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Brian E. Lacy, PhD, MD; Brooks D. Cash, MD

JAMA. 2008;299(5):555-565.

ABSTRACT
Functional dyspepsia is a highly prevalent disorder that accounts for 5% of visits to primary care clinicians. It frequently coexists with other gastrointestinal tract disorders, including irritable bowel syndrome and gastroesophageal reflux disease. Symptoms of functional dyspepsia, including epigastric pain, early satiety, and postprandial nausea, are nonspecific, making its diagnosis difficult. Functional dyspepsia is a heterogeneous disorder involving a number of different pathophysiologic processes, culminating in both gastrointestinal sensory and motor dysfunction. Although functional dyspepsia does not impart any increased risks to long-term health, it significantly affects both individuals and society. The economic burden of evaluating and treating functional dyspepsia is estimated to be at least $1 billion per year, and patients with functional dyspepsia experience a markedly reduced quality of life. Using the case of Ms C, we apply an evidence-based approach to highlight current knowledge in the diagnosis, evaluation, and treatment of functional dyspepsia.

INTRODUCTION

Jump to Section  • Top  • Introduction  • Ms c: her view  • At the crossroads: questions...  • Recommendations for ms c  • Author information  • References

DR CASH: Ms C is a 32-year-old woman referred because of a 1-year history of abdominal pain. She describes an epigastric ache that occurs 3 to 4 times per week, may last for several hours, and fluctuates in intensity. Large, fatty meals worsen her pain and she has symptoms of early satiety. Ms C also describes recurrent episodes of heartburn and symptoms of lower abdominal discomfort, constipation (straining and feelings of incomplete evacuation), and bloating. The lower symptoms are relieved with the evacuation of stool.

Ms C has no chronic diseases involving the heart, lungs, kidneys, skin, or endocrine system. She does not smoke, drinks 2 to 3 glasses of wine each week, and consumes 25 to 30 g of fiber each day. Her appendix was removed when she was a young child. She has not been anemic, has not seen blood in her stool, has never had an ulcer, and denies problems with difficulty swallowing, food getting stuck in her throat, jaundice, or a history of pancreatitis. Her weight has been stable over the last year, and a recent gynecological examination had normal results. She is not allergic to any medications. She takes an oral contraceptive and uses over-the-counter nonsteroidal anti-inflammatory agents infrequently. A month-long trial of a twice-daily histamine-2 receptor antagonist did not improve her symptoms.

Ms C is single and works full-time at a publishing company. She was born in the United States and has never traveled outside of the country. Her race is white. Her mother underwent cholecystectomy at age 39 years for gallstones. Ms C's father does not have any gastrointestinal concerns, while a sister has irritable bowel syndrome (IBS). There is no family history of ulcer disease, gastrointestinal malignancies, inflammatory bowel disease, or celiac disease.

On examination, Ms C was afebrile with normal vital signs. Her height was 5 ft, 7 in and her weight was 132 lb (body mass index, 20.7). Her examination was remarkable for a well-healed scar in the right lower quadrant and mild epigastric tenderness present with palpation but with no evidence of rebound or guarding. She had normal bowel sounds and her abdomen was soft to palpation, her liver was not enlarged, and her spleen could not be felt. There was no evidence of ascites or a mass. A rectal examination was normal and a hemoccult stool test was negative for blood.

Ms C was told that her symptoms were consistent with dyspepsia, although acid reflux disease and choledocholithiasis remained possible, and she started oral omeprazole, 20 mg every morning, and was advised to refrain from all anti-inflammatory agents. Results of laboratory tests (including complete blood cell count, thyrotropin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, -glutamyl-transferase, bilirubin, lipase, and serum Helicobacter pylori IgG antibody) were normal except for the H pylori result, which was positive. Her omeprazole was increased to twice-daily dosing and she completed a 7-day course of twice-daily metronidazole and clarithromycin.

At the follow-up appointment 1 month later, Ms C's heartburn symptoms had resolved but her epigastric pain had worsened. Nausea was present after eating, and symptoms of lower abdominal discomfort and constipation had worsened. An upper endoscopy was performed because of persistent symptoms and revealed mild erythema in the antrum and body of the stomach. Biopsies taken from throughout the stomach revealed mild inflammation with scattered neutrophils and plasma cells but no evidence of H pylori.

Ms C was told that she likely had functional dyspepsia. Treatment options were discussed, including the risks and benefits of various medications. Desipramine was started (10 mg by mouth nightly), with a slow escalation in dose. One month later the epigastric discomfort had improved but not resolved. Both her nausea and constipation persisted and her abdominal examination results remained unchanged. Because of the maternal history of gallstones and her persistent symptoms, a right upper-quadrant ultrasound was obtained, which was interpreted as normal. The desipramine was increased to 50 mg by mouth nightly, but 1 week later she reported feeling groggy in the morning, with worsening of her constipation symptoms. Desipramine was tapered off and metoclopramide was started (10 mg by mouth before every meal). Laboratory tests for celiac disease provided normal results. A lactose-free diet provided minimal symptom improvement. Two weeks later, the bloating and nausea had improved but the epigastric pain and constipation persisted. Metoclopramide was increased to 20 mg by mouth before every meal and polyethylene glycol (17 g nightly) was begun.

At the next follow-up appointment, the nausea and constipation were better but the epigastric discomfort persisted. Ms C felt very fatigued, possibly because of the higher dose of metoclopramide. This was stopped and domperidone was started; polyethylene glycol was continued at the same dose. Two weeks later, she reported that the nausea was better while taking 10 mg of domperidone 4 times per day; however, the epigastric pain persisted. She stated that she would like to try desipramine again, after which she reported that the pain was tolerable at a dose of 25 mg nightly. She was referred to a cognitive behavioral therapist for treatment of chronic functional abdominal pain and was scheduled for another follow-up appointment 6 weeks later.

MS C: HER VIEW

Jump to Section  • Top  • Introduction  • Ms c: her view  • At the crossroads: questions...  • Recommendations for ms c  • Author information  • References

My worst symptom is pressure and pain in my stomach and lower chest, which is always more severe after eating. I also feel very full a lot after eating and sometimes feel queasy after eating. I feel like I am going to throw up, but I don’t. My symptoms are present every day. The pressure is always there. It is hard to go out and eat dinner or go to a friend's house. Eating out should be fun but it's not because I have pain and nausea after eating. The pressure makes it hard to exercise as well. My friends tell me it is just heartburn, but this feels different than regular heartburn, and I’m not sure why it doesn't get better when I take the heartburn medicine. I don't know why I have these symptoms. Sometimes I wonder whether it is due to something that I ate; however, the next day I can eat the same foods and they don't bother me. I wonder whether I was born with this problem. It is very frustrating to have these symptoms. I feel like I have to take a lot of medications all the time and I am not always sure if they are helping me. I’m too young to have to take medications all of the time. I do wonder if my symptoms will ever go away or if they will turn into something else. I am concerned that I might get an ulcer as I get older, and I wonder whether I could give this problem to my children.

AT THE CROSSROADS: QUESTIONS FOR DRS LACY AND CASH

Jump to Section  • Top  • Introduction  • Ms c: her view  • At the crossroads: questions...  • Recommendations for ms c  • Author information  • References

How is functional dyspepsia defined? What are its epidemiology and impact? What pathophysiologic processes underlie symptom expression in patients with functional dyspepsia? Does functional dyspepsia overlap with other common gastrointestinal disorders? How should functional dyspepsia be evaluated, and what is the yield of diagnostic testing? What is the evidence that nonpharmacological or pharmacological treatment is effective? What do you recommend for Ms C?

Definition of Functional Dyspepsia

DR LACY: Dyspepsia is a frequent reason for consultation, accounting for up to 5% of primary care practice visits.¹ Dyspepsia may have an identifiable organic basis (gastroesophageal reflux disease [GERD], peptic ulcer, gastric cancer) or, in patients in whom an organic basis cannot be identified, is designated as functional. Despite detectable pathophysiologic changes, functional dyspepsia remains an accurate designation for these patients even if a gastric motor or sensory abnormality is identified, as discussed later.^2-3 The criteria most commonly used to define functional dyspepsia in the United States are those formulated by the Rome Committee on Functional Gastrointestinal Disorders.^2-3 The American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) (Box 1)^2-5 based their definitions on the Rome Committee; thus, their definitions are virtually identical to those criteria. Using these definitions, the predominance of epigastric pain or discomfort distinguishes dyspepsia from GERD, in which heartburn and/or regurgitation are typically dominant or frequent (more than once a week) symptoms. In contrast, guidelines from the United Kingdom's National Institute for Clinical Excellence (NICE) and from the Canadian Dyspepsia Working Group include heartburn in the definition, recognizing that there is significant symptom overlap.^6-7

Box 1. Commonly Used Definitions of Functional Dyspepsia and Dyspepsia Rome II criteria for functional dyspepsia2,a Persistent or recurrent dyspepsia (pain or discomfort centered in the upper abdomen) No evidence of organic disease (including on upper endoscopy) that is likely to explain the symptoms No evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a sudden change in stool frequency or stool form (ie, not irritable bowel syndrome) Criteria fulfilled for at least 12 weeks, which need not be consecutive, within the preceding 12 months American Gastroenterological Association for functional dyspepsia4 Dyspepsia is restricted to mean chronic or recurrent pain or discomfort centered in the upper abdomen (ie, the epigastrium); symptoms of reflux (heartburn or regurgitation) and acute abdominal conditions are not included. American College of Gastroenterology for functional dyspepsia5 Dyspepsia is defined as chronic or recurrent pain or discomfort centered in the upper abdomen. Discomfort is defined as a subjective negative feeling that is not painful and can incorporate a variety of symptoms including early satiety or upper abdominal fullness. Patients presenting with predominant or frequent (more than once a week) heartburn or acid regurgitation should be considered to have gastroesophageal reflux disease until proven otherwise. Rome III criteria3,a Functional dyspepsia (For all categories noted below, criteria must be fulfilled for the last 3 months, with symptom onset at least 6 months prior to diagnosis.)   Patients must have 1 or more of the following symptoms:     Postprandial fullness     Early satiety     Epigastric burning   No evidence of structural disease that is likely to explain symptoms (including upper endoscopy) Postprandial distress syndrome (Diagnostic criteria must include both of the first 2 listed symptoms.)   Bothersome postprandial fullness occurring after ordinary sized meals at least several times per week   Early satiation that prevents finishing a regular meal at least several times per week   Other supporting criteria:     Upper abdominal bloating or postprandial nausea or excessive belching can be present     Epigastric pain syndrome may coexist Epigastric pain syndrome (Diagnostic criteria must include all of the first 5 listed symptoms.)   Pain or burning localized to the epigastrium, of at least moderate severity at least once per week   Pain is intermittent   Not generalized or localized to other abdominal or chest regions   Not relieved by defecation or passage of flatus   Not fulfilling criteria for biliary pain   Other supporting criteria:     Pain may be of a burning quality but without a retrosternal component.     Pain is commonly induced or relieved by ingestion of a meal but may occur while fasting.     Postprandial distress syndrome may coexist. National Institute for Clinical Excellence (NICE [United Kingdom])6 Dyspepsia is defined as any symptom of the upper gastrointestinal tract, including recurrent pain, heartburn, or acid regurgitation, with or without bloating, nausea, or vomiting. Canadian Dyspepsia Working Group7 Dyspepsia is a symptom complex of epigastric pain or discomfort thought to originate in the upper gastrointestinal tract and may include any of the following symptoms: heartburn, acid regurgitation, excessive burping/belching, increased abdominal bloating, nausea, feeling of abnormal or slow digestion, or early satiety. aRome refers to the Rome Committee on Functional Gastrointestinal Disorders. RETURN TO TEXT

Functional dyspepsia was previously characterized as ulcer-like, dysmotility-like, or unspecified, depending on the predominant symptom.¹ However, this classification system did not predict the underlying pathophysiology or the response to treatment and has fallen out of favor.⁸ In the updated Rome criteria (Rome III), functional dyspepsia is defined as the presence of symptoms thought to originate in the gastroduodenal region in the absence of any organic, systemic, or metabolic disease likely to explain the symptoms.³ When possible, functional dyspepsia should now be divided into 2 new subcategories: postprandial distress syndrome and epigastric pain syndrome (Box 1). Patients with functional dyspepsia should have 1 or more of the following symptoms: postprandial fullness, early satiety, epigastric pain, or epigastric burning.. These symptoms should be present for at least 3 months, with the onset of symptoms at least 6 months before diagnosis.

Epidemiology and Impact

While most patients with dyspepsia do not seek medical attention, the condition is common, with an estimated prevalence of 15% to 30% in developed nations.^9-10 Functional dyspepsia, which can only be diagnosed after an appropriate diagnostic evaluation fails to identify an etiology (see section on the cost-effective evaluation of patients with functional dyspepsia), is diagnosed in nearly two-thirds of patients with dyspeptic symptoms.^9-10 A recent systematic review documented the prevalence of uninvestigated dyspepsia (including heartburn and regurgitation) worldwide to be 10% to 40%, while the prevalence of functional dyspepsia (after normal upper endoscopy) was 12% to 15%.¹¹ Although more difficult to assess, one study estimated the incidence of dyspepsia to be less than 1% over 3 months, while another study found the incidence of new-onset dyspepsia (using the Leeds Dyspepsia Questionnaire) to be 2.8% per year.^12-13

The clinical course of dyspepsia remains poorly understood and the prognosis is variable. Symptoms may fluctuate in severity and character over time, perhaps even meeting criteria for other functional gastrointestinal disorders.^14-18 Although many patients experience chronic dyspepsia, an estimated 50% to 66% of patients with functional dyspepsia improve or become asymptomatic over a median follow-up of 5 years.¹¹

Functional dyspepsia is not associated with an increased risk of cancer or a decline in longevity; however, symptoms can dramatically reduce patients' quality of life.^19-21 This reduction in quality of life is similar to that experienced by perimenopausal women and patients with mild heart failure.²² However, the direction of causation is not clear; a recent study found that a lower quality of life is itself a risk factor for developing dyspepsia (odds ratio, 2.63; 99% confidence interval [CI], 1.86-3.71).¹³

Dyspepsia also has a significant economic impact. A study in the United Kingdom estimated a societal cost due to dyspepsia of £1 billion each year, mainly in time off from work, whereas the direct costs associated with dyspepsia to the UK health service for the period 1992-1994 were estimated at £500 million.²² Few data on the economic impact of functional dyspepsia are available.

Pathophysiologic Processes Underlying Symptom Expression

In addition to abdominal pain or discomfort, symptoms of functional dyspepsia include postprandial abdominal fullness (80%-90%), bloating (80%-90%), early satiety (60%-70%), nausea (60%-70%), retching (25%-30%), vomiting (25%-30%), and belching (50%-70%).^{3, 8, 23} The designation of functional dyspepsia remains correct in the absence of an organic process (eg, peptic ulcer disease, GERD, malignancy), even if a patient has a specific pathophysiologic abnormality identified by specialized testing. Pathophysiologic mechanisms involved in the generation of functional dyspepsia symptoms include disturbances in gastrointestinal motor function and altered visceral sensation. Gastrointestinal motor abnormalities identified in patients with functional dyspepsia include delayed emptying, impaired gastric accommodation, antral hypomotility, gastric dysrhythmias, and abnormal duodenojejunal motility.24-25 Other contributory factors include visceral hypersensitivity (both gastric and duodenal), altered brain-gut function, abnormal gut immune function, and psychosocial factors.^{3, 8, 24} Unfortunately, the root causes of many of these disturbances in gastrointestinal sensory and motor functions are not known, and individual pathophysiologic abnormalities do not accurately predict symptom expression or response to therapy.⁸

Like Ms C, many patients with functional dyspepsia experience symptoms related to meals. Delayed gastric emptying has been reported in 25% to 35% of patients with functional dyspepsia, although a specific symptom pattern associated with gastric-emptying abnormalities has not been identified.^{3, 25} One study noted an association with postprandial fullness and vomiting,²⁶ while another study of 864 patients with functional dyspepsia and postprandial fullness was only weakly associated with delayed gastric emptying (odds ratio, 1.98; 95% CI, 1.02-3.86; P = .04), and epigastric pain, early satiety, nausea, and bloating were not associated with delayed gastric emptying.²⁰ Less commonly, accelerated gastric emptying is present in patients with functional dyspepsia (10% of patients) and may be associated with postprandial symptoms.²⁷

Impaired gastric accommodation is present in approximately 40% of patients with dyspepsia.⁵ Abnormalities in postprandial gastric accommodation are thought to produce symptoms because of increased intragastric pressure and activation of mechanoreceptors in the proximal gastric wall. Gastric barostat studies have shown that symptoms of early satiety predict impaired accommodation with a sensitivity of 81% and specificity of 52%, whereas weight loss had a sensitivity of 65% and specificity of 52%.²⁸ The low specificity argues against these symptoms being characteristic of impaired accommodation.

Gastric balloon distension studies show that 34% to 66% of patients with functional dyspepsia have heightened visceral perception, often experienced as epigastric pain. However, this hypersensitivity does not consistently correlate with any symptom complex.²³ In a study of 160 patients with functional dyspepsia, a subset of patients who experienced hypersensitivity to gastric distension had a higher prevalence of postprandial pain, belching, and weight loss.²⁹ However, a subsequent study found that the specificity of each of these 3 symptoms for visceral hypersensitivity was less than 50%.²⁸

An acute gastrointestinal infection may be associated with the development of functional dyspepsia in up to 20% of cases.³⁰ Helicobacter pylori infection is widely acknowledged to be a risk factor for peptic ulcer disease, although its role in functional dyspepsia is less clear. A systematic review did not find a strong association between H pylori infection and functional dyspepsia but could not rule out a modest association.³¹ As described in the treatment section below, however, some patients with functional dyspepsia who are H pylori–positive note an improvement in symptoms after H pylori eradication.³²

A genetic predisposition to develop functional dyspepsia has been hypothesized, and recent findings demonstrate that the GNβ3 CC genotype (a G-protein polymorphism involved in cell signaling) is twice as prevalent in patients with functional dyspepsia, especially those with so-called dysmotility-like dyspepsia.^33-34 Whether this genotype is associated with any specific pathophysiologic mechanism or particular Rome III functional dyspepsia subtype remains to be established.

A recent endoscopic study found that Swedish patients with functional dyspepsia were more likely to have elevated numbers of eosinophils in the duodenum (but not the stomach) compared with control patients.³⁵ Early satiety, a common symptom of functional dyspepsia, was positively associated with duodenal eosinophilia.

Finally, psychological symptoms such as anxiety and depression tend to be more common in patients with functional dyspepsia than in the general population and may influence physiological functions that underlie symptom generation.^{3, 6, 12, 36} These factors appear to be particularly important in patients with gastric hypersensitivity.³⁷

Overlap of Functional Dyspepsia With Other Common Gastrointestinal Disorders

Functional dyspepsia can overlap with other conditions and can also be confused with other diseases.^{23, 38} Symptoms of IBS or GERD frequently coexist in patients with functional dyspepsia.^14-15,39 Although predominant heartburn symptoms exclude a patient from being classified as having functional dyspepsia using the Rome criteria, the presence of heartburn does not exclude a concurrent diagnosis of functional dyspepsia, especially if a trial of acid suppression therapy fails to suppress dyspeptic symptoms. Irritable bowel syndrome and functional dyspepsia share pathophysiologic similarities, and the disorders frequently coexist.38-39 The prevalence of IBS is higher among patients with functional dyspepsia than in the general population, and an overlap between functional dyspepsia and IBS is seen in more than 50% of patients.^{38, 40-41} Patients with concomitant symptoms are more likely to be female, have gastric hypersensitivity, and have a higher symptom severity rating.⁴²

On review, Ms C's persistent upper gastrointestinal symptoms likely stem from functional dyspepsia, although she clearly had coexisting symptoms of GERD, which resolved with empirical proton-pump inhibitor (PPI) therapy. Her symptoms of lower abdominal discomfort, relieved by the passage of stool, suggest coexisting IBS.

Evidence-Based Evaluation of Functional Dyspepsia

Evidence-supported, cost-effective evaluation of patients with dyspepsia remains a challenge. For patients with uninvestigated dyspepsia, initial efforts should focus on differentiating organic causes of dyspepsia from functional dyspepsia (Box 2).

Box 2. Common Organic Causes of Dyspepsia Gastroesophageal reflux disease with or without esophagitis Esophageal dysmotility Peptic ulcer disease (gastric or duodenal ulcer) Gastric erosions and gastritis (confirmed histologically) Gastroparesis (with or without bezoar formation) Malignancy of the upper gastrointestinal tract (stomach, pancreas, small intestine) Pancreatitis Hepatitis Cholelithiasis/cholecystitis Other hepatobiliary disorders Medication-induced (eg, nonsteroidal anti-inflammatory drugs, antibiotics, aspirin-containing products) RETURN TO TEXT

History and Clinical Examination. In the absence of any accepted biological marker, symptoms remain the cornerstone of identifying patients with functional dyspepsia, but the ability of either symptom cues or the clinical examination to distinguish organic dyspepsia from functional dyspepsia is controversial.^3-5 An investigation of adults with upper gastrointestinal tract symptoms who underwent upper endoscopy compared the predictive accuracy of clinicians with that of a computer model for distinguishing organic dyspepsia from functional dyspepsia.⁴³ The diagnosis of organic dyspepsia had a positive likelihood ratio of 1.6 (95% CI, 1.4-1.8) and a negative likelihood ratio of 0.46 (95% CI, 0.38-0.55), highlighting the inaccuracy of a symptom-based diagnosis. The computer models performed similarly to the clinician. Despite the unsatisfactory predictive accuracy of symptoms, the clinical history remains important for a number of reasons, including identifying patients with GERD and NSAID-induced dyspepsia, establishing that the symptoms arise from the upper gastrointestinal tract and not another organ system, and identifying patients with alarm symptoms.^{4, 43}

The presence of alarm symptoms (dysphagia, recurrent vomiting, unexplained weight loss, gastrointestinal bleeding, anemia, jaundice, palpable mass, or ascites) helps to identify patients who require urgent or additional investigations.^3-5 Upper gastrointestinal tract malignancy is rarely present in young patients without alarm features, although the positive predictive value of alarm features is very poor—4% for malignancy and 11% for ulcers.⁴⁴ Even then, most patients who develop upper gastrointestinal tract cancer or an ulcer do not present with alarm symptoms.⁴⁴ A study evaluating the potential of symptom-based algorithms plus the presence of alarm features found that alarm features did not discriminate functional dyspepsia from organic disease and that only 17.1% of patients were classified accurately by decreased appetite (an alarm feature) and 5 nonalarm items.⁴⁵ An analysis of 15 studies involving 57 363 patients with dyspepsia found a sensitivity for alarm symptoms (dysphagia, weight loss, anemia) predicting a malignancy of 0% to 83%, with a specificity of 40% to 98%.⁴⁶

For Ms C, the absence of these alarm features, as well as her young age, strongly argue against serious underlying disease, particularly malignancy, as the cause of her symptoms. In addition, Ms C's pain is not likely to be of cardiac origin given the absence of cardiac risk factors. Peptic ulcer disease as a cause of her symptoms is unlikely given her only occasional use of nonsteroidal anti-inflammatory drugs and the absence of other risk factors (prior peptic ulcer disease, family history of ulcers, tobacco use), but it cannot be excluded given her positive H pylori antibody test result. Persistent epigastric discomfort from acid reflux is unlikely since she can distinguish her heartburn symptoms from her dyspepsia symptoms and because omeprazole eliminated her heartburn symptoms. Her frequent episodes of epigastric pain as well as postprandial fullness and early satiety are suggestive of functional dyspepsia encompassing the subcategories of both postprandial distress syndrome and epigastric pain syndrome, as defined in the Rome III classification.⁸ Overlapping IBS must also be considered, given her symptoms of abdominal bloating and distension, constipation, and lower abdominal discomfort that are relieved with stool evacuation and the frequent coexistence of these 2 highly prevalent disorders.^38-39

Ms C has a family history of gallstones. However, Ms C's pain differs from biliary colic, which characteristically is more episodic, severe, and associated with vomiting.^{4, 43} Celiac disease and inflammatory bowel disease are uncommon causes of dyspepsia symptoms, and the absence of anemia, diarrhea, and a positive family history make these diagnoses unlikely.

No prospective study has assessed the clinical utility of screening for depression or anxiety in patients suspected to have functional dyspepsia, and there is no evidence that these diagnoses are responsible for Ms C's symptoms.

As noted, the physical examination is of limited use in the evaluation of patients with dyspepsia symptoms. With the exception of epigastric tenderness, the findings are usually normal, as in Ms C's case. Epigastric tenderness on palpation is of little diagnostic value for upper gastrointestinal tract pathology (sensitivity of 64% and specificity of 30%).^{43, 47} However, a palpable epigastric mass, nodular enlargement, or lymphadenopathy could indicate a malignant process of the upper gastrointestinal tract.

Yield of Diagnostic Testing. Although routine chemistry and hematology evaluations are usually included in the diagnostic workup of dyspepsia, their clinical value has not been formally validated.^{3, 5, 8} A complete blood cell count should be performed to rule out anemia. Additional laboratory testing depends on the nature and duration of symptoms, the level of clinical suspicion, and the response to initial therapy. Liver tests should be performed if a hepatobiliary source of pain is suspected, while a serum lipase test may be useful if pancreatitis is suspected.

If the history, physical examination, and initial laboratory tests do not lead to a diagnosis, clinicians can follow management guidelines recommended by the AGA and ACG.^4-5 The available strategies include the "test-and-treat" strategy for H pylori, prompt endoscopy, and empirical antisecretory therapy.

The AGA recommends that dyspeptic patients younger than 55 years without alarm features undergo testing and treatment for H pylori provided that the geographical prevalence of infection is greater than 10%.⁴ A Cochrane systematic review of 4 randomized trials showed that this strategy led to outcomes equivalent to prompt endoscopy (relative risk of cure, 1.01; 95% CI, 0.84-1.22) and reduced the endoscopy workload.⁴⁸ A meta-analysis of individual patient data from 5 trials found a small but statistically significant benefit of prompt endoscopy compared with a test-and-treat approach,⁴⁹ but prompt endoscopy was not cost-effective at any reasonable level. Ms C underwent a serological test for H pylori, although this method is not recommended in younger patients (<40 years) because of a lower positive predictive value (70%-80%) compared with the urea breath test or the stool antigen test.^50-51

There is general consensus that endoscopy should be reserved for patients with onset of symptoms after 55 years, those with alarm features, and those in whom antisecretory therapy or the H pylori test-and-treat strategy fail.4-5,48 During endoscopy, approximately 10% of patients with upper gastrointestinal tract symptoms are found to have a peptic ulcer, 20% have reflux esophagitis, and a malignancy is found in less than 2% of patients.⁴³ However, the absence of esophagitis on endoscopy does not exclude GERD; endoscopy-negative reflux disease may occur in 20% of patients.⁴³ In a study of 1040 primary care patients with uninvestigated dyspepsia, 58% had clinically significant endoscopic findings.⁵² Reflux esophagitis was the most common finding (43% of patients), peptic ulcer disease was found in 4.4%, and no cases of malignancy were identified. Overall, 30% had H pylori infection, although among those with peptic ulcer disease, the infection rate was higher (62%). The yield from upper endoscopy increases with age in patients with dyspepsia.⁵²

Functional dyspepsia, the final diagnosis in at least two-thirds of patients with dyspeptic symptoms, remains a diagnosis of exclusion.⁴ In Ms C's case, the lack of suspicious findings on physical examination, coupled with normal endoscopy, laboratory test, and right upper-quadrant ultrasound results, argues against severe organic disease as an explanation for her dyspepsia.

Because of her age and absence of alarm features, Ms C was treated empirically with omeprazole and underwent testing for H pylori. When she continued to have epigastric pain despite treatment for H pylori and escalation of the omeprazole dose, she underwent upper endoscopy, although the AGA, NICE, and Canadian Dyspepsia Working Group guidelines all note that endoscopy is not mandatory in this population since the likelihood of changing medical management based on endoscopic findings is low.^{4, 6-7}

In evaluation of younger patients (<45 years) with dyspeptic symptoms and without warning signs on history or examination, empirical antisecretory therapy may provide valuable diagnostic information in addition to possible therapeutic benefits. Histamine-2 receptor antagonists have been shown to be marginally better than placebo at improving symptoms of epigastric pain, although they were no better than placebo at treating overall dyspeptic symptoms.⁵³ A recent meta-analysis found that PPIs were about 10% better than placebo at improving dyspeptic symptoms, with a calculated number needed to treat of 9. The risks of empirical antisecretory therapy for a 4- to 6-week trial are low, but long-term empirical therapy can be expensive and has the potential to mask a more serious disease (eg, an ulcer or malignancy) or delay initiation of more appropriate therapy.^{4, 6, 8} In addition, data suggest that long-term therapy with a PPI increases the risk of developing Clostridium difficile colitis (odds ratio, 2.05; 95% CI, 1.47-2.85), community-acquired pneumonia (adjusted relative risk, 1.89; 95% CI, 1.36-2.62), and osteoporotic hip fractures (adjusted odds ratio, 1.44 for >1 year of PPI use; 95% CI, 1.30-1.59).^54-56

In younger patients with dyspeptic symptoms, other tests have little proven clinical value, and their yield has not been systematically evaluated in dyspepsia. Barium studies of the gastrointestinal tract can exclude an obstruction, an ulcer, or a mass but cannot adequately assess the mucosa and, thus, may miss the diagnosis of esophagitis in many patients.^4-5,57 Ultrasonography of the gallbladder may be helpful for distinguishing biliary pain from dyspepsia.⁵⁸ Ms C does not have characteristic biliary pain; however, her persistent pain and maternal history of gallstones prompted a right upper-quadrant ultrasound, which yielded a normal result.

Ms C's symptoms of early satiety and nausea suggest delayed gastric emptying, and the solid-phase gastric emptying scan is considered the most readily available clinical test to evaluate delays in gastric emptying.⁵⁹ Twenty-five percent to 35% of patients with functional dyspepsia have delays in gastric emptying,^25-26 but the relationship between gastric emptying and dyspepsia symptoms is vague, and accelerating or normalizing delayed gastric emptying may not improve symptoms.³ Alternatively, symptoms of postprandial fullness and early satiety suggest an underlying abnormality in gastric accommodation. In the research setting, single-photon emission computed tomography can detect a 10% change in gastric volume with high sensitivity.⁶⁰

Effectiveness of Treatment Options

An all-encompassing, evidence-based therapeutic strategy for functional dyspepsia does not currently exist. This is in part because of the multiple pathophysiologic mechanisms that result in symptom generation. The complex pathophysiology likely accounts for the limited efficacy of many currently prescribed medications, since they target only a single pathophysiologic mechanism (Table). At present, none of the medications commonly used to treat this condition is approved by the US Food and Drug Administration for treatment of functional dyspepsia.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table. Current Treatment Strategies for Functional Dyspepsia

Nonpharmacological Approaches. Dietary Modification. Since many symptoms of functional dyspepsia are related to food intake, dietary and lifestyle modifications are commonly recommended, although none has been formally evaluated in large clinical trials.⁶¹ Limited evidence suggests that dietary fat may increase gastric sensitivity to distension and cause dyspeptic symptoms.^62-63 Other dietary modifications, such as avoidance of late-evening meals and eating smaller, more frequent meals, have also been advocated.^{23, 61, 64} Specific foods commonly implicated in symptom induction include onions, peppers, citrus fruit, coffee, carbonated beverages, and spices.^{61, 64} If patients are consistently bothered by specific foods, they should avoid them, although patients should be appropriately counseled so that they do not become food-phobic.

Psychological Therapies. A recent systematic review identified only 4 randomized controlled trials that evaluated psychological interventions for functional dyspepsia.⁶⁵ Therapeutic interventions included cognitive therapy, hypnotherapy, psychodynamic psychotherapy, and applied relaxation therapy. Each study was small, used different techniques, and analyzed the data differently, making it difficult to determine whether psychological interventions are helpful. A recent study found that hypnotherapy improved symptom scores and quality of life and reduced medication use and clinician visits in patients with functional dyspepsia compared with patients who received either supportive therapy or medical treatment.⁶⁶ Psychological therapies may be a useful adjunct to conventional therapy in patients with functional dyspepsia and may alleviate symptoms of dyspepsia by reducing stress and anxiety. When Ms C's symptoms persisted despite multiple medication trials, she was referred for cognitive behavioral therapy to help manage any stressors that may have been contributing to her chronic epigastric discomfort.

Pharmacological Treatment. H pylori Eradication. The benefits of H pylori eradication in the treatment of functional dyspepsia are significantly more limited than in peptic ulcer disease. The most recent Cochrane database included 21 trials and reported a small but significant symptom benefit of eradicating H pylori in patients with functional dyspepsia (relative risk reduction, 10%; 95% CI, 6%-14%), with a number needed to treat of 14.³² Empirical treatment for presumed (undocumented) H pylori in patients with functional dyspepsia is not recommended because of the low likelihood of achieving symptomatic improvement, concern about widening antibiotic resistance, and reduced prevalence of H pylori in many Western countries.73 The AGA recommends the H pylori test-and-treat strategy as the initial management strategy for uncomplicated dyspepsia in patients younger than 55 years if the prevalence of infection is greater than 10%. Empirical PPI therapy is recommended as the initial management strategy in these patients when H pylori prevalence is low (<5%).⁴

Antisecretory Therapy. Proton pump inhibitor therapy is the treatment of choice for patients with functional dyspepsia without H pylori infection and those who remain symptomatic after treatment for H pylori. Proton pump inhibitors are more effective at alleviating functional dyspepsia symptoms than histamine 2 receptor antagonists in trials that have compared the 2 treatments.⁴ Moayyedi et al^{32, 67} showed that PPIs produce a small but statistically significant improvement in symptom scores for dyspepsia compared with placebo (relative risk reduction, 14%; 95% CI, 5%-22%) with a number needed to treat of 9. In a meta-analysis, PPIs were more effective than placebo for reducing symptoms in functional dyspepsia, with a relative risk reduction of 10.3% (95% CI, 2.7%-17.3%) and a number needed to treat of 14.⁶⁸ However, another recent study found that twice-daily esomeprazole was no better than placebo at relieving dyspeptic symptoms, although this study may have been underpowered (n = 188 with 37.4% considered ineligible because of clinically significant endoscopic findings).⁶⁹ Proton pump inhibitors appear to be more effective in patients with reflux-predominant and ulcerlike symptoms than in those with symptoms of dysmotility, such as nausea and bloating.^67-68 Nausea, headache, constipation, nasopharyngitis, and bronchitis are the most frequently reported adverse effects of PPIs; longer-term adverse effects of PPIs are listed above.⁶⁹

Ms C's symptoms were not relieved with a histamine-2 receptor antagonist. Omeprazole relieved her heartburn symptoms but not the epigastric pain or postprandial symptoms. Treatment of patients in whom initial (once-daily) antisecretory therapy fails is not defined, although doubling the dosage (to twice daily) may improve symptoms in a small percentage of patients.

Prokinetic Agents. Prokinetic drugs accelerate gastrointestinal motility and may improve symptoms of functional dyspepsia by accelerating gastric emptying or relaxing the gastric fundus. A systematic review reported that as a class, prokinetic agents were twice as effective as placebo in relieving dyspeptic symptoms (relative risk reduction, 48%; 95% CI, 27%-63%).⁷² However, in an analysis evaluating a funnel plot based on effect size and the size of the trial, the authors found that the larger studies showed no benefit over placebo and concluded that the positive benefits of prokinetic agents may represent publication bias. A subsequent meta-analysis that included high-quality trials did not show any benefit of prokinetic agents over placebo.⁷⁶ In the United States, the availability of prokinetic agents is limited, and some (eg, metoclopramide) have frequent adverse effects, so these agents are generally used after H pylori eradication and PPI therapy has failed.

Prokinetic agents currently used or under investigation for the treatment of functional dyspepsia include the dopamine antagonists metoclopramide, domperidone, and itopride, the mixed 5-hydroxytryptamine 4 (5-HT₄) agonists/5-HT₃ antagonists renzapride and mosapride, and the 5-HT₄ partial agonist tegaserod. Cisapride, a mixed 5-HT3 antagonist/5-HT₄ agonist, is no longer commercially available because of adverse cardiac effects.⁷⁴ Although commonly prescribed for the treatment of functional dyspepsia, the efficacy of metoclopramide is questionable and it has significant adverse effects, including dystonic reactions and drowsiness.^{32, 73, 77} Domperidone, which is not readily available in the United States, does not have the adverse central effects associated with metoclopramide, although it can cause breast tenderness and galactorrhea, and cardiac toxicity is a rare event.^{23, 32} However, a Cochrane analysis noted that only 1 study had evaluated domperidone, and this double-blind study was limited by its brief duration (4 weeks), small patient population (n = 40), and minimally positive results at improving symptoms of early satiety compared with placebo.³² Mosapride, a mixed 5-HT₃ antagonist/5-HT₄ agonist, has variable efficacy for functional dyspepsia in clinical trials.^{71, 78} Itopride, a dopamine antagonist with acetylcholinesterase properties, improved symptoms of functional dyspepsia in one trial but did not show benefit in another.^79-80

Tegaserod is approved for the treatment of women with constipation-predominant IBS and men and women younger than 65 years with chronic constipation.^81-82 In preliminary studies of functional dyspepsia, tegaserod enhanced postprandial gastric compliance and meal-induced gastric accommodation in patients with functional dyspepsia.^83-84 In a recent trial, tegaserod (6 mg by mouth daily) improved symptoms of early satiety and postprandial fullness in patients with functional dyspepsia and normal gastric emptying compared with randomized placebo treatment.⁸⁵ In 2 multicenter studies in patients with dysmotility-type functional dyspepsia, more patients treated with tegaserod reported satisfactory relief of dyspepsia, with a greater reduction in the daily composite symptom score; the number needed to treat ranged from 15.1 to 17.9.⁸⁶ Because of concerns about possible increased risk of adverse cardiovascular events (noted in an internal review of data from randomized trials of tegaserod [written communication, Novartis Pharmaceuticals, December 2007]), sales and marketing of this agent were suspended in the United States and several other countries on March 30, 2007 (http://www.fda.gov/cder/drug/advisory/tegaserod.htm). Its future status for treatment of functional dyspepsia is not known.

To relieve her postprandial nausea and epigastric discomfort, Ms C was treated with metoclopramide. Although her nausea was somewhat relieved, the treatment left her fatigued. The switch to domperidone improved her nausea further but did not relieve her epigastric pain.

Antidepressants. Antidepressants are of uncertain efficacy in functional dyspepsia but are often prescribed based largely on anecdotal data.^{5, 23} A recent systematic review reported that symptoms of dyspepsia were improved significantly with antidepressants or anxiolytic agents; a meta-analysis performed on 4 of the 11 studies demonstrated a relative risk of 0.55 (95% CI, 0.36-0.85).⁷⁰ Fourteen patients whose functional dyspepsia symptoms had not responded to famotidine or mosapride had improved symptoms with amitriptyline.⁷¹ As with IBS, it is thought that tricyclic antidepressants may benefit patients through an anticholinergic effect that reduces intragastric pressure and motility combined with analgesic action that blunts visceral hypersensitivity.⁸⁷ Lower doses of tricyclic antidepressants are typically used when treating functional dyspepsia as opposed to depression, and second-generation agents may have better tolerability. In general, antidepressants should be reserved for patients such as Ms C whose symptoms persist after a trial of conventional therapies. Ms C was prescribed an escalating dose of desipramine, which helped alleviate but not cure her abdominal discomfort.

Although selective serotonin reuptake inhibitors provide benefit in some patients with IBS,⁸⁸ their efficacy in relieving gastrointestinal symptoms in functional dyspepsia has not been studied.

Complementary Treatment. Iberogast, a preparation of 9 plant extracts, has been evaluated in several European functional dyspepsia studies. A recent multicenter, double-blind, placebo-controlled trial of 315 patients with functional dyspepsia found that iberogast (20 drops by mouth 3 times per day) significantly improved dyspeptic symptoms at both 4 weeks and 8 weeks compared with placebo (P < .05) using a validated symptom score.⁸⁹ Iberogast may improve dyspeptic symptoms by increasing fundic relaxation and stimulating antral motility.⁹⁰

Investigational Agents. Many emerging therapies are being directed at normalizing pain perception and gastrointestinal motor and reflex function in functional dyspepsia. A variety of neuropeptides and their receptors and pathways are emerging as possible therapeutic targets. Potential targets include cholecystokinin receptors, -opioid receptors, N-methyl-D-aspartate receptors, and neurokinin receptors.^{23, 36, 73, 87} Cholecystokinin is a neuropeptide believed to mediate pain in the gut. The cholecystokinin antagonist dexloxiglumide reduced dyspeptic symptoms induced by lipid infusion and gastric distension.⁹¹ Neurokinin receptors (NK1, NK2, and NK3) are widely expressed in the enteric nervous system and are thought to modulate pain perception in the gastrointestinal tract. Although NK1 receptor antagonists were antinociceptive in animal studies, these results have not been replicated in humans.²³ N-Methyl-D-aspartate receptors may play a role in visceral hypersensitivity, and in rodent models, N-methyl-D-aspartate antagonism has reduced the nociceptive response to colonic distension.⁹²

RECOMMENDATIONS FOR MS C

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Like Ms C, some patients do not respond to standard therapeutic measures, and such patients may benefit from an ongoing relationship with a physician with whom they can partner in management decisions. Behavioral therapy may help relieve anxiety levels and improve symptoms.⁹³

At the next follow-up visit, Ms C reported an improvement in her epigastric discomfort after 3 visits with the cognitive behavioral therapist. She seemed more optimistic about her diagnosis, reported less epigastric pain, and stated that she did not have any problems with nausea or heartburn. Ms C also noted a resolution of her constipation symptoms with nightly polyethylene glycol. At this time, we recommend that she continue a daily PPI for heartburn symptoms, with the goal of tapering this medication at the next follow-up visit in 2 months. She can continue domperidone (10 mg by mouth 3 times per day) and low-dose desipramine for her dyspeptic symptoms and also continue polyethylene glycol for her symptoms of constipation. Ms C plans to continue her every-other-week visits with the therapist for the next 2 months, at which point the need for further treatment would be reassessed.

Ms C's case illustrates the complex decisions primary care clinicians must face when evaluating a patient with dyspepsia. Currently available treatment guidelines,^4-6 combined with the stepwise approach illustrated in this case, should enable health care practitioners to evaluate and diagnose functional dyspepsia. Continued research efforts focusing on the etiology and pathophysiology of this highly prevalent disorder should lead to more effective treatment options in the future.

AUTHOR INFORMATION

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Corresponding Author: Brian E. Lacy, PhD, MD, Division of Gastroenterology and Hepatology, Area 4C, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756 (brian.e.lacy{at}hitchcock.org).

Additional Contributions: We thank the patient for sharing her story and providing permission to publish it.

Financial Disclosures: Dr Lacy reported having served as a consultant for Novartis and Takeda and reported having received unrestricted, investigator-initiated funding from AstraZeneca, Novartis, and Medtronics. Dr Cash reported having served as a consultant for Novartis Pharmaceuticals, Takeda, Sucampo, and Salix.

This case was presented at the Medical Grand Rounds at the Dartmouth-Hitchcock Medical Center by Drs Lacy and Cash on April 6, 2007.

Author Affiliations: Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (Dr Lacy); Division of Gastroenterology, Bethesda Naval Medical Center, Bethesda, Maryland (Dr Cash).

REFERENCES

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Is functional dyspepsia really the right diagnosis?
Lorenzo Fuccio
JAMA Online, 31 Jan 2008.
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