least six months before diagnosis

The Rome working group has proposed two distinct syndromes under functional dyspepsia based on the belief that patients described by the two syndromes may have different underlying abnormalities. These are the “Epigastric Pain Syndrome,” which is characterized by pain or burning in the upper abdomen, and the “Postprandial Distress Syndrome,” which is characterized by bothersome fullness after a meal and/or early loss of appetite that prevents finishing a regular meal.

Dyspepsia and normal endoscopy: Two notes of caution

Although most patients with dyspepsia and normal endoscopy are categorized appropriately as having functional dyspepsia, two notes of caution are needed. First, it is possible for patients to have gastroesophageal reflux without visible esophagitis, and those with typical heartburn and regurgitation (passage of stomach contents to the mouth) should be considered to have gastroesophageal reflux disease and should be treated with acid suppression. Second, many patients are treated with proton pump inhibitors before endoscopy, and a small number of them may have had esophagitis or ulcers when they were initially treated. With treatment, esophagitis and ulcers can heal and endoscopy can then be normal. If an ulcer was the cause of pain and the ulcer has healed, one would expect the pain to go away. If the pain persists, that patient may have ulcer disease as well as functional dyspepsia.

What causes functional dyspepsia?

Functional dyspepsia is an umbrella term for what are likely to be a group of different underlying abnormalities. By definition, standard medical tests do not show abnormalities in functional dyspepsia, but multiple studies have shown that subgroups of patients with functional dyspepsia exhibit differences from persons without functional dyspepsia when specialized tests or research studies are performed.[1, 12] These include abnormally slow emptying of food from the stomach and other abnormalities in the motor function of the stomach such as inadequate relaxation to accept a meal or weak contractions. Subgroups of patients with functional dyspepsia display “hypersensitivity” to a variety of challenges including distension of the stomach with a balloon, acid infusion into the duodenum, or delivery of fat into the intestine. The link between these abnormalities and patients’ symptoms is not clearly established.

It has been disappointing that in most persons with functional dyspepsia and H. pylori infection, treatment of the infection does not cure the dyspepsia. However, there is evidence that a small minority of these persons do experience cure of their symptoms when H. pylori is eradicated.[10] There is an association between functional dyspepsia and psychological factors, including anxiety.

Can all persons with functional dyspepsia really be lumped together in one group? If they don’t all have the same symptoms, do they all have one “disorder”? Are there different causes for symptoms in different patients? A major challenge has been that specific symptoms and specific physiological “abnormalities” do not go hand in hand. Past attempts to divide people into those with “ulcer-like” symptoms such as burning pain and those with symptoms of “dysmotility” (abnormal muscle function of the gastrointestinal tract) such as fullness or early loss of appetite have not been very successful because of the significant overlap between groups. It remains to be seen whether the “Epigastric Pain Syndrome” and “Postprandial Distress Syndrome” will prove to be useful categories.

Sub-categorization of patients would be most useful if symptoms and/or specific tests could identify groups that should receive different treatments. Unfortunately, few treatments are available currently and most tests are imperfect or impractical.

How is functional dyspepsia managed?

It is disappointing, but the reality is that the treatment options for functional dyspepsia are limited. Some patients may do well with education and reassurance. Even though symptoms tend to be chronic, allaying the fear over serious disease may allow some patients to adjust and live with their symptoms. No specific dietary advice is universally successful, and patients should be encouraged to eat a normal, healthy diet. Limiting fat intake may help some patients.

Many patients wish to try medications to decrease their symptoms and improve their quality of life. Acid suppression with proton pump inhibitors or histamine receptor antagonists may help some patients.[11] This may be due to the fact that some patients who are labeled as having functional dyspepsia actually have reflux, and that some others may have hypersensitivity to acid in the stomach or duodenum. Antacids do not seem to be effective.[11] Medications to improve the motor function of the stomach are limited, some are no longer available, and it is not clear that available drugs help in functional dyspepsia.[11]

Patients who have H. pylori should have treatment to eradicate the infection.[5] It is estimated that 10-25 persons need to be treated to achieve one cure in functional dyspepsia.[10] Given that there are few treatment options for functional dyspepsia, these are actually reasonable odds of success. Eradicating H. pylori may have the additional benefit of decreasing subsequent risk of ulcer disease and cancer.

Antidepressant medications may help in functional dyspepsia even when patients are not depressed, but there has been relatively little research in this area.[1] These medications may affect the perception of symptoms. There is stronger evidence that antidepressants help in irritable bowel syndrome, another classic functional gastrointestinal disorder. Antidepressants are used in functional dyspepsia in part based on an extension of the evidence in irritable bowel syndrome. The tricyclic antidepressants include amitriptyline (Elavil), nortriptyline (Pamelor), imipramine (Tofranil), and desipramine (Norpramin), and the selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa) and fluvoxamine (Luvox). The rationale for using these medicines should be explained to the patient since the doctor-patient relationship can be damaged if patients look up information on the prescribed drug, learn it is an “antidepressant” and question their doctor’s justification for prescribing the medication.

There is some evidence that functional dyspepsia may improve with a variety of psychiatric treatments.[13] These include hypnotherapy, cognitive therapy, relaxation, and psychodynamic-interpersonal therapy. It’s not clear how long-lasting the benefit may be, and these therapies are not currently available for most patients.

Conclusion

Dyspepsia is very common. Patients with dyspepsia may be concerned that there is something “seriously wrong inside.” Fortunately, serious disease, including cancer, is a very uncommon explanation for dyspepsia. Older patients and those with “alarm symptoms” should have prompt endoscopy. Younger patients without alarm symptoms can be managed without endoscopy initially, with endoscopy reserved for those with persistent symptoms. Eradication of H. pylori infection treats peptic ulcer disease, can decrease the risk of cancer, and may help a minority of patients with functional dyspepsia. Acid suppression is excellent therapy for gastroesophageal reflux disease and may help in functional dyspepsia. Although it can be challenging to treat functional dyspepsia, patients should be reassured that they are not at higher risk of cancer or other serious disease and that they have a normal life expectancy. A variety of treatments can be tried, and the focus should be on leading a normal life even if symptoms cannot be eliminated.

        

Useful Links

National Digestive Disease Information Clearinghouse (National Institutes of Health)

http://digestive.niddk.nih.gov/index.htm

http://digestive.niddk.nih.gov/ddiseases/pubs/indigestion/index.htm

International Foundation for Functional Gastrointestinal Disorders

http://www.iffgd.org/

American Gastroenterological Association Patient Center

http://www.gastro.org/wmspage.cfm?parm1=478

American College of Gastroenterology Patient Information

http://www.gi.org/patients/

Rome Foundation

http://www.romecriteria.org/

References

1.         Talley NJ, Vakil NB, Moayyedi P. American gastroenterological association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.

2.         Talley NJ, Vakil N. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005;100:2324-37.

3.         Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, Stanghellini V. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466-79.

4.         Talley NJ. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 2005;129:1753-5.

5.         Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772-81.

6.         Ford AC, Delaney BC, Forman D, Moayyedi P. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev 2006:CD003840.

7.         Delaney B, Ford AC, Forman D, Moayyedi P, Qume M. Initial management strategies for dyspepsia. Cochrane Database Syst Rev 2005:CD001961.

8.         Ford AC, Qume M, Moayyedi P, Arents NL, Lassen AT, Logan RF, McColl KE, Myres P, Delaney BC. Helicobacter pylori "test and treat" or endoscopy for managing dyspepsia: an individual patient data meta-analysis. Gastroenterology 2005;128:1838-44.

9.         Vakil N, Moayyedi P, Fennerty MB, Talley NJ. Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis. Gastroenterology 2006;131:390-401; quiz 659-60.

10.       Moayyedi P, Soo S, Deeks J, Delaney B, Harris A, Innes M, Oakes R, Wilson S, Roalfe A, Bennett C, Forman D. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev 2006:CD002096.

11.       Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2006:CD001960.

12.       Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology 2004;127:1239-55.

13.       Soo S, Moayyedi P, Deeks J, Delaney B, Lewis M, Forman D. Psychological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2005:CD002301.