This chapter outlines the evaluation and management of dyspepsia, with a primary focus on functional dyspepsia, also interchangeably called nonulcer dyspepsia. The term dyspepsia derives from the Greek “dys,” meaning bad, and “pepsis,” meaning digestion. Dyspepsia is a symptom, not a diagnosis. The term encompasses a broad spectrum of symptoms that include upper abdominal pain or discomfort, bloating, early satiety, postprandial fullness, nausea with or without vomiting, anorexia, symptoms of GERD, regurgitation, and belching.

A. Classification

The multiple causes of dyspepsia can be classified as organic or functional. Among the organic causes are esophagitis, gastritis, peptic ulcer disease, benign esophageal strictures, upper gastrointestinal malignancies, chronic intestinal ischemia, small intestinal bacterial overgrowth or dysbiosis, underlying dysmotility, and pancreaticobiliary disease. In addition, several medications can cause dyspeptic symptoms (Table 17–1). Most notable are nonsteroidal anti-inflammatory drugs (NSAIDs), which can cause mucosal injury leading to gastritis. Functional dyspepsia excludes all organic causes.

Previously, the Rome II criteria defined functional dyspepsia as pain centered in the upper abdomen in the setting of a normal endoscopy, with three main subtypes: ulcer-like, dysmotility-like, and unspecified (nonspecific). Recognizing that patients with functional dyspepsia may present with epigastric symptoms other than pain, the revised Rome III criteria in 2006 added bothersome postprandial fullness, early satiation, and epigastric burning to the diagnostic criteria (Table 17–2). Therefore, functional dyspepsia is now defined as “the presence of symptoms thought to originate from the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms.” In addition, the prior subtypes were revised to improve their clinical utility. Per Rome III criteria, functional dyspepsia symptoms fall into two main, distinctively defined disorders: postprandial distress syndrome and epigastric pain syndrome. Postprandial distress syndrome includes bloating, fullness, or early satiety with meals, while epigastric pain syndrome is defined by focal burning or pain localized to the epigastric region not relating to gallbladder or biliary causes. Postprandial distress syndrome and epigastric pain syndrome may coexist in patients with functional dyspepsia.

B. Epidemiology

Prior studies estimated that 20–30% of community patients report dyspeptic symptoms each year, with the majority believed to be related to functional dyspepsia. In prospective studies, the incidence of patients reporting dyspeptic symptoms for the first time is approximately 1% per year. It is believed that only about half of the patients with dyspeptic symptoms ultimately seek medical care, with severity of pain and anxiety being the significant predictive factors. Of patients who have not been worked up, 40% may have an organic cause for their dyspepsia. The prevalence of functional dyspepsia is about 12–15%.

Dyspepsia has led to sizeable health care burden, with new cases accounting for 5–7% of primary care office visits. Dyspeptic symptoms can account for up to 40–70% of gastrointestinal complaints in a general gastroenterology practice. The cost of treatment is substantial.

Organic dyspepsia can develop as a consequence of the varied disease processes mentioned in this chapter and described elsewhere in this text. The pathogenesis of functional dyspepsia is unclear. Factors that play a role in causation include altered visceral sensitivity, disturbances in motility, changes in gastric or abdominal accommodation, dietary factors, and psychosomatic factors. The role of Helicobacter pylori in the genesis of symptoms is controversial.

A. Altered Gastrointestinal Motility

Disturbances in gastrointestinal motility may be associated with dyspepsia symptoms and represent the underlying causative factor in functional dyspepsia. Motor disorders such as gastroesophageal reflux, gastroparesis, small bowel dysmotility, and biliary dyskinesia may cause dyspeptic symptoms. Disturbances in gastric emptying and gastrointestinal motor function occur in subgroups of patients with functional dyspepsia, and studies of these patients show female sex predominance. The prevalence of motility disorders has varied markedly between studies, likely due to subject selection criteria and study methodology. A meta-analysis of studies investigating functional dyspepsia and disturbed solid-phase gastric emptying found 40% of patients with functional dyspepsia had slower emptying, and the pooled estimate of slowing was 1.5 times that of normal patients. On the other hand, a prospective study using a liquid test meal demonstrated that decreased maximum-tolerated meal volume and increased postprandial symptoms were associated with faster gastric emptying.

As mentioned, symptoms of GERD often overlap with dyspepsia symptoms. Poor visceral localization of symptoms can often cause a reflux event to be confused with other upper gastrointestinal sources of discomfort. A study of patients with diagnosis of functional dyspepsia per Rome III criteria revealed that almost one-third had pathologic signs of acid reflux. In addition, both acid and nonacid reflux can cause symptoms. A report noted that patients with functional dyspepsia swallow air more frequently than controls; this finding was associated with an increase in nonacid reflux, which can also cause epigastric symptoms.

B. Altered Accommodation

Alterations in gastric accommodation or compliance have been hypothesized to be a cause of functional dyspepsia. During normal ingestion of food, the gastric fundus relaxes to “accommodate” the food particles. This accommodation is mediated by serotonin (5-HT_1p) and nitric oxide via vagal inhibitory neurons of the enteric nervous system. The accommodation reflex may be impaired in as many as 40% of patients with functional dyspepsia, as demonstrated by gastric scintigraphy and ultrasound. Measurement of gastric pressure by a barostat, or a polyethylene balloon inflated in the stomach, connected to a pressure monitor has shown impaired meal-induced accommodation as well.

Abnormal abdominal wall accommodation, or abdominal wall dyssynergia, has also been studied in recent years as a possible cause of dyspepsia symptoms, particularly postprandial bloating. When eating a meal, normal abdominal wall accommodation to the ingested meal consists of diaphragmatic relaxation and upper abdominal wall muscles’ contraction. Functional dyspepsia patients with postprandial distress syndrome have been shown to tolerate a lower maximal volume meal compared to healthy individuals, and they also develop a paradoxical muscular response to meal ingestion, namely diaphragmatic contraction and upper abdominal wall relaxation. This dyssynergic abdominal muscular response is thought to be a cause of postprandial abdominal distension symptoms and decreased meal toleration.

C. Visceral Hypersensitivity

While poor gastric compliance may result in dyspepsia symptoms, some patients may instead have normal gastric compliance but a lowered pain threshold. With visceral hypersensitivity or hyperalgesia, patients begin to experience pain or discomfort at a level of gastric distention normally not associated with symptoms in healthy individuals, resulting from increased sensory input to and from the stomach. Such enhanced perception is not limited to mechanical distention, but may also occur in response to temperature stress, acid exposure, chemical or nutrient stimuli, or hormones, such as cholecystokinin and glucagons-like peptide 1. In patients with visceral hypersensitivity, there may be altered central nervous system processing of these stimuli. Studies have demonstrated hypersensitivity to balloon distention in the stomach in as many as 50% of patients with functional dyspepsia. Compared with controls, patients with functional dyspepsia had a significantly lower threshold to both initial sensation of balloon distention and to sensation of pain. Some have suggested that such alteration in perception may be the main distinguishing factor between functional and organic dyspepsia. A similar mechanism of pathogenesis has also been proposed for irritable bowel syndrome. Recent studies also suggest that lower postprandial gastric distention thresholds significantly correlate with severity of meal-related symptoms, including fullness, bloating, nausea, discomfort, and impaired accommodation to a meal.

D. Dietary Factors

Dietary factors may be a potential cause of symptoms in functional dyspepsia. Patients with functional dyspepsia appear to have altered eating patterns as well as food intolerances. They frequently report being able to tolerate only small quantities of food, with a high prevalence of snacking and low prevalence of eating large meals. Food intolerances are also high in prevalence among these patients. Fatty foods, in particular, have been linked to dyspepsia. Other intolerances with a reported prevalence greater than 40% include spices, alcohol, spicy foods, chocolate, peppers, citrus fruits, and fish. However, a recent epidemiologic study found no difference in total caloric, protein, fat, and carbohydrate intake between patients with dyspepsia and healthy controls. In particular, the percentages of protein, fat, and carbohydrate in their diet were also similar. In the same study, alcohol and nicotine use were not found to be risk factors for dyspepsia.

Food allergy has been cited as a possible mechanism for development of dyspeptic symptoms, especially postprandial symptoms. Some common food-specific immunoglobulin G antibody titers have been found to be elevated in functional dyspepsia patients compared to controls.

E. Helicobacter pylori Infection

The role of H pylori in functional dyspepsia is controversial, and no clear causal relationship has been established. This is true for both the symptom profile and pathophysiology of functional dyspepsia. Although some epidemiologic studies have suggested an association between H pylori infection and functional dyspepsia, others have not. The discrepancy may stem in part from differences in methodology and lack of adequate consideration of confounding factors such as past history of peptic ulcer disease and socioeconomic status. Controlled trials disagree about whether or not H pylori eradication is beneficial in functional dyspepsia, with roughly half of the trials showing improvement and the other half no improvement. A prior systematic review in the Annals of Internal Medicine on the benefit of eradicating H pylori in functional dyspepsia suggested no statistically significant effect, with an odds ratio (OR) for treatment success versus control of 1.29 (95% confidence interval [CI], 0.89–1.89; P = .18). However, the most recent update of a Cochrane Database review showed a small but statistically significant effect in curing symptoms (H pylori cure vs placebo, 36% vs 30%, respectively; relative risk reduction [RRR], 8%; 95% CI, 3–18%; number needed to treat [NNT] = 18). Despite the conflicting results, current guidelines by both major gastroenterological societies in the United States recommend H pylori test-and-treat as one of the first-line noninvasive strategies in management of patients with dyspepsia.

F. Duodenal Eosinophilia

In recent years, some have hypothesized that duodenal eosinophilia may play a role in a subset of patients with functional dyspepsia. Several recent studies have shown significantly greater eosinophil counts in duodenal biopsies from patients with functional dyspepsia compared to those from healthy controls. These studies suggest that duodenal eosinophils may play a role in functional dyspepsia. However, eosinophilic infiltration has also been described in many different clinical scenarios, including healthy individuals. Therefore, the role of duodenal eosinophils in functional dyspepsia remains to be elucidated.

G. Psychological Factors

Psychosomatic and cognitive factors are important in the evaluation of patients with chronic dyspepsia. The psychiatric hypothesis holds that the symptoms of dyspepsia maybe due to depression, increased anxiety, or a somatization disorder. Epidemiologic studies suggest there is an association between functional dyspepsia and psychological disorders. Symptoms of neurosis, anxiety, hypochondriasis, and depression are more common in patients being evaluated for unexplained gastrointestinal complaints than in healthy controls. In addition, prior studies have demonstrated significant associations between dyspepsia symptoms and a history of abuse in childhood or adulthood. Comparisons of functional and organic dyspepsia have shown that patients with functional dyspepsia are less likely to have decreased stress or anxiety at 1-year follow-up after being reassured of having no serious disease. This suggests that functional dyspepsia symptoms are long-lasting, compared with those of organic dyspepsia, and that the emotional ties are strong.