Functional (Nonulcer) Dyspepsia
Definition and Clinical Picture
The term “dyspepsia” is derived from the Greek term for “bad digestion”. Used broadly and in a general sense, it may be used to describe a number of upper gastrointestinal disorders of known or unknown etiology. The most common disorders in the group of dyspeptic syndromes with a known cause are peptic ulcer disease, gastroesophageal reflux disease (GERD), and biliary colic.
Functional dyspepsia, often referred to as nonulcer dyspepsia, is the term used to describe the upper gastrointestinal syndrome in which no demonstrable cause can be detected. It is one of the most common problems encountered by the physician. It is characterized by an episodic, recurrent, or persistent symptom complex of the upper gastrointestinal tract that includes epigastric discomfort or pain, nausea, vomiting, early satiety, bloating, distension, anorexia, and indigestion. The symptoms usually occur postprandially and in the absence of identifiable organic or systemic disease1. Although the symptoms may resemble those of peptic ulcer disease, functional nonulcer dyspepsia occurs without demonstrable objective findings. The symptom history serves to distinguish it from the retrosternal burning discomfort of heartburn or gastroesophageal reflux disease and from biliary colic. Similarly, the irritable bowel syndrome may be differentiated by its predominance of lower abdominal symptoms, an alteration in bowel habits, and symptoms associated with defecation.
The “Rome” criteria have been utilized as a basis for the diagnosis of functional dyspepsia. They consist of: (1) chronic or recurrent abdominal pain or discomfort in the upper abdomen, the duration of which is less than one month, with symptoms present more than 25% of the time; (2) no clinical, biochemical, endoscopic or ultrasonographic evidence of any known disease likely to explain the symptoms; and, (3) subcriteria for ulcer-, reflux-, or dysmotility-like dyspepsia. In its definition of discomfort, the international panel authoring the criteria included nausea, vomiting, early satiety and bloating, as well as actual pain.
The inclusion of pain as a necessary component of the clinical picture of functional dyspepsia has led to problems. One large clinic-based database of several thousand patients revealed that up to 34% of patients with functional dyspepsia had no pain. Moreover, several studies on the pathophysiologic mechanisms underlying functional dyspepsia have not necessitated that pain be an entry criterion and have focused primarily on patients with nausea, vomiting, early satiety, or bloating. The inclusion of pain as an integral component of the Rome criteria also interfered with the concept of separating the complex into three subgroups of ulcer-like, reflux-like, or dysmotility symptomatology. However, other investigators argue that prominent reflux-like symptoms should be considered a manifestation of gastroesophageal reflux disease, not functional dyspepsia. Moreover, in a recent study from Sweden, the investigators claimed that 87% of patients with the irritable bowel syndrome fulfilled the Rome criteria.
Pathogenesis of Functional Dyspepsia
At least five major factors have been advanced as possible etiological factors in the pathogenesis of functional dyspepsia:
1. Gastric acid hypersecretion
2. Gastric motor abnormalities (possibly associated with vagal efferent dysfunction and abnormal intestinal reflexes)
3. Altered gastric sensation (possibly associated with psychosocial or mechanosensory factors or both)
4. Helicobacter pylori infection
5. Psychosocial factors
Gastric Acid Hypersecretion
Measurements of basal and peak gastric acid output have revealed no evidence of hypersecretion in functional dyspepsia. However, on meta-analysis, a 20% mean therapeutic advantage of H2receptor antagonists over placebo in the control of the symptoms associated with functional dyspepsia has been reported. Typically, antacids are the first line of empiric therapy utilized in these patients. This suggests that, at least in some cases of functional dyspepsia, acid plays a role as a mechanism for symptomatology.
Gastric Motor Abnormalities
A number of parameters of gastrointestinal motility have been assessed in the investigation of the pathogenesis of functional dyspepsia. These include assessment of interdigestive motor complexes, gastric emptying, gastric antral motility, small bowel transit, and assessment of myoelectric activity in the upper gastrointestinal tract.
Antral hypomotility and/or impaired gastric emptying of solids has been noted in about 40% to 50% of patients with functional dyspepsia. Additionally, studies suggest that the intragastric distribution of a solid meal is abnormal in these patients23,24. Perhaps the strongest argument favoring impaired motor function as an important factor in the pathogenesis of functional dyspepsia is that treatment aimed at correcting the abnormal motor function has been shown to decrease symptomatology.
The mechanism(s) responsible for impaired gastrointestinal motor function is/are unknown. Greydanus et al reported a reduced response of pancreatic polypeptide to sham feeding in seven of nine patients, suggesting an efferent vagal dysfunction. The defect was present in patients with abnormal upper gut transit as well as in those with normal transit but with increased visceral perception. Haug et al28 confirmed the presence of low vagal tone, antral hypomotility, and epigastric discomfort in patients with functional dyspepsia. Impaired gastric emptying in these patients was also associated with increased responsiveness of central serotonergic 1A receptors.
Altered Gastric Sensation
Gastric sensation is usually evaluated by the response to gastric distension. In comparison with normal healthy subjects, patients with functional dyspepsia have similar fasting gastric compliance but lower thresholds for the induction of pain and bloating by distension with latex barostat balloons. These sensory deficits were independent of delayed gastric emptying8. Balloon distension of the duodenum and jejunum has been reported to reveal intestinal hypersensitivity. These visceral abnormalities do not extend to the somatic sensory system; several studies have demonstrated that somatic sensitivity is normal in patients with functional dyspepsia.
Using a gastric barostat, Moragas et al measured postcibal gastric tone and sensory perception at various pressure distensions. In 16 healthy normal volunteers, they showed that the stomach relaxed following a meal and the intragastric pressure clearly altered gastric perception. Holtmann et al34 tested intestinal perception thresholds by a randomized distension procedure performed by a barostat device. On a separate day an insulin hypoglycemic test was performed to assess the response of plasma levels of pancreatic polypeptide (PP) to hypoglycemia as an indication of efferent vagal function. First perception of intestinal balloon distension occurred at significantly lower pressures in patients with functional dyspepsia compared to normal controls. In healthy controls, hypoglycemia significantly elevated levels of PP more than two-fold, but only two of seven patients with functional dyspepsia had as much as a two-fold rise in plasma PP levels.
If altered gastric sensation is a mechanism responsible for the symptoms of functional dyspepsia, agents that alter visceral afferent function, such as K-opioid agonists or 5-hydroxytrytamine type 3 antagonists, might be useful therapeutic agents. Although initial data from preliminary studies were unconvincing, subsequent studies have been encouraging. In a double-blind, placebo-controlled study of fifty patients with irritable bowel syndrome, some of whom had upper gastrointestinal symptoms of functional dyspepsia, ondansetron, a 5 HT3-receptor antagonist, not only improved the symptoms of diarrhea-predominant irritable bowel syndrome, but also the dyspeptic symptoms of post-prandial epigastric discomfort (p = 0.008), flatulence (p = 0.22), and heartburn (p = 0.003).
Helicobacter pylori Infection
Although the association of H. pylori and gastritis is well established, its association with functional dyspepsia is controversial. Although the incidence of H. pylori in functional dyspepsia has been reported as high as 87%, there is a similarity in the prevalence of H. pylori infection in patients with dyspepsia and age-matched control subjects without dyspepsia. The effect of H. pylori infection on upper gastrointestinal motility has yielded conflicting results. Whereas Goh et al reported no significant difference in gastric emptying between patients with functional dyspepsia and H. pylori infection, and normal controls, others have reported an effect of H. pylori infection on antroduodenal motility patterns43 and on migrating motor complexes. The data suggest that H. pylori may be a factor in some, but certainly not all cases of functional dyspepsia. Tucci et al provided evidence of the existence of two groups of patients who could be classified as having dyspepsia: those with H. pylori infection and a normal gastric emptying time who have predominantly epigastric pain or burning symptoms, and those without H pylori who have delayed gastric emptying and symptoms predominantly related to dysmotility such as postprandial fullness and discomfort.
The possibility also exists that the infection load of H. pylori may play a role in the pathogenesis of functional dyspepsia by altering duodenal mechanosensory thresholds that are known to play a role in the disorder. Holtmann et al reported that in patients with defined high H. pylori titers (>50 units/ml) thresholds for first sensory perception of balloon distension were significantly lower compared to patients with H. pylori titers below this level.
The identification of specific H. pylori adherence and virulence factors may be important in identifying various sub-populations of infected individuals and differentiating those in whom the organism is pathogenic from those in whom it is nonpathogenic. The gene CagA is present in 60% of H. pylori strains but is present in all patients with H. pylori-associated peptic ulcerations46. Heikkinen et al studied the association of H. pylori serological classifications with nonorganic upper gastrointestinal symptoms in 193 patients with functional dyspepsia47. Of these, 87 (45%) were H. pylori negative, 70 (36%) were H. pylori and CagA positive, and 36 (19%) were H. pylori positive but CagA negative. There were no differences between the three groups in clinical symptomatology.
Although no unique personality profile has been identified in patients with functional dyspepsia, studies have revealed that these patients have more anxiety, neuroticism, and depression than do healthy subjects. Moreover, factors such as advanced age, male gender and unmarried status are associated with greater frequency and severity of symptoms. Environmental factors such as smoking, alcohol and non-steroidal anti-inflammatory drugs are often mentioned as contributory factors in the pathogenesis of functional dyspepsia, but in a controlled study, Talley et al recently noted that these factors were not associated with an increased risk of functional dyspepsia in outpatients presenting for endoscopy. Similarly, Halter and Brignoli recently reported that the frequency of smoking and a positive H. pylori status did not differ from controls in patients with functional dyspepsia in contrast to their frequency in patients with esophagitis and duodenal ulcer (16% vs. 46% respectively).
An increased need for sick leave from work has been reported for patients with functional dyspepsia, a mean 2.6 times that for a control population. he dyspeptic complaints are often accompanied, or even overshadowed, by complaints of a psychosomatic nature. Efforts have been made to link these psychosocial factors with the biological characteristics of functional dyspepsia. Psychological factors have been associated with variances in vagal activity and antral tone. It has been demonstrated that visceral perception of distension and tone in the colon can be influenced by arousal and autonomic stimuli, and it is postulated that a similar process may occur in the upper gastrointestinal tract. In 28 patients with functional dyspepsia, gastric emptying was prolonged by attempts to control and suppress anger and to adopt a “fighting” spirit when dealing with stress factors.
Management of the Patient with Functional Dyspepsia
The heterogenecity in the pathophysiology of functional non-ulcer dyspepsia confronts and frequently confounds the physician when faced with such a patient. Patients seeking medical attention for their dyspepsia do so for a variety of reasons. They generally want reassurance that their complaints are not related to a serious underlying disease. Furthermore, they want an adequate explanation of the etiology of their problems. Finally, they want treatment to alleviate their symptoms. The dyspeptic patient warrants a complete history and physical examination; first, in an attempt to exclude the possibility of severe underlying disease, and second, to attempt to discover which one or more of the potential pathogenetic factors may be operative in that particular patient.
In 1985 the Health and Public Policy Committee of the American College of Physicians recommended that in patients with dyspepsia under the age of 45 (without alarm symptoms such as loss of weight, hematemesis or melena, anemia, and without a family history of gastric cancer,) there is no emergent need for endoscopy. The patient should undergo an empiric therapeutic trial based on the most likely pathogenetic factor responsible for his/her symptoms.
The ready availability of finger-stick serological and sensitive C-urea breath testing for Helicobacter pylori will enable this procedure to be an initial, efficient and inexpensive diagnostic test in these patients. Patients who are H. pylori positive should receive eradicative antibiotic therapy. This will be curative in those patients with peptic ulcer disease and that subset of functional dyspeptic patients (probably 20 to 25%) who are also positive and will respond to anti H. pylori therapy.
In those patients who are H. pylori positive, but whose symptoms do not respond to H. pylori eradication, or in those who are H. pylori negative but have symptoms suggestive of ulcer or reflux, referral for endoscopy or an empirical trial with H2-receptor antagonists or proton pump inhibitors should be the next step. In the presence of a normal esophagogastroduodenoscopy and failure of acid suppression to control symptoms, the physician should turn to the alternative therapies of prokinetic agents (for example, cisapride), antidepressants, and/or K-opioid agonists with visceral analgesic properties (for example, amitriptyline or fedotozine, respectively) such as are being used in large-scale studies at the present time. As reported in a recent Japanese study, psychiatric assessment and treatment may be a necessary adjunctive measure. The investigators reported that in a group of patients with “serious” nonulcer dyspepsia, those who received psychiatric therapy in addition to drug therapy (n=86), showed significant improvement compared to controls (n=42) who were treated with drug therapy alone (p<0.0001). Clearly, there is a need for outcome-based studies, including cost-effectiveness, that have been based on the rough algorithm outlined above.