The management of functional dyspepsia in clinical practice: what lessons can be learnt from recent literature?

Introduction

About 20% of the population has chronic symptoms that can be attributed to disorders of gastroduodenal motility and function, which the recently published Rome IV criteria have classified into four categories: functional dyspepsia (FD), belching disorders, chronic nausea and vomiting disorders, and rumination syndrome¹. This diagnostic classification is largely unchanged from previous iterations with only minor changes made to the definition (Table 1).

Definition

FD is a functional gastrointestinal (GI) disorder characterized by one or more of the following symptoms: postprandial fullness, early satiation, epigastric pain, and epigastric burning¹. Nausea and vomiting are no longer considered cardinal FD symptoms and have been moved into separate categories of functional nausea and vomiting disorders². Based on factor analyses of digestive symptoms in the general population and FD patients, the Rome Committee further divided patients with FD into two subgroups: postprandial distress syndrome (PDS), which is characterized by meal-induced symptoms, and epigastric pain syndrome (EPS), which refers to epigastric pain or epigastric burning that does not occur exclusively postprandially and can even be improved by meal ingestion². In clinical practice, PDS is more prevalent than EPS¹; however, the overlap between PDS and EPS patients has been reported to be as high as 50%^1,2. Therefore, the clinical utility of this subdivision has been questioned¹, even though it seems reasonable to distinguish between patients with symptoms induced by food intake (that is, PDS, previously called “dysmotility-like”) and those in whom symptoms are largely independent of GI function (that is, EPS, previously called “ulcer-like”). Moreover, a recent study has demonstrated that the overlap can be reduced by a more rigorous linking of postprandially occurring symptoms to PDS, regardless of their qualitative nature^3,4. This means that epigastric pain or burning, if postprandial, can also be present in PDS^3,4. One change made by Rome IV is to limit the diagnosis of FD to patients with “bothersome symptoms… severe enough to impact on usual activities” occurring with a minimal frequency of 3 days per week¹. This is necessary to distinguish those with clinically relevant disease from healthy subjects with occasional, relatively mild symptoms that can be considered part of normal daily life. FD patients who meet these diagnostic criteria have reduced quality of life and incur significant direct costs through medical expenses and indirectly through loss of productivity¹.

Pathophysiology

The causes of FD are not completely understood; however, several mechanisms appear to be involved. These include altered gastric emptying, impaired gastric accommodation, gastric and duodenal hypersensitivity, and previous GI infections¹. Additionally, the presence of psychiatric disease and psychosocial stress factors has a role in FD aetiology and severity¹. Delayed gastric emptying has been reported in up to 35% of patients with FD, whereas rapid gastric emptying, even if less studied, is probably present in a lower percentage of patients¹. Impaired gastric relaxation in response to food (that is, impaired accommodation) has also been found in about one third of patients with FD¹. Hypersensitivity to mechanical stimulation (for example, distention) of the stomach or the small bowel (or both) is frequent, and affected patients may also show hypersensitivity to chemical stimuli such as acid and lipids¹. Acute infection is known to trigger so-called “post-infectious FD” in at least 10–20% of individuals¹. The diagnosis of “Helicobacter pylori-associated dyspepsia” can be made if successful eradication leads to long-term resolution of symptoms¹. A relationship between the gut and psyche has been described in this condition because patients with psychological disease (that is, anxiety or depression) are at increased risk of developing FD, and vice versa¹. Many of these factors can impact on mucosal integrity and duodenal permeability, effects that have been related to the activation of the innate mucosal immune system. Experimental evidence provides some insight into this complex mechanism in humans. Psychological stress mediated by corticotrophin-releasing hormone has been shown to alter intestinal permeability through a mast cell–dependent mechanism⁵. Recent research has also shown differences in the duodenal microbiome between patients with FD and controls, although it remains uncertain whether this represents “cause or effect”.

Studies have also evaluated whether the two FD subgroups—PDS and EPS—differ with regard to pathophysiological mechanisms. The results suggest that PDS is associated with gastric hypersensitivity, delayed gastric emptying, anxiety, and the presence of increased intra-epithelial eosinophils in the duodenum and other evidence of an activated mucosal immune system^6–9. Additionally, PDS presents frequently “as an overlap syndrome” with other functional GI disorders (for example, irritable bowel syndrome, or IBS)¹⁰. In contrast, patients with EPS have little evidence of abnormal GI motility and function. EPS may be associated with the presence of other centrally mediated pain syndromes (for example, fibromyalgia)¹¹.

Diagnosis

The diagnosis of FD is based on clinical assessment and exclusion of organic disease. Thus, before the diagnosis of FD is made, laboratory tests and upper GI endoscopy with biopsies are normally performed to exclude infection (in particular, H. pylori), peptic ulceration, celiac disease, and neoplasia¹. Physiological investigations are normally not required at this stage¹.

Management

The management of patients with FD should start with reassurance and education about the possible pathophysiological and risk factors associated with FD appropriate for the PDS or EPS subgroup or both¹. Lifestyle and dietary recommendations may be helpful^1,24. Avoidance of non-steroidal anti-inflammatory drugs, coffee, high-fat foods, alcohol, and smoking is commonly recommended on the basis of physiological studies and case reports; however, the real value of these recommendations is unclear^1,24.

The next step recommended by the Rome committee is to exclude iatrogenic causes of dyspeptic symptoms and to recognize and treat overlapping disease. Identification of H. pylori infection is appropriate, as prospective trials indicate that eradication therapy is curative in approximately 1 in 10 infected patients¹. If the patient is not infected, then an empirical trial of acid suppression is justified to suppress symptoms related to an atypical presentation with GERD¹. Individuals with overlap IBS may respond to spasmolytics and stool regulation.

Pharmacological treatments for FD that are more effective than placebo in randomized controlled trials and are available in the market are limited^1,24. These include acid suppression (PPIs), H2 receptor antagonists (H2RAs), prokinetics, herbal preparations, and antidepressants^1,24. Dietary interventions and medications that modulate digestive function may be more likely to be effective in PDS patients in whom abnormal gastric function is present¹. Conversely, pain modulators and, if appropriate, antidepressants may be most appropriate in EPS¹. This hypothesis is (indirectly) supported by the observation that the presence of normal gastric emptying on scintigraphy in patients with FD is associated with a good response to low-dose antidepressant medications that target visceral hypersensitivity (see below).

Is this information from the literature of any relevance for an evidence-based approach in our clinical practice?

The authors of the present review work as clinical gastroenterologists with a specialist research interest in functional GI disorders and with experience in different European countries. They consider that the recent literature provides information that can inform and hopefully improve clinical practice. Table 2 and Figure 1, respectively, report the pharmacological options and the practical management algorithm in FD.

Figure 1. Practical management algorithm in functional dyspepsia.

EPS, epigastric pain syndrome; FD, functional dyspepsia; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; GERD, gastro-oesophageal reflux disease; GI, gastrointestinal; IBS, irritable bowel syndrome; PDS, postprandial distress syndrome; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Whenever we consider the primary, secondary, or tertiary setting, it is of key importance to recognize the typical presentation of patients with FD. The Rome criteria are not primarily intended for use in clinical practice; however, it can be helpful to use symptom-based criteria to establish a “positive” diagnosis of this condition. This aids communication with the patient. At the same time, the criteria can help to differentiate FD from other conditions (for example, GERD alone, IBS alone, or chronic nausea and vomiting disorders). If alarm symptoms are present, then these should be investigated (even if there is a high suspicion of functional disease). If they are absent, then endoscopy is not mandatory at the initial presentation and non-invasive investigation is recommended to test for the presence of H. pylori and, if present, to eradicate it, regardless of the presence of different subgroups of patients with FD. Resolution of symptoms after eradication should be reassessed in a few months. In patients with a negative test for H. pylori or without resolution of symptoms after eradication, the symptoms of FD should be carefully evaluated to identify those with EPS, PDS, and overlap, which according to the recent publication should be considered PDS³.

EPS should be treated with acid suppressants. If PPI therapy is not effective, then some patients may benefit more from H2RAs²⁴. An alternative (or supplementary) therapy is the addition of an alginate preparation, recently re-evaluated and found to be effective in the treatment of GERD²⁶.

In patients with EPS, if a trial of acid and reflux suppression fails, then tricyclic antidepressants, such as amitriptyline, should be considered. In clinical practice, we start with slow increasing of the dose (normally amitriptyline 25 mg one quarter daily for 1 week, then one half daily for another week, and finally one daily until the next consultation in about 2 months), informing the patient about possible delayed benefit and early minor side effects (that is, dry mouth). We find this approach useful to minimize side effects and improve compliance. Moreover, a follow-up consultation at about 2 months reinforces the patient’s motivation to continue the treatment.

In contrast, in patients with PDS, prokinetic therapy may improve symptoms. However, as summarized above, the market does not offer much choice. Taken on an as-required basis, domperidone or metoclopramide is a reasonable first choice for this patient group; however, long-term treatment is no longer recommended. The authors of the present review have obtained good clinical responses applying prucalopride in some patients with FD, as recently suggested by the literature. Starting with half the licenced dose for constipation (prucalopride 1 mg daily) and building up to 2 mg daily if tolerated is a useful addition, in particular in FD patients with overlapping constipation. In PDS patients who fail to respond, treatment with an antidepressant is the next step; however, it may be reasonable to check gastric emptying prior to starting treatment because the treatment response appears to be poor if delayed gastric emptying is present³⁶. In severe cases, especially those with weight loss, mirtazapine can be a good choice since it also relaxes the stomach and promotes weight gain⁴⁰. Given the frequent association with anxiety, if this is considered a likely driver of symptoms, then treatment with SSRIs is reasonable, even though no data support this approach in FD patients per se. Certainly, anxiety and depression have been shown to impact on gastric motor and sensory function⁴¹.

In patients who do not respond to empirical treatment, further functional evaluations are normally advocated to select appropriate management¹. However, many of these investigations are available in highly specialized referral centres or used primarily for research purposes or both⁴². The electronic barostat is considered the gold standard to assess gastric accommodation and visceral sensitivity, but the technique is invasive and is mainly used for research, and recent studies have suggested that the barostat bag could influence the gastric motor response⁴². New, less invasive techniques are in evaluation to replace the barostat. The nutrient drink test has been proposed as an alternative. In this test, a defined nutrient meal is ingested over a period of time until dyspeptic symptoms develop or the patient reports feeling full⁴². Response to treatment can be measured by repeating the test⁴². More recently, intragastric pressure measurement during a nutrient meal change was proposed as a minimally invasive test of nutrient tolerance and accommodation in FD⁴². However, the test needs further validation⁴². Gastric scintigraphy is the reference test of gastric emptying and is clinically more widely accessible than tests of accommodation⁴³. Methodology has been extensively validated; however, unfortunately, standard test meals are not widely applied⁴³. In most centres, only the gastric emptying of solids is evaluated⁴³. If gastric emptying is delayed, then the diagnosis of “gastroparesis” is made; however, unless the delay is severe (for example, three times the upper limit of normal), there is only a weak association between this finding and patient symptoms or disease severity⁴⁴. Moreover, it is not clear that the finding of gastroparesis predicts positive outcome for prokinetic medication⁴⁴. Conversely, the diagnosis of gastric dumping has implications for dietary and pharmacological therapy⁴⁴. It is interesting to note that patients with rapid gastric emptying (that is, dumping) can present with symptoms identical to those of gastroparesis and this may be the strongest reason to do the test⁴⁴.

However, the reality is that after performing tests, at this time, not so many specific pharmacological therapies are available to correct abnormal physiology¹. Nevertheless, there is evidence that a clear explanation for symptoms improves patient acceptance of disease and reduces out-patient attendance⁴⁵. Otherwise, an intensified medical management involving psychological intervention could be applied, as this has been reported to give superior long-term outcomes⁴⁶.

At present, the information obtained from gastric emptying studies is limited. For example, gastric scintigraphy studies often provide only a single measurement of gastric emptying of a solid meal. As already suggested⁴³, it is unlikely that this captures the complexity of GI function (Figure 2). In particular, a single summary outcome measurement, normalized after ingestion of a meal, misses the “early gastric emptying” that occurs even during meal ingestion⁴⁷. Moreover, the current way of performing the gastric emptying test does not incorporate the report of sensations experienced during meal ingestion⁴⁷. A new development in this field is the combination of a nutrient drink test with gastric scintigraphy to obtain a comprehensive assessment of gastric motor and sensory function⁴⁷. Assessment of the scintigraphic images after ingestion of the relatively large (400 mL) “Nottingham Test Meal” provides an evaluation of gastric accommodation and sensitivity in addition to gastric emptying⁴⁷. The test uses standard technology, and normal values of this test have been published⁴⁸. Ongoing studies will disclose whether this test can predict the response to pharmacological treatments in clinical practice.

Figure 2. Abnormal gastric motility and function could be implicated in the pathophysiology of symptoms in functional dyspepsia, especially in patients with postprandial distress syndrome.

Heightened visceral sensitivity has an important role in epigastric pain syndrome but is also present in many individuals with postprandial distress. In clinical practice, with the exception of detection of abnormal gastric emptying by scintigraphy, it is currently not possible to identify the specific causes of disease.

Conclusions

The literature of these last five years concerning FD has provided some relevant information for clinical practice. It has indeed confirmed the importance of correctly recognizing the different symptoms affecting the patient in order to identify PDS or EPS. This classification indeed seems to correspond to different pathophysiological mechanisms and treatments. However, it also reveals that we urgently need new tests to better study the GI function of these patients in order to develop effective treatments and better understand the pathophysiological mechanisms to target.

Abbreviations

CHS, cannabinoid hyperemesis syndrome; CNVS, chronic nausea and vomiting syndrome; CVS, cyclic vomiting syndrome; EPS, epigastric pain syndrome; ERD, erosive reflux disease; FD, functional dyspepsia; FH, functional heartburn; GERD, gastro-oesophageal reflux disease; GI, gastrointestinal; IBS, irritable bowel syndrome; NERD, non-erosive reflux disease; PDS, postprandial distress syndrome; PPI, proton pump inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin receptor inhibitor.