Functional dyspepsia (FD) is a common disorder in the population worldwide, but its pathophysiologic mechanisms have not been completely elucidated yet. Diverse pathophysiologic mechanisms including novel concepts have been proposed. Classically, the main pathophysiologic mechanisms include hypersensitivity to distending or chemical stimuli, impaired gastric accommodation to a meal and delayed gastric emptying.1-6 Although therapeutic approaches targeting underlying mechanisms are considered to be efficient in the treatment of FD, it is unclear whether symptom-based subtypes are useful for predicting underlying mechanisms and choosing appropriate therapeutic agents. A relationship of the several distinct pathophysiological mechanisms with individual dyspeptic symptoms has been suggested,1-5 but it is not clearly established. Furthermore, dyspeptic patients commonly complain of multiple dyspeptic symptoms rather than a single symptom, and their symptoms can change over time.
The Rome IV criteria prefer to use the diagnostic names of subtypes such as postprandial stress syndrome (PDS) and epigastric pain syndrome (EPS) rather than FD as a whole.7 Such a suggestion is based on the assumption that each subtype is more homogenous in terms of underlying pathophysiologic mechanisms, compared with FD as a whole. Thus, symptom-based subtypes may be useful for choosing appropriate therapeutic agents. Actually, in real clinical practice, proton pump inhibitors (PPIs) or visceral analgesics are recommended to be used as the first treatment of EPS, and the use of prokinetics are recommended first for the treatment of PDS.8-11 Besides classic pathophysiologic mechanisms such as delayed gastric emptying, impaired gastric accommodation to a meal, and hypersensitivity to distending or chemical stimuli, novel concepts have recently been proposed. Duodenal abnormalities such as altered microbiota, enhanced mucosal permeability, infiltration and activation of eosinophils and mast cells, and increased acid exposure have been suggested to be implicated in the pathogenesis of FD.5,12 Further, gastric dysbiosis,
Optimal treatment strategy for FD should be based on a detailed understanding of the abnormalities involved in the genesis of dyspeptic symptoms. Symptom-based subtypes based on the Rome criteria are commonly used to select therapeutic agents. However, it is unclear yet whether those subtypes are useful for targeted therapeutic approaches, particularly when considering therapeutic agents targeting novel mechanisms. The aim of this review is to evaluate the usefulness of symptom-based subtypes of FD based on the Rome criteria for predicting underlying pathophysiologic mechanisms and choosing appropriate therapeutic agents.
FD is considered to be a heterogeneous disorder with different pathophysiological mechanisms or pathogenetic factors. Several classic pathophysiologic mechanisms have been suggested to be associated with a certain dyspeptic symptom. The association of delayed gastric emptying with nausea and postprandial fullness was reported.3,4 Impaired gastric accommodation to a meal was found to be associated with early satiety.2 Hypersensitivity to gastric distension was reported to be frequently related to epigastric pain and belching.1 Although the prevalence of impaired gastric accommodation is highest in patients with early satiety as a predominant symptom, such abnormality is also commonly observed in patients with other predominant symptoms including epigastric burning, epigastric pain, or postprandial fullness (Fig. 1).13 Similarly, the prevalence of delayed gastric emptying for solids is highest in patients with a predominant symptom of postprandial fullness, but that abnormal mechanism can be associated with patients with other predominant symptoms such as early satiety or epigastric burning (Fig. 1).13 Delayed gastric emptying and impaired gastric accommodation may lead to increased gastroesophageal reflux generating burning symptoms. Moreover, some studies failed to show a positive association of delayed gastric emptying with specific FD symptoms.14-16 Irrespective of predominant symptoms, hypersensitivity to gastric distension is similarly prevalent in patients with FD (Fig. 1).13 Actually, each of classic pathophysiologic mechanisms may be associated with both PDS and EPS (Fig. 1).17
In keeping with those findings, a previous study showed that hypersensitivity to gastric distension can induce diverse dyspeptic symptoms, depending on the level of stimuli. For instance, in the induced condition of hypersensitivity to gastric distension in healthy volunteers, sequentially increased distending stimuli to the stomach generated fullness and bloating first, and then nausea, satiety, and epigastric burning, followed by epigastric pain.18 Thus, one pathophysiologic mechanism can be associated with multiple dyspeptic symptoms, and a specific dyspeptic symptom may be induced by diverse pathophysiologic mechanisms. Consequently, individual predominant symptoms are likely to have low sensitivities and specificities for predicting underlying pathophysiological mechanisms. Moreover, there may be a considerable overlap of classic pathophysiologic mechanisms that makes it difficult to predict underlying mechanisms by individual dyspeptic symptoms or symptom-based subtypes.
In the Rome III and IV criteria, symptom-based subtypes of FD are recommended rather than FD as a whole: (1) PDS, characterized by the presence of postprandial fullness and/or early satiety, and (2) EPS, characterized by the presence of epigastric pain and/or epigastric burning.6 The rationale for this subdivision is based on the expectation that pathophysiological mechanisms underlying each subtype are different and appropriate therapeutic agents can be selected based on those subtypes. However, a previous study failed to demonstrate any differences between PDS and EPS in the prevalence of gastric hypersensitivity, impaired gastric accommodation, and delayed gastric emptying.17 There was no difference in the prevalence of gastric hypersensitivity to distension between subgroups (PDS 30.5%, EPS 21.4%, and overlap 40.6%). The prevalence of impaired gastric accommodation was also comparable between subgroups (PDS 27.6%, EPS 42.9%, and overlap 38.7%). Likewise, the prevalence of delayed gastric emptying did not significantly differ between subgroups (PDS 23.2%, EPS 14.9%, and overlap 23.8%).17 In addition, a substantial overlap between PDS and EPS can decrease the usefulness of those subtypes in predicting underlying pathophysiologic abnormalities.17,19
The use of subtypes such as PDS and EPS is further emphasized in the Rome IV as compared to the Rome III.7 Compared with Rome III criteria, the overlap between PDS and EPS groups is reported to be reduced by the Rome IV criteria.20,21 However, a previous population-based study using the Rome IV criteria also showed a considerable overlap between PDS and EPS (21.0% in the adult population of the USA, Canada, and the UK).22 This overlap hinders prediction of underlying pathophysiologic mechanisms based on symptom-based subtypes. Besides the overlap between PDS and EPS, there may be substantial overlap between underlying pathophysiological mechanisms.17 PDS is defined as meal-induced dyspeptic symptoms and more associated with the effect of meal ingestion. Therefore, delayed gastric emptying, impaired gastric accommodation to a meal, and hypersensitivity to distending or chemical stimuli can be associated with meal-related dyspeptic symptoms. Although EPS appears to be less associated with the effect of meal ingestion, visceral hypersensitivity, that is considered to be the main mechanisms of EPS, may produce symptoms postprandially as well as preprandially. Actually, postprandial epigastric pain or burning may occur even in patients with EPS diagnosed by the Rome IV criteria.7 Food and dietary factors may also be involved in the pathogenesis of FD. Those factors may be associated with dysbiosis, enhanced mucosal permeability, and low-grade immune activation, particularly in the duodenum.23 Those duodenal abnormalities can induce gastric sensorimotor dysfunction and play a role in the generation of both PDS and EPS symptoms. Data on treatment responses to acid suppressants or prokinetic agents in patients with FD using the Rome IV criteria are lacking. Thus, the real effect of the Rome IV definition of FD subgroups on treatment responses needs further investigation.
Pathological gastroesophageal acid reflux was reported to be observed in 18.5% of FD patients without heartburn. They were characterized by a higher prevalence of epigastric pain.24 Similarly, a previous study from China demonstrated high prevalence of pathological gastroesophageal acid reflux in patients with FD.25 The prevalence of pathological gastroesophageal acid reflux was the highest (48.9%) in patients with epigastric burning, 36.6% in patients with PDS, and 28.7% in patients with EPS.25 The positive rates for PPI tests did not significantly differ between patients with PDS (65.5%) and EPS (60.6%) (
The sensorimotor dysfunction of the gastroduodenal region can be induced by diverse pathogenetic factors. Patients with FD are known to have more psychological problems such as anxiety, depression, and psychological distress than those who do not have FD.27 Dyspeptic symptoms are found to be significantly associated with psychosocial factors such as depression and somatization.28 Stress is known to be a trigger for dyspeptic symptoms.29 Psychological factors or stress may induce abnormal central modulation and enhance visceral sensitivity.30,31 It is also found that stress can cause alterations in gastrointestinal motility, enhanced visceral sensitivity, increased epithelial permeability, impaired intestinal barrier function, immune activation, and gut dysbiosis in animal models,32-34 and irritable bowel syndrome patients.35 Various kinds of psychosocial stress have been shown to induce diverse gastric sensorimotor abnormalities, including delayed gastric emptying, impaired gastric accommodation to a meal, and gastric hypersensitivity to distension in healthy volunteers, suggesting that psychological factors or stress may play a role in the pathogenesis of both PDS and EPS.36,37 Therefore, it is unlikely that the involvement of psychological factors or stress is predicted by symptom-based subtypes.
FD is defined as a disorder characterized by the presence of recurrent or persistent symptoms thought to originate in the gastroduodenal region without any organic, systemic, or metabolic disease that is likely to explain the symptoms.6,7 Recently, the duodenum is regarded as the key organ in the generation of dyspepsia symptoms, and it has been proposed that gastric sensorimotor dysfunction may be induced by duodenal abnormalities.38-43 Infiltration and activation of eosinophils and mast cells have been identified in the duodenum of patients with FD, and suggested to play a key role in the pathogenesis of FD.41-43 Infiltration and activation of eosinophils and mast cells in the duodenum lead to low-grade inflammation and increased mucosal permeability. Those duodenal abnormalities can induce submucous neural changes, neuronal hyperexcitability, and sensitization of the afferent nerve, which triggers duodeno-gastric reflexes, impairs gastric accommodation, and enhances gastroduodenal sensitivity.43-46 Thus, duodenal abnormalities found in a subset of patients FD can be theoretically associated with both PDS and EPS symptoms. Duodenal dysbiosis, food, and dietary factors are also suggested to play a role in inducing duodenal abnormalities such as enhanced mucosal permeability and low-grade immune activation. However, their role in the pathogenesis of FD needs to be further investigated.
Abnormally increased duodenal acid exposure is observed in a subset of patients with FD.47,48 Like low-grade immune activation and inflammation of the duodenum, increased duodenal acid exposure can induce gastric sensorimotor dysfunction, probably through triggering duodeno-gastric reflexes, impairing gastric accommodation, and enhancing gastroduodenal sensitivity.40,49,50 Therefore, this abnormality leads to pathophysiologic mechanisms generating both PDS and EPS symptoms. Taken together, it appears to be difficult to predict the presence of duodenal abnormalities by symptom-based subtypes of FD.
The importance of gut microbiota in gastrointestinal physiology has been well described, and they are believed to be associated with pathophysiology in various diseases.51,52 The mechanistic implications of gut microbiome in the pathophysiology of functional gastrointestinal disorders have also been suggested.53 Gut microbiome is involved in modulating physiological processes such as immune response, motility, secretion, epithelial barrier integrity, and brain–gut communication.54 Animal studies have shown that gut dysbiosis induces visceral hypersensitivity.55,56 Induction of epithelial opioid and cannabinoid receptors, regulation of central and peripheral neuronal pathways, antinociceptive effects through inhibition of transient receptor potential cation channel subfamily V member 1, and the effect of microbial metabolites on sensation are suggested as the plausible mechanism.57-62 However, the exact mechanisms by which gut microbiota affects visceral sensitivity are not clearly explored in human beings.
It has been shown that intestinal dysbiosis is associated with irritable bowel syndrome.63 Similarly, altered gastric microbiota was recently demonstrated in patients with FD.64,65 Initially, dysbiosis in the gastric fluid of patients with FD was reported. The abundance of genus
It cannot be completely excluded that delayed gastric emptying, the use of PPIs, and dietary changes due to dyspepsia may affect microbiota composition in the stomach and duodenum of patients with FD. Although current data cannot explain a direct causative process in FD, dysbiosis is likely to be associated with symptom generation or exacerbation in a subset of patients with FD. Microbial products or metabolites might be involved in the regulation of gastrointestinal motility.69-71 On the other hand, duodenal dysbiosis is suggested to play a role in altering mucosal permeability.72 Although gastroduodenal dysbiosis may be associated with the generation of both PDS and EPS symptoms, its mechanistic role in FD needs further investigation.
The association of
Although some epidemiological studies show association of
Gastric emptying was reported to be delayed in patients with atrophic gastritis and hypochlorhydria,97 suggesting that progression of atrophic gastritis to the proximal stomach by long-lasting
It is ideal to choose appropriate therapeutic agents for FD based on underlying pathophysiologic mechanisms. However, many patients with FD may be associated with multiple pathophysiologic mechanisms, who are less likely to respond to an agent targeting a single mechanism. Furthermore, each dyspeptic symptom is not specific for a particular pathophysiologic mechanism or pathogenetic factor. Each pathogenetic factor may influence the overall function of the gastroduodenal region, and lead to diverse sensorimotor dysfunctions, that may be associated with multiple dyspeptic symptoms including both PDS and EPS symptoms. Figure 3 depicts the relationship between symptom-based subtypes of FD and pathophysiologic mechanisms. The presence of a single functional abnormality such as delayed gastric emptying or impaired gastric accommodation to a meal may be associated with one subtype such as PDS or a single dyspeptic symptom. This may explain clinical data of Acotiamide, a prokinetic agent with a feature of fundic relaxants, showing that meal-related PDS symptoms, unlike EPS symptoms, have more prominent therapeutic gains compared to the placebo group.107,108 However, in the real world situation, multiple functional abnormalities are more likely to be involved in the generation of dyspeptic symptoms rather than a single functional abnormality. Actually, gastric hypersensitivity, delayed gastric emptying, and impaired gastric accommodation may commonly overlap.17 Therefore, in many cases, symptom-based subtypes such as PDS and EPS do not accurately reflect underlying pathophysiologic abnormalities. It is presumed that patients with EPS are more likely to improve with a PPI and those with PDS are more likely to respond to a prokinetic agent.9-11 This assumption may be applied in a subset of patients with a functional abnormality related to the action mechanism of the agent. However, some studies have shown that therapeutic responses to a PPI or a prokinetic agent do not differ in the group of EPS or PDS, respectively.109-111 In general, a PPI is not expected to show benefit in patients with dysmotility-like dyspepsia. However, a previous study from Japan demonstrated that PPI monotherapy was significantly more effective in improving dysmotility-like symptoms than prokinetics,109 suggesting that symptom-based subtypes of FD may not be useful for choosing effective therapeutic agents. The previous data are mostly based on the Rome III criteria, and clinical trial data using the Rome IV subgroup definition are lacking. However, when considering the complex interactions between pathophysiologic mechanisms and pathogenetic factors, and their common overlap, prediction of underlying pathophysiologic abnormalities simply by symptom-based subtypes does not seem to be accurate. Particularly, novel concepts on the pathophysiology of FD makes it more difficult and complex than before.
The addition of objective parameters or subclassification reflecting physiologic or pathologic tests seems to be necessary for the targeted therapeutic approaches, particularly when therapeutic agents targeting novel mechanisms are available. The pathophysiologic mechanisms, that can be therapeutic targets at present, include increased acid exposure of the duodenum or esophagus, reduced gastric or duodenal motility, impaired gastric accommodation, atrophic gastritis with
Although several classic pathophysiologic mechanisms are suggested to be associated with individual dyspeptic symptoms, symptom-based subtypes of FD are not specific for a certain pathogenetic factor or pathophysiologic mechanism, and may be frequently associated with multiple pathophysiologic abnormalities. Novel concepts on the pathophysiology of FD show complex interactions between pathophysiologic mechanisms and pathogenetic factors, and prediction of underlying mechanisms of individual patients simply by the symptom pattern or symptom-based subtypes may not be accurate in a considerable proportion of cases. Therefore, subtyping by the Rome criteria appears to have limited value to guide therapeutic strategy, suggesting that the addition of objective parameters or subclassification reflecting physiologic or pathologic tests may be necessary for the targeted therapeutic approaches, particularly when therapeutic agents targeting novel mechanisms are available.
Kwang Jae Lee wrote the manuscript and approved the last version.