Earlier definitions considered dyspepsia to consist of all upper abdominal and retrosternal sensations—in effect, all symptoms considered to be referable to the proximal gastrointestinal tract.⁴ The Rome I and II consensus committees both defined dyspepsia as pain or discomfort centered in the upper abdomen.^1,² Discomfort includes postprandial fullness, upper abdominal bloating, early satiation, epigastric burning, belching, nausea, and vomiting. Heartburn may occur as part of the symptom constellation, but the Rome II committee decided that when heartburn is the predominant symptom, the patient should be considered to have GERD and not dyspepsia.

The most recent consensus committee, Rome III, has defined dyspepsia as the presence of symptoms considered by the physician to originate from the gastroduodenal region (Table 13-1).⁵ Only four symptoms (bothersome postprandial fullness, early satiation, epigastric pain, and epigastric burning) are now considered to be specific for a gastroduodenal origin, although many other symptoms are acknowledged to coexist with dyspepsia.

Table 13-1 Dyspeptic Symptoms and Their Definitions *

SYMPTOM	DEFINITION
More Specific
Postprandial fullness	An unpleasant sensation perceived as the prolonged persistence of food in the stomach
Early satiation	A feeling that the stomach is overfilled soon after starting to eat, out of proportion to the size of the meal being eaten, so that the meal cannot be finished. Previously, the term early satiety was used, but satiation is the correct term for the disappearance of the sensation of appetite during food ingestion.
Epigastric pain	Epigastric refers to the region between the umbilicus and lower end of the sternum, within the midclavicular lines. Pain refers to a subjective, unpleasant sensation; some patients may feel that tissue damage is occurring. Epigastric pain may or may not have a burning quality. Other symptoms may be extremely bothersome without being interpreted by the patient as pain.
Epigastric burning	Epigastric refers to the region between the umbilicus and lower end of the sternum, within the midclavicular lines. Burning refers to an unpleasant subjective sensation of heat.
Less Specific
Bloating in the upper abdomen	An unpleasant sensation of tightness located in the epigastrium. Bloating should be distinguished from visible abdominal distention
Nausea	Queasiness or sick sensation; a feeling of the need to vomit
Vomiting	Forceful oral expulsion of gastric contents associated with contraction of the abdominal and chest wall muscles. Vomiting is usually preceded by and associated with retching, repetitive contractions of the abdominal wall without expulsion of gastric contents.
Belching	Venting of air from the stomach or the esophagus

* According to the Rome III committee.

Adapted from Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. In: Drossman DA, Corazziari E, Delvaux M, et al, editors. Rome III. The Functional Gastrointestinal Disorders. 3rd ed. McLean, Va: Degnon Associates; 2006. p 422.

In patients with dyspepsia, additional clinical investigations may identify an underlying organic disease that is the likely cause of the symptoms. In these persons, dyspeptic symptoms are attributable to an organic cause of dyspepsia (Table 13-2). In most people with dyspeptic symptoms, however, no organic abnormality is identified by a routine clinical evaluation, and patients who have undergone a diagnostic investigation (including endoscopy) and have not been found to have an obvious specific cause of their symptoms are said to have functional dyspepsia. The term uninvestigated dyspepsia refers to dyspeptic symptoms in persons in whom no diagnostic investigations have yet been performed and in whom a specific diagnosis that explains the dyspeptic symptoms has not been determined.

Table 13-2 Causes of Dyspepsia

Luminal Gastrointestinal Tract

Chronic gastric volvulus

Chronic gastric or intestinal ischemia

Food intolerance

Functional dyspepsia

Gastroesophageal reflux disease

Gastric or esophageal neoplasms

Gastric infections (e.g., cytomegalovirus, fungus, tuberculosis, syphilis)

Gastroparesis (e.g., diabetes mellitus, postvagotomy, scleroderma, chronic intestinal pseudo-obstruction, postviral, idiopathic)

Infiltrative and inflammatory gastric disorders (e.g., Crohn’s disease, eosinophilic gastroenteritis, sarcoidosis, amyloidosis)

Irritable bowel syndrome

Ménétrier’s disease

Peptic ulcer disease

Parasites (e.g., Giardia lamblia, Strongyloides stercoralis)

Medications

Acarbose

Aspirin, other nonsteroidal anti-inflammatory drugs (including cyclooxygenase-2 selective agents)

Colchicine

Digitalis preparations

Pancreaticobiliary Disorders

Biliary pain—cholelithiasis, choledocholithiasis, sphincter of Oddi dysfunction

Chronic pancreatitis

Pancreatic neoplasms

Systemic Conditions

Adrenal insufficiency

Congestive heart failure

Diabetes mellitus

Hyperparathyroidism

Intra-abdominal non-gastrointestinal malignancy

ORGANIC CAUSES OF DYSPEPSIA

The most important identifiable causes underlying dyspeptic symptoms are peptic ulcer disease and GERD. Malignancies of the upper gastrointestinal tract and celiac disease are less common but important causes of dyspeptic symptoms (see Table 13-2).⁶^–¹⁰ The investigation of choice in persons with dyspeptic symptoms is endoscopy, which may identify erosive esophagitis, peptic ulcer, or gastric or esophageal cancer.

Systematic studies indicate that approximately 20% of patients with dyspeptic symptoms have erosive esophagitis, 20% have endoscopy-negative GERD, 10% have peptic ulcer, 2% have Barrett’s esophagus, and 1% or less have malignancy.⁶ Minor findings such as duodenitis or gastritis do not seem to correlate with the presence or absence of dyspeptic symptoms.

INTOLERANCE TO FOOD OR DRUGS

Contrary to popular beliefs, ingestion of specific foods such as spices, coffee, or alcohol, or of excessive amounts of food, has never been established as causing dyspepsia.^11,¹² Although ingestion of food often aggravates dyspeptic symptoms, this effect probably is related to the sensorimotor response to food rather than to specific food intolerances or allergies. Studies have shown that acute ingestion of capsaicin induces dyspeptic symptoms in healthy persons and in those with functional dyspepsia, with greater intensity in the latter group.¹³

Dyspepsia is a common side effect of many drugs, including iron, antibiotics, narcotics, digitalis, estrogens and oral contraceptives, theophylline, and levodopa. Medications may cause symptoms through direct gastric mucosal injury, changes in gastrointestinal sensorimotor function, provocation of gastroesophageal reflux, or idiosyncratic mechanisms. Nonsteroidal anti-inflammatory drugs (NSAIDs) have received the most attention because of their potential to induce ulceration in the gastrointestinal tract. Chronic use of aspirin and other NSAIDs may provoke dyspeptic symptoms in up to 20% of persons, but the occurrence of dyspepsia correlates poorly with the presence of an ulcer. In controlled trials, dyspepsia develops in 4% to 8% of persons treated with NSAIDs, with odds ratios ranging from 1.1 to 3.1 compared with placebo; the magnitude of this effect depends on the dose and type of NSAID.¹⁴ Compared with NSAIDs, selective cyclooxygenase-2 inhibitors are associated with a lower frequency of dyspepsia and peptic ulceration.¹⁵

PEPTIC ULCER DISEASE

Peptic ulcer is a well-established cause of dyspeptic symptoms and is an important consideration for clinicians in the management of patients who present with dyspepsia. The frequency of peptic ulcer in patients with dyspepsia, however, is only 5% to 10%.^6,^10,¹⁴ Increasing age, NSAID use, and Helicobacter pylori infection are the main risk factors for peptic ulcer (see Chapters 50 and 52).

GASTROESOPHAGEAL REFLUX DISEASE

Erosive esophagitis is a diagnostic marker for GERD, but many patients with symptoms that are attributable to the reflux of stomach contents into the esophagus have no endoscopic signs of esophageal erosion; this is referred to as nonerosive GERD. Erosive esophagitis is found in approximately 20% of dyspeptic patients, and a similar number of patients may have nonerosive GERD (see Chapter 43).^6,¹⁰

GASTRIC AND ESOPHAGEAL CANCER

The risk of gastric or esophageal malignancy in patients with dyspeptic symptoms is estimated to be less than 1%.⁹ The risk of gastric cancer is increased among persons with H. pylori infection, persons with a family history of gastric malignancy, persons with a previous history of gastric surgery, and immigrants from areas endemic for gastric malignancy. The risk of esophageal cancer is increased in men, smokers, persons with a high consumption of alcohol, and those with a long-standing history of heartburn (see Chapters 46 and 54).

PANCREATIC AND BILIARY TRACT DISORDERS

Despite the high prevalence of dyspepsia and gallstones in adults, epidemiologic studies have confirmed that cholelithiasis is not associated with dyspepsia. Therefore, patients with dyspepsia should not be investigated routinely for cholelithiasis, and cholecystectomy in patients with cholelithiasis is not indicated for dyspepsia alone. The clinical presentation of biliary pain is easily distinguishable from that of dyspepsia (see Chapter 65).

Pancreatic disease is less prevalent than cholelithiasis, but symptoms of acute or chronic pancreatitis or of pancreatic cancer may initially be mistaken for dyspepsia. Pancreatic disorders, however, are usually associated with more severe pain and are often accompanied by anorexia, rapid weight loss, or jaundice (see Chapters 58 to 60).

OTHER GASTROINTESTINAL AND SYSTEMIC DISORDERS

Several gastrointestinal disorders may cause dyspepsia-like symptoms. These include infectious (e.g., Giardia lamblia and Strongyloides stercoralis parasites, tuberculosis, fungal infections, syphilis), inflammatory (e.g., celiac disease, Crohn’s disease, sarcoidosis, lymphocytic gastritis, eosinophilic gastroenteritis), and infiltrative (e.g., lymphoma, amyloidosis, Ménétrier’s disease) disorders of the upper gastrointestinal tract. Most of these causes will be identifiable by upper gastrointestinal endoscopy with mucosal biopsies. Recurrent gastric volvulus and chronic mesenteric or gastric ischemia may present with dyspeptic symptoms (see Chapters 27, 29, 35, 47, 104, 109, 111, and 114).

The symptom pattern associated with gastroparesis (idiopathic, drug-induced, or secondary to metabolic, systemic, or neurologic disorders) is similar to dyspepsia, and the distinction between idiopathic gastroparesis and functional dyspepsia with delayed gastric emptying (see later) is not well-defined (see Chapter 48).

Finally, dyspepsia may be the presenting or accompanying symptom of acute myocardial ischemia, pregnancy, acute or chronic kidney disease, thyroid dysfunction, adrenal insufficiency, and hyperparathyroidism (see Chapters 35 and 38).

FUNCTIONAL DYSPEPSIA

According to the Rome III criteria, functional dyspepsia is defined as the presence of early satiation, postprandial fullness, epigastric pain, and epigastric burning in the absence of organic, systemic, or metabolic disease that is likely to explain the symptoms.

THE DYSPEPSIA SYMPTOM COMPLEX

Pattern and Heterogeneity

The dyspepsia symptom complex is broader than the four cardinal symptoms that constitute the Rome III definition. It includes multiple symptoms such as epigastric pain, bloating, early satiation, fullness, epigastric burning, belching, nausea, and vomiting. Although often chronic, the symptoms in patients with functional dyspepsia are mostly intermittent, even during highly symptomatic episodes.^3,¹⁶ In persons with functional dyspepsia who present to a tertiary care center, the most frequent symptoms are postprandial fullness and bloating, followed by epigastric pain, early satiation, nausea, and belching.¹⁷^–²⁰ Heterogeneity of symptoms is considerable, however, as shown, for example, in the number of symptoms that patients report (Fig. 13-1). In the general population, the most frequent dyspeptic symptoms are postprandial fullness, early satiation, upper abdominal pain, and nausea.²¹^–²³

Figure 13-1. Prevalence of symptoms and their severity ratings in 674 patients with functional dyspepsia seen at a tertiary referral center. (Unpublished, University Hospital Gasthuisberg, Leuven, Belgium).

Weight loss is traditionally considered an alarm symptom, pointing toward potentially serious organic disease. Patients with functional dyspepsia who present to a tertiary care center also have a high frequency of unexplained weight loss,^17,¹⁸ and population-based studies in Australia and in Europe have established an association between uninvestigated dyspepsia and unexplained weight loss.^22,²³

Subgroups

The heterogeneity of the dyspepsia symptom complex is well accepted. Factor analyses of dyspepsia symptoms in the general population and in patients who present to a tertiary care center have not supported the existence of functional dyspepsia as a homogeneous (i.e., unidimensional) condition.²²^–²⁴ These studies confirmed the heterogeneity of the dyspepsia symptom complex but did not provide clinically meaningful subdivisions of the syndrome.

Several attempts have been made to identify clinically meaningful dyspepsia subgroups to simplify the intricate heterogeneity of the dyspepsia symptom complex and to guide management. The Rome II consensus committee proposed a classification based on a predominant symptom of pain or discomfort. Although correlations were found between the two subdivisions and the presence or absence of H. pylori infection, the absence or presence of delayed gastric emptying, and response or lack of response to gastric acid suppressive therapy,^25,²⁶ the subdivisions have been criticized because of the difficulty in distinguishing pain from discomfort, the lack of a widely accepted definition of predominant, uncertainty concerning overlap between the symptom subgroups, the lack of an association with putative pathophysiologic mechanisms and, especially, the lack of stability of the predominant symptom over short time periods.^5,²⁷^–³⁰

The Rome III consensus committee has proposed different subdivisions (Fig. 13-2). Studies of patients referred to a tertiary care center and of patients with uninvestigated dyspepsia in the general population have revealed that between 40% and 75% of dyspeptic persons report aggravation of symptoms after ingestion of a meal.^23,^31,³² Assuming that a distinction between meal-related and meal-unrelated symptoms might be pathophysiologically and clinically relevant, the Rome III consensus committee proposed that functional dyspepsia be used as an umbrella term and that postprandial distress syndrome (PDS; meal-related dyspeptic symptoms, characterized by postprandial fullness and early satiation) be distinguished from the epigastric pain syndrome (EPS; meal-unrelated dyspeptic symptoms, characterized by epigastric pain and epigastric burning; Table 13-3).⁵ Few studies have evaluated the Rome III–based classification of functional dyspepsia. One study of postprandial symptom patterns in persons with functional dyspepsia has provided some support for the distinction between EPS and PDS,³² and a population-based study confirmed the existence of the two distinct subgroups, with less than anticipated overlap between EPS and PDS.³³ On the other hand, an open-access endoscopy-based study found considerable overlap in endoscopic findings between patients with EPS or PDS and a large group of dyspeptic patients who were not classified with either.³⁴ The validity of the Rome III classification will have to be assessed in additional ongoing and future studies.

Figure 13-2. Classification of uninvestigated dyspepsia, functional dyspepsia (FD), and subtypes of functional dyspepsia, according to the Rome III criteria.

Table 13-3 Classification of and Diagnostic Criteria for Functional Dyspepsia, Postprandial Distress Syndrome, and Epigastric Pain Syndrome *

Functional Dyspepsia^†

Includes one or more of the following:

1. Bothersome postprandial fullness

2. Early satiation

3. Epigastric pain

4. Epigastric burning

and

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

Postprandial Distress Syndrome^†

Must include one or both of the following:

1. Bothersome postprandial fullness, occurring after ordinary-sized meals, at least several times per week

2. Early satiation that prevents finishing a regular meal, at least several times per week

Supportive Criteria

1. Upper abdominal bloating or postprandial nausea or excessive belching can be present

2. Epigastric pain syndrome may coexist

Epigastric Pain Syndrome^†

Must include all of the following:

1. Pain or burning localized to the epigastrium of at least moderate severity, at least once per week

2. Pain is intermittent

3. Not generalized or localized to other abdominal or chest regions

4. Not relieved by defecation or passage of flatus

5. Not fulfilling criteria for gallbladder or sphincter of Oddi disorders

Supportive Criteria

1. Pain may be of a burning quality, but without a retrosternal component

2. Pain is commonly induced or relieved by ingestion of a meal, but may occur while fasting

3. Postprandial distress syndrome may coexist

* According to the Rome III committee.

† Criteria fulfilled for the previous 3 months with symptom onset at least 6 months prior to diagnosis.

Overlap with Heartburn and Irritable Bowel Syndrome

The issue of overlap of dyspepsia with GERD has been a challenging one. Although earlier investigators considered a group of patients with reflux-like dyspepsia,⁴ the Rome committees did not consider heartburn to arise primarily from the gastroduodenal region, and this symptom was thus excluded from the definition of dyspepsia.^2,⁵ Heartburn commonly occurs along with dyspeptic symptoms, however, both in the general population and in those with a diagnosis of functional dyspepsia.^23,^27,³⁵ Nevertheless, separating GERD from dyspepsia is hampered by a number of confounding factors, such as the presence of dyspepsia-type symptoms in many patients with GERD³⁶ and difficulties in recognizing heartburn by patients and physicians.^37,³⁸

The Rome II consensus committee stated that patients with typical heartburn as a dominant complaint almost invariably have GERD and should be distinguished from patients with dyspepsia.² Although this distinction is probably valid, it has become clear that the predominant symptom approach does not reliably identify or exclude patients with GERD. The Rome III consensus committee has proposed identification of patients with frequent heartburn, and the suggestion has been made that a word-picture questionnaire be used to facilitate recognition of heartburn by patients and to identify patients with functional dyspepsia who may respond to acid suppressive therapy or in whom pathologic esophageal acid exposure can be demonstrated.^39,⁴⁰ Whereas the Rome II definition for functional dyspepsia excluded patients with predominant heartburn and was unclear about those with nonpredominant heartburn, the Rome III definition stated that heartburn is not a gastroduodenal symptom, although it often occurs simultaneously with symptoms of functional dyspepsia and its presence does not exclude the diagnosis of functional dyspepsia.⁵ Similarly, the frequent co-occurrence of functional dyspepsia and irritable bowel syndrome (IBS)⁴¹ is explicitly recognized and does not exclude a diagnosis of functional dyspepsia.

EPIDEMIOLOGY

Dyspeptic symptoms are common in the general population, with frequencies ranging from 10% to 45%.^11,^16,^23,^27,⁴²^–⁴⁴ The frequency of dyspepsia is slightly higher in women, and the influence of age varies among studies. The results of prevalence studies are strongly influenced by the criteria used to define dyspepsia, and several studies included patients with typical symptoms of GERD or did not take into account the presence of dyspepsia-like symptoms in many patients with GERD. When heartburn is excluded, the frequency of uninvestigated dyspepsia in the general population is in the range of 5% to 15%.^43,⁴⁴ Long-term follow-up studies have suggested improvement or resolution of symptoms in approximately half of patients. The annual incidence rate of dyspepsia has been estimated to range from 1% to 6%.

Quality of life is significantly affected by dyspepsia, especially functional dyspepsia. Although most patients do not seek medical care, a significant proportion will eventually proceed with a consultation, constituting a major impact on the cost of care.^16,⁴⁵^–⁴⁷ Factors that influence health care–seeking are the severity of symptoms, fear of underlying serious disease, psychological distress, and lack of adequate psychosocial support (see later).⁴⁸

PATHOPHYSIOLOGY

Several pathophysiologic mechanisms have been suggested to underlie functional dyspeptic symptoms. These suggested mechanisms include delayed gastric emptying, impaired gastric accommodation to a meal, hypersensitivity to gastric distention, altered duodenal sensitivity to lipids or acid, abnormal intestinal motility, and central nervous system dysfunction.³ The heterogeneity of functional dyspepsia seems to be confirmed in the contribution of one or more of these disturbances in subgroups of patients. The studies that have investigated the pathophysiologic mechanisms of functional dyspepsia predate the Rome III consensus committee and classification. Therefore, most studies define functional dyspepsia according to the Rome I and II consensus definitions.

Delayed Gastric Emptying

Several studies have investigated gastric emptying and its relationship to the pattern and severity of symptoms in patients with functional dyspepsia. The frequency of delayed gastric emptying has ranged from 20% to 50%.^3,⁵ In a meta-analysis of 17 studies involving 868 dyspeptic patients and 397 control subjects, a significant delay in gastric emptying of solids was present in almost 40% of patients with functional dyspepsia.⁴⁹ Most of the studies, however, were performed in small groups of patients with small groups of control subjects. In the largest studies, gastric emptying of solids was delayed in about 30% of the patients with functional dyspepsia. Most studies failed to find a convincing relationship between delayed gastric emptying and the pattern of symptoms. Three large-scale single-center studies from Europe have shown that patients with delayed gastric emptying for solids are more likely to report postprandial fullness, nausea, and vomiting,^20,^50,⁵¹ although two other large multicenter studies in the United States found no or a very weak association.^52,⁵³ Whether delayed gastric emptying causes symptoms or is an epiphenomenon is a matter of ongoing controversy.

Impaired Gastric Accommodation

The motor functions of the proximal and distal stomach differ remarkably. Whereas the distal stomach regulates gastric emptying of solids by grinding and sieving the contents until the particles are small enough to pass the pylorus, the proximal stomach serves mainly as a reservoir during and after ingestion of a meal. Accommodation of the stomach to a meal results from a vagally mediated reflex relaxation of the proximal stomach that provides the meal with a reservoir and enables the stomach to handle large intragastric volumes without a rise in intragastric pressure.⁵⁴

Studies using a gastric barostat, scintigraphy, ultrasonography, single photon emission computed tomography (SPECT), or noninvasive surrogate markers (e.g., satiety drinking test) have all suggested the presence of impaired gastric accommodation in approximately 40% of patients with functional dyspepsia.^3,^5,^17,^19,⁵⁴ Insufficient accommodation of the proximal stomach during and after the ingestion of a meal may be accompanied by increased intragastric pressure and activation of mechanoreceptors in the gastric wall, thus inducing symptoms. Although a number of studies found associations between impaired accommodation and both early satiation and weight loss, other studies failed to find such associations. In addition, the mechanisms whereby impaired accommodation can be a cause of symptoms is still unclear; meal ingestion in the absence of proper relaxation of the proximal stomach may be accompanied by activation of tension-sensitive mechanoreceptors in the proximal stomach. On the other hand, insufficient accommodation of the proximal stomach may force the meal into the distal stomach, thereby causing activation of tension-sensitive mechanoreceptors in a distended antrum.

Hypersensitivity to Gastric Distention

Visceral hypersensitivity, defined as abnormally enhanced perception of visceral stimuli, is considered one of the major pathophysiologic mechanisms in the functional gastrointestinal disorders (see Chapters 11, 21, and 118).⁵⁵ Several studies have established that as a group, patients with functional dyspepsia are hypersensitive to isobaric gastric distention.^3,^5,¹⁸ The level at which visceral hypersensitivity is generated is unclear, and evidence exists for involvement of tension-sensitive mechanoreceptors as well as alterations at the level of visceral afferent nerves or of the central nervous system.⁵⁶^–⁵⁸