Dyspepsia: Guidelines for Evaluation and Treatment

Introduction

Approximately 20% of the global population experiences symptoms of dyspepsia. Dyspepsia is more common among women, smokers, and patients taking nonsteroidal anti-inflammatory drugs. Survival among patients with dyspepsia does not differ from that of healthy individuals; however, the symptoms negatively affect quality of life and impose an economic burden on healthcare systems and society. In the United States (US), dyspepsia costs the healthcare system more than $18 billion annually, while societal costs are approximately twice as high, with as much as 2–5% attributable to employee sick leave issued because of dyspeptic symptoms. This article presents updated guidelines from the American College of Gastroenterology and the Canadian Association of Gastroenterology on the evaluation and treatment of dyspepsia.

Definition of Dyspepsia

A clinically relevant definition of dyspepsia is predominant epigastric pain lasting for at least 1 month. The pain may be associated with other upper gastrointestinal symptoms, such as epigastric fullness, nausea, vomiting, or heartburn; however, it is important that epigastric pain is the predominant complaint. Functional dyspepsia is defined as dyspepsia in which endoscopy, and other investigations if necessary, has excluded organic pathology that could explain the patient's symptoms.

Recommendation 1

Patients with dyspeptic symptoms who are older than 60 years should undergo endoscopy to exclude upper gastrointestinal neoplasia (conditional recommendation, very low level of evidence).

Gastric cancer is the third most common cause of cancer-related death worldwide, accounting for nearly 1 million cases annually, and it frequently presents with symptoms of dyspepsia. Endoscopy can detect early-stage gastric cancer and is therefore recommended for patients at high risk of the disease. Endoscopy can also diagnose esophageal adenocarcinoma.

Endoscopy is the gold standard for diagnosing malignant diseases; however, it is an expensive and invasive investigation associated with a small risk of serious complications. Recommendations for evaluating patients with dyspepsia who are at low risk of developing cancer vary among different guidelines. The risk of developing cancer depends primarily on age. Some guidelines use an age threshold of 55 rather than 60 years. Economic analyses have shown that performing endoscopy from the age of 55 years is of questionable cost-effectiveness.

The risk of upper gastrointestinal cancer is increased in patients who grew up and spent their childhood in certain geographical regions, such as Southeast Asia and several South American countries. Given that this is a conditional recommendation supported by a low level of evidence, the age threshold for endoscopy should be lowered for patients originating from these regions and for other patients based on clinical judgment. When uncertainty remains, sex may also be taken into account, because the age-adjusted risk of upper gastrointestinal cancer is approximately twice as high in men as in women. Clinical decisions should be based on symptoms and objective, laboratory, and radiological findings.

Recommendation 2

In patients younger than 60 years who experience so-called alarm symptoms, endoscopy to exclude upper gastrointestinal neoplasia is not recommended (conditional recommendation, moderate level of evidence).

Previous guidelines recommended upper gastrointestinal endoscopy in patients of any age who developed alarm symptoms, such as weight loss, anemia, dysphagia, or persistent vomiting. However, a systematic review of 7 studies involving more than 46,000 patients with dyspeptic symptoms who underwent upper gastrointestinal endoscopy found that alarm symptoms had limited value.

Alarm symptoms have a limited ability to identify any organic pathology, including malignancy, peptic ulcer disease, or esophagitis. Alarm symptoms such as weight loss, anemia, or dysphagia have a sensitivity and specificity of approximately 66% and a positive likelihood ratio of 2.74 (95% confidence interval [CI], 1.47–5.24). Thus, a patient with dyspeptic symptoms who also has alarm symptoms has a 2–3-fold greater risk of developing upper gastrointestinal malignancy.

However, in patients younger than 60 years, the risk of gastrointestinal cancer is generally very low, even when alarm symptoms are present, at <1%. Therefore, performing endoscopy in all younger patients with alarm symptoms is not cost-effective.

It should be noted that these guidelines do not address alarm symptoms such as progressive dysphagia and/or weight loss in the absence of epigastric pain. Such patients do not meet the definition of dyspepsia and are therefore not discussed in these guidelines.

Pancreatic cancer may present with epigastric pain; therefore, it may be appropriate to exclude this diagnosis in patients older than 60 years who present with new-onset dyspepsia by combining endoscopy with other imaging investigations, such as abdominal ultrasonography. Pancreatic cancer is rare in patients younger than 60 years. It is important to mention a systematic review involving more than 57,000 patients with dyspepsia, of whom <0.01% had pancreatic cancer. In patients younger than 60 years who present with dyspepsia, the likelihood of pancreatic cancer is very low; therefore, routine pancreatic imaging is not recommended. However, each case should be assessed individually. For example, in a patient with dyspepsia and a positive family history of upper gastrointestinal malignancy, performing endoscopy would be appropriate.

Recommendation 3

Patients younger than 60 years with dyspeptic symptoms should undergo noninvasive testing for H. pylori and, if the results are positive, should receive eradication therapy (strong recommendation, high level of evidence).

It is recommended that clinicians wait at least 4 weeks before assessing the clinical response to H. pylori eradication.

Recommendation 4

Patients younger than 60 years with dyspeptic symptoms who test negative for H. pylori, or whose symptoms persist after H. pylori eradication, should receive empirical proton pump inhibitor (PPI) therapy (strong recommendation, high level of evidence).

H2-receptor antagonists are an alternative to PPI therapy for reducing gastric acidity. Seven randomized controlled trials involving 2,456 patients with dyspepsia compared PPI therapy with H2-receptor antagonists. The studies found no clinically significant difference between PPIs and H2-receptor antagonists in reducing dyspeptic symptoms, although considerable heterogeneity was observed among the studies.

Four studies found an advantage in favor of PPIs, 2 found no difference, and 1 found an advantage in favor of H2-receptor antagonists. There is no substantial difference in cost between PPI and H2-receptor antagonist therapy; however, more evidence supports the greater effectiveness of PPI therapy. It is worth noting that the studies used a standard PPI dose administered once daily; therefore, it is doubtful that higher PPI doses would provide additional benefit in the treatment of dyspepsia.

Recommendation 5

Patients younger than 60 years in whom PPI therapy and H. pylori eradication have been unsuccessful should be offered treatment with prokinetic agents (conditional recommendation, very low level of evidence).

No randomized trials comparing prokinetic therapy with placebo have been conducted. Only 3 studies involving 680 patients with dyspepsia compared PPI therapy with prokinetic therapy. Participants were followed for 4–52 weeks. An advantage of PPI therapy was observed (relative risk [RR] 0.78, 0.60–1.02; p=0.06), although it was not clinically significant. Prokinetic therapy is recommended when a patient has been evaluated and treated for H. pylori and/or when PPI therapy is ineffective, because it is more effective in the treatment of gastroesophageal reflux disease, peptic ulcer disease, and functional dyspepsia, based on randomized trial data. The prokinetic agents evaluated in randomized trials (cisapride and mosapride) are unavailable in many countries. Given the risk of adverse events, prokinetic agents should be used at the lowest effective dose and in accordance with country-specific safety recommendations (e.g., metoclopramide should be used for less than 12 weeks, and the daily dose of domperidone should be 30 mg or less).

Recommendation 6

Patients younger than 60 years in whom PPI therapy and H. pylori eradication have been unsuccessful should be offered treatment with tricyclic antidepressants (TCAs) (conditional recommendation, low level of evidence).

Thirteen studies involving 1,241 patients with functional dyspepsia compared psychotropic drug therapy with placebo. Of these, 3 studies evaluated TCAs as the psychotropic treatment; these drugs were effective in reducing dyspeptic symptoms (RR 0.74, 95% CI 0.61–0.91). However, no effect was observed with serotonin reuptake inhibitors. The decision to use TCAs should be made individually.

Recommendation 7

Patients with functional dyspepsia who are H. pylori-positive should receive eradication therapy (strong recommendation, high level of evidence).

Patients whose endoscopic examination shows no abnormalities but whose predominant symptom is epigastric pain have functional dyspepsia. A diagnosis of functional dyspepsia may also be established without endoscopy based on clinical symptoms and medical history. In patients whose endoscopy reveals no pathology, gastric biopsies should be obtained to test for H. pylori infection if the bacterium has not previously been investigated using noninvasive tests.

Twenty-two randomized controlled trials involving 4,896 H. pylori-positive patients with functional dyspepsia compared eradication therapy with placebo. Patients were followed for 3–12 months to assess the resolution of functional dyspepsia symptoms. Dyspeptic symptoms persisted in 1,767 of 2,604 patients (67.9%) in the H. pylori eradication group compared with 1,751 of 2,292 patients (76.4%) in the control group. H. pylori eradication had a statistically significant beneficial effect on dyspeptic symptoms (RR for persistent dyspeptic symptoms 0.91, 95% CI 0.88–0.94; p<0.00001). Although the beneficial effect of H. pylori eradication on dyspeptic symptoms is modest, eradication may also reduce the future risk of gastric cancer and peptic ulcer disease; therefore, the benefits outweigh the harms associated with antibiotic use.

Recommendation 8

Patients with functional dyspepsia who are H. pylori-negative or whose symptoms persist after H. pylori eradication should receive PPI therapy (strong recommendation, moderate level of evidence).

There is evidence that some symptoms of functional dyspepsia may be associated with increased sensitivity to gastric acid.

According to the latest data, there is no benefit in doubling the PPI dose. If there is no response to treatment with a standard once-daily dose, treatment should be discontinued after 8 weeks. The potential risks of long-term PPI use have also been evaluated, including hip fracture, community-acquired pneumonia, C. difficile infection, electrolyte imbalance, and dementia. Considering all available data, the benefits of PPI therapy outweigh the potential harms. However, PPI therapy should be discontinued if treatment no longer provides benefit. Furthermore, patients should not use PPIs continuously without attempting to discontinue treatment every 6–12 months.

Recommendation 9

Patients with functional dyspepsia in whom PPI therapy or H. pylori eradication is ineffective should be offered treatment with TCAs (conditional recommendation, moderate level of evidence).

Antidepressant therapy has reduced symptoms of irritable bowel syndrome in randomized trials. There is an overlap between irritable bowel syndrome and functional dyspepsia; therefore, antidepressants may also be beneficial in functional dyspepsia. Studies have shown that TCAs significantly reduce symptoms of functional dyspepsia compared with placebo. Unlike TCAs, serotonin reuptake inhibitors were ineffective.

The recommendation is conditional because TCAs cause numerous adverse events, including constipation, dry mouth, urinary retention, and drowsiness, and many patients are therefore unwilling to take them. It is also worth emphasizing that, unlike in Recommendations 5 and 6, TCAs are recommended before prokinetic therapy because the superiority of TCAs has been demonstrated specifically in the treatment of functional dyspepsia.

Recommendation 10

Patients with functional dyspepsia in whom PPI therapy, H. pylori eradication, or TCA therapy is ineffective should be offered prokinetic therapy (conditional recommendation, very low level of evidence).

Patients with functional dyspepsia frequently have abnormalities of gastric motility. Numerous pharmacological agents have been developed to facilitate gastric emptying. Many studies of prokinetic agents have been conducted in patients with functional dyspepsia (26 randomized trials involving 8,788 patients). A statistically significant effect of prokinetic agents in reducing symptoms associated with functional dyspepsia was observed.

However, none of the prokinetic agents studied are available in the US, Canada, or Europe. There are no clinical trials of metoclopramide. Seven studies of domperidone involving 263 patients with upper gastrointestinal symptoms have been conducted. A statistically significant beneficial effect on symptoms was observed with domperidone (RR for persistent symptoms with domperidone 0.71, 95% CI 0.53–0.97). However, the level of evidence is very low because none of the studies met the inclusion criteria and there were numerous inconsistencies among the studies.

In addition, some prokinetic agents carry a substantial risk of adverse events. For example, metoclopramide is associated with dystonia, parkinsonian-type movements, and/or other dyskinesias, while domperidone may cause QT prolongation, which can lead to serious cardiac arrhythmias in patients with pre-existing heart disease.

Recommendation 11

Patients who do not respond to pharmacological treatment should be offered psychological therapy (conditional recommendation, very low level of evidence).

Numerous studies have demonstrated that psychological therapy is effective in patients with irritable bowel syndrome, although the quality of these studies is very low. Twelve randomized controlled trials involving 1,563 patients with functional dyspepsia have been conducted. All studies demonstrated a statistically significant benefit of psychological therapy compared with the control group.

Cognitive behavioral therapy or other forms of psychotherapy were most commonly used. The quality of the evidence is very low despite the favorable effect on reducing dyspeptic symptoms. There were numerous inconsistencies in the studies, unexplained heterogeneity among them, and many used different forms of psychological therapy; therefore, no specific form of psychological therapy can be recommended. In addition, this treatment may be expensive and requires time and motivation from the patient.

Recommendation 12

Routine use of supplements and complementary and alternative medicine treatments/interventions is not recommended for functional dyspepsia (conditional recommendation, very low level of evidence).

Supplements and complementary and alternative medicine treatments/interventions are used by approximately 20% of the general population to relieve and treat various gastrointestinal symptoms. Clinical trials have investigated acupuncture, a preparation containing a combination of 5 herbal components, and Chinese medicine; however, the quality of these studies was very low and their methodology was unreliable. Supplements and complementary and alternative medicine treatments may be appropriate in individual cases, but patients should be informed that scientifically sound evidence is currently lacking.

Recommendation 13

Routine gastric motility testing is not recommended in patients with functional dyspepsia (conditional recommendation, very low level of evidence).

Diagnosing and treating functional dyspepsia can be very challenging because symptoms develop as a result of multiple different pathophysiological processes. Abnormal gastric accommodation is identified in approximately 40% of patients. However, this abnormality can be detected only by 2 specialized tests—a gastric barostat or single-photon emission computed tomography—neither of which is readily available.

Delayed gastric emptying assessed using scintigraphic or breath tests has been identified in up to 30% of patients with functional dyspepsia, although the abnormality is usually mild. Symptoms of functional dyspepsia may be associated with a previous infection (viral, bacterial, or protozoal), visceral hypersensitivity, medications, duodenal eosinophilia, or abnormal or excessive feedback from the upper small intestine.

Because tests used to assess gastric accommodation are not readily available, are expensive, invasive, and uncomfortable (barostat), and because delayed gastric emptying is not directly associated with symptoms, routine gastric motility testing is not recommended in patients with functional dyspepsia.

Recommendation 14

Gastric motility testing is recommended in selected patients with functional dyspepsia in whom gastroparesis is suspected (conditional recommendation, very low level of evidence).

Gastroparesis may be diagnosed based on a combination of symptoms, such as nausea, vomiting, abdominal pain, early satiety, and bloating, together with upper gastrointestinal endoscopy to assess for mechanical obstruction and evidence of delayed gastric emptying. Although functional dyspepsia and gastroparesis were previously considered separate disorders, they overlap and together represent part of the spectrum of gastric sensorimotor disorders.

As noted above, most patients (70–80%) with functional dyspepsia have normal gastric emptying; therefore, routine gastric motility testing is not recommended. When gastric emptying is delayed, the degree of impairment is usually mild, with only 10–20% of gastric contents remaining after 4 hours. Patients who vomit daily or very frequently may have gastroparesis rather than functional dyspepsia and should therefore undergo appropriate evaluation…

Read more in Gastroenterologija, 2018.

Rugilė Mickūnienė, MD

Vilnius University Hospital Santaros Klinikos