What Is Known
- Functional dyspepsia is considered a constellation of symptoms referable to the gastroduodenal region.
- In children, the reported prevalence is between 3% and 27%.
- The Rome III criteria include functional dyspepsia as recurrent pain or discomfort centered in the upper abdomen without evidence of organic disease.
What Is New
- The symptoms are not easily recognizable.
- The diagnostic approach is based on medical history and physical examination.
- In patients with functional dyspepsia with mild symptoms, reassurance and lifestyle advice are sufficient.
- Medical therapy targeted to the specific pathophysiologic mechanism is preferred, but symptom-based therapy may also be useful.
The term dyspepsia consists of a heterogeneous group of symptoms that are localized in the epigastric region. Children and adults may report symptoms such as postprandial fullness (68%–86%), upper abdominal bloating (68%–84%), epigastric pain (68%–74%), and early satiation (49%–72%). Additional symptoms include belching (50%–60%), epigastric burning (35%–75%), nausea (39%–65%), and vomiting (23%–31%) (1). Functional dyspepsia (FD) is a common condition, with a high prevalence in children varying from 3% to 27%, with effect on quality of life and increased health care costs (2). According to the pediatric Rome III criteria, FD is defined as persistent or recurrent pain or discomfort centered in the upper abdomen (above the umbilicus), at least once per week for at least 2 months, not relieved by defecation or associated with the onset of a change in stool frequency or stool form, and no evidence of an inflammatory, anatomic, metabolic, or neoplastic process (3). Most of these symptoms, however, are difficult to objectify in children younger than 8 years of age. In adults, FD has been classified into 2 different subgroups, according to the symptoms presented: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) (4). The former includes bothersome postprandial fullness, occurring after ordinary-sized meals at least several times per week, with upper abdominal bloating or postprandial nausea or excessive belching; the latter is characterized by pain or burning (without a retrosternal component) localized in the epigastrium, of moderate severity and once per week, not relieved by defecation or passage of flatus but commonly induced or relieved by ingestion of a meal (5). A new key issue is the role of meals in the generation of symptoms, and most patients with FD have meal-related symptoms (6). PDS and EPS are not included within the pediatric FD symptoms definition due to lack of supportive evidence. Only recently in a prospective, observational study, despite a high percentage of overlap, has it been demonstrated that adult FD subtypes are distinguishable in the pediatric population: a total of 100 patients with FD were enrolled, fulfilling the pediatric Rome III criteria, and classified as EPS and PDS FD subtypes using the adult Rome III classification. In 36% of patients at recruitment time and in 29%, 6 months later, no distinction between EPS and PDS was possible, and 43% of children switched from 1 subtype to the other or to the overlap group, suggesting a common pathophysiology (7). Some subtle structural abnormalities have been linked to FD, such as Helicobacter pylori (Hp) gastritis, erosive prepyloric changes, duodenal inflammation, and increased eosinophil counts (8). The diagnosis and management of FD in adults consists, in most cases, of the clarification of the cause by means of upper gastrointestinal endoscopy, whereas in children it consists of defining the character of symptoms accurately, and clinically recognizing the functional pattern, avoiding a strategy based on overuse of empirical antisecretory therapy or referring the patient immediately for endoscopy or subspecialty care. The goal of this article is to provide a narrative review of diagnosis and management options for FD in pediatric populations. To accomplish this, a comprehensive search of published literature using the PubMed and Ovid MEDLINE databases was performed (1998 to November 2015). The 3 key terms “FD,” “functional gastrointestinal disorders (FGIDs),” and “children” were used.
To date, the pathophysiology of FD is not completely understood. Multiple mechanisms are involved with specific combinations of physiologic, genetic, environmental, and psychological factors that are responsible for the different symptoms. Functional and structural changes are described in FD as gastric abnormalities (impaired accommodation, delayed emptying, and hypersensitivity). A number of duodenal abnormalities may also be responsible for the generation of symptoms, such as increased sensitivity to duodenal acid, increased sensitivity to duodenal lipids, and low-grade inflammation (9). Tack and Talley (1) distinguish 3 major mechanisms (motility, accommodation, and hypersensitivity) in the pathophysiology of FD.
Several studies have demonstrated abnormal gastroduodenal motility in adults with FD (10). Indeed, the stomach plays a central role with abnormal motor function ranging from impairment of gastric accommodation, to delayed gastric emptying, antral hypomotility, or intragastric concentrations of solid and liquid food. Two thirds may have abnormalities of antral and duodenal motility with predominant symptoms such as postprandial fullness, nausea, and vomiting (11,12). Haag et al (13) reported no differences in gastric emptying between the 2 subgroups (EPS and PDS) of FD. Delayed gastric emptying occurs in 20% to 50% of children with FD (14). A case-control study in 42 Sri Lankan children with FD investigated the role of delayed gastric emptying and antral dysmotility, using a validated noninvasive ultrasonography method. These parameters were impaired in children with FD compared with controls, reporting a significant negative correlation between gastric emptying rate and severity of abdominal pain (15).
Impaired gastric accommodation (ability of the stomach to distend appropriately during a meal with an increase in gastric volume in the absence of increased gastric pressure) is implicated as a motor abnormality responsible for symptoms in patients with FD. It occurs in 40% of adult patients and has been associated with symptoms of either early satiation or pain caused by increased intragastric pressure after meal ingestion (14). It has been suggested that patients with FD display impaired accommodation of the proximal stomach. Studies using scintigraphy and ultrasonography have demonstrated an abnormal intragastric distribution of food, with preferential accumulation in the distal stomach (16). Although Tack and Talley (17) showed that early satiety is reported in >90% of adult patients with impaired accommodation, other studies did not find any association between gastric accommodation and symptoms (18). The etiology of impaired accommodation may be correlated by abnormalities of the vago-vago reflex, of the intrinsic inhibitory innervation (myenteric plexus) or alteration in the smooth muscles of the proximal stomach (19).
Visceral hypersensitivity is defined as the increased perception of visceral sensation (20). The prevalence of hypersensitivity to gastric distension has been demonstrated in adult populations and ranges from 34% to 66%. FD can be considered a model of a brain–gut disorder. The presence of food in the gastrointestinal tract is signaled to regions in the brain via neurohormonal pathways (10). Caldarella et al (21) showed a coexistence of hypersensitive fundic and antral distension. The symptoms are triggered by meal ingestion and sensitivity to gastric distension in the postprandial period. This kind of hypersensitivity can be central or peripheral, and, in FD, visceral sensations are transmitted from the gut to the brain via afferent nerves. It was demonstrated that gastric distension by balloon revealed higher levels of brain signal elicitation in patients with FD than in healthy controls (3). Alterations of the mechanisms that modulate pain transmission from the stomach to the brain could explain the presence of hypersensitivity to gastric distension. Normal sensory signaling from the gastrointestinal tract to the brain may be inappropriately perceived in the case of defective sensory filtering, for instance, in the case of an overactive reward system or an impaired descending modulatory system. This defective sensory filtering may impair food intake regulation and increased perception of physiological stimuli as painful. Duodenal hypersensitivity to acid has also been described in the generation of dyspeptic symptoms. Samsom et al (22) in adult populations showed that short perfusion of acid in the duodenum induced nausea in a subset of patients with FD, but not in healthy individuals. This hypersensitivity is present also after lipid infusion in dyspeptic symptoms. A dose-related effect of lipid infusion on dyspeptic symptoms was observed and these effects seem to be specific for fat, such as duodenal lipid (23). A recent systematic review in adults with FD showed that the mean prevalence of developing FD after infectious gastroenteritis was higher compared with a control population (24). Salmonella, Escherichia coli O157, Campylobacter jejuni, Giardia lamblia, and norovirus may induce FD; the risk factors include genetic factors and smoking (25). Various studies have focused on the characterization of inflammatory cells in the gastrointestinal tract of patients with postinfectious FD with the presence of focal aggregates of T cells, reduced numbers of CD4+ T cells, and increased macrophage counts in the duodenal mucosa. Kind et al (26) analyzed 24 duodenal samples of patients with FD and showed a focal T cells aggregation with elevated CD8 in patients with postinfectious FD (3 months after infectious episode); CD4 cells were less frequently observed in postinfectious FD. Limited studies in pediatric FD are available, although some evidence supports adult data in which hypersensitivity is considered an important mechanism (27). Inflammation and infections play an important role in FD. It is likely that there is an association with abnormal activation of the immune system suggested by the fact that FD occurs at higher rates in patients with a history of acute infectious gastroenteritis (26).
It is well-known that stress also plays a significant role in the development of FD. An important intrinsic role for psychosocial factors and psychiatric disorders, especially anxiety and depression, has been described in the etiopathogenesis of FD, in addition to their putative influence on health care–seeking behavior. Compared with controls with organic disease, Haug et al (28) show higher levels of anxiety and depression in adult patients with FD. Approximately 50% of children and adolescents with FD demonstrate elevated anxiety scores (29). Stress is associated with activation of the hypothalamus, which releases corticotrophin-releasing factor, with a significant response including inflammation (particularly mast cell activation), sympathetic nervous system activation, altered gastric accommodation, gastric dysmotility, and visceral hypersensitivity (30). Several genetic polymorphisms are associated with visceral hypersensitivity and other symptoms of FD. Oshima et al (31,32) have defined the association between adult FD and serotonin transporter gene polymorphism, in particular with EPS.
OVERLAP WITH GERD AND IRRITABLE BOWEL SYNDROME
Although gastroesophageal reflux disease (GERD) and FD are generally thought of as totally distinct disorders with unique symptoms and treatments, they are in many ways more similar than different. For example, symptoms of GERD and FD frequently overlap, and evaluation and treatment are often similar (6). A careful separation between these 2 entities can be quite difficult, as substantial overlap exists epidemiologically, symptomatically, and even diagnostically. This overlap makes precise diagnosis a challenge; given the limited treatment options, the primary goal is to identify those patients who will respond to acid suppressive therapy. Heartburn and regurgitation are the main symptoms in GERD, particularly after meals. GERD can be subdivided into nonerosive reflux disease, erosive (esophagitis), and complicated disease (Barrett esophagus). In the past, heartburn itself was a diagnostic symptom of dyspepsia (old reflux-like dyspepsia), but was removed from the Rome III criteria from the group of symptoms typical of FD (33). In an adult population, a study found that nearly 32% of patients with FD had pathological esophageal acid reflux (34). Indeed, it has been demonstrated that many adult patients with FD present with GERD-like symptoms and it is difficult to differentiate between GERD and FD (23). When abdominal pain is the main symptom, an overlap syndrome may exist between FD and irritable bowel syndrome (IBS). A meta-analysis has shown that the prevalence of IBS in patients with dyspepsia is higher compared with patients without dyspepsia (35). Some studies have also reported some associations between FD and obesity (36), weight loss (37), and psychiatric comorbidity, such as anxiety (38). Indeed, Rippel et al (39) showed that among pediatric patients with dyspepsia, both those with normal endoscopy and those with esophagitis are at increased risk for chronic dyspeptic symptoms, anxiety disorders, and reduced quality of life in adolescence and young adulthood.
HELICOBACTER PYLORI DISEASE
Upper gastrointestinal endoscopy findings appear normal in approximately 75% of patients with dyspepsia and most of these individuals are consequently diagnosed with FD (40). Although a variety of bacterial infections have been implicated in the pathogenesis of this disorder, Hp is one of the most likely causes. There is some evidence of an association between chronic Hp infection and dyspepsia (41). The exact role of Hp in FD, however, remains controversial. Indeed, in adult populations, there is growing consensus that Hp-positive FD should be considered a separate entity, with eradication being beneficial and appropriate (42). In the Helicobacter Eradication Relief of Dyspeptic Symptoms trial in adults with Hp-positive FD, symptomatic improvement after antibiotic therapy was 49% versus 36% after omeprazole and placebo therapy, respectively (43). As data have emerged, however, it has become clear that Hp eradication has a small but statistically significant effect on FD symptoms. Hp eradication seemed to be effective in both epigastric-pain-predominant dyspepsia and dysmotility-type dyspepsia, with no heterogeneity in effect between the subgroups. Thus, a test and treatment strategy for Hp, especially in populations with a high prevalence of the disease, may be a correct approach. On the contrary, in children, at present, there is inadequate evidence supporting a causal relation between Hp gastritis and FD. Therefore, cases of abdominal pain consistent with the diagnostic criteria of functional pain should not be investigated for Hp unless upper endoscopy is performed during the diagnostic workup.
DIETARY AND LIFESTYLE FACTORS
A large proportion of patients with FD report that their symptoms are triggered by meal ingestion, and potential factors, which may be related to meal ingestion include overall caloric intake, eating patterns, and nutrient composition of the diet; lifestyle factors may include exercise, smoking, alcohol, coffee consumption, sleeping habits, and emotional state (44). The responses in patients with FD can be variable, and the eating patterns are different. Aspects of eating patterns that have been assessed include meal size (ie, consumption of meals vs snacks), eating speed, and time spent fasting. Mullan et al (45) have demonstrated a higher prevalence of snacking and a lower prevalence of large meals in FD and, compared with healthy controls, a greater proportion of “fast eaters.” Fat intake was reported to be higher and carbohydrate intake to be lower, and, with regard to the role of specific foods, Park et al (46) reported an association between dyspeptic symptoms and consumption of fried foods (52% of patients), pastry (33%), pickles (30%), spices (27%), and oranges (26%).
In children, diseases that can mimic symptoms similar to dyspepsia include food allergy, celiac disease, chronic pancreatitis, and medication adverse effects (Table 1). An alternative diagnosis should be considered throughout the work-up of dyspepsia, especially in patients not reporting improvement with a therapeutic approach. The clinical diagnosis of FD, based on the pediatric Rome III criteria, however, does not appear specific enough to rule out organic causes (47). In the presence of alarm signals, diagnostic tests are required to demonstrate possible structural diseases, such as organic, systemic, or metabolic disease, above all, upper endoscopy (Fig. 1). Thus, an initial diagnostic approach should be focused on any alarm signals including bleeding, anemia, persistent vomiting or dysphagia, an epigastric mass, and weight loss. In these cases, patients should be referred for upper endoscopy, similar to patients with heartburn and regurgitation as predominant symptoms in suspected GERD. In the absence of alarm signals, the first approach should be conservative: other sources of symptoms can be considered, or it may be possible to start empirical therapies including acid-suppression therapy, prokinetic agents, antidepressants, psychological therapy, and/or cognitive behavioral therapy. In the case of treatment failure, the diagnosis should be reconsidered by means of further investigations such as upper gastrointestinal endoscopy, and other tests for determining the pathophysiology of FD, such as the study of gastric emptying with scintigraphy, testing gastric accommodation with single-photon emission computed tomography, the study of gastric sensory function with water/nutrient test and antroduodenal manometry or electrogastrography for testing myoelectrical activity (48).
TREATMENT OF FUNCTIONAL DYSPEPSIA
Placebo or Reassurance
The rate of response to placebo in trials involving children with FD is 20% to 60% (49). Reassurance, as a treatment strategy, includes explanation of the symptoms and evaluation of relevant psychosocial factors and dietary advice (50). There have not been any randomized trials of reassurance as a treatment strategy in patients with FD, although this approach is often used by health care professionals (4).
Dietary and Lifestyle Factors
The reported relation between food ingestion and meal-related symptoms suggests a role for dietary adjustments in the treatment of FD. Patients with FD have abnormal sensory and reflex activity in the upper gastrointestinal tract exacerbated by dietary and lifestyle factors (51). A possible dietary approach consists of having more frequent or smaller meals and avoiding food with a high fat content, as lipids stimulate gastric hypersensitivity. Current treatments for FD in children generally ignore the potential role of diet. A diary to prospectively assess dyspeptic symptoms in temporal association with eating patterns can be useful. Further investigations are, however, needed to demonstrate the role for dietary interventions in FD.
Medical therapy targeted to the specific pathophysiologic mechanism is preferred, but symptom-based therapy may also be useful (27).
In the case of acid sensitivity, antiacid therapy may be useful, including histamine-2 receptor antagonists and proton-pump inhibitors (PPIs). As literature suggests, adult patients with EPS may obtain more beneficial effects with acid-suppressive therapy, used as a first-line therapeutic approach, compared with patients with PDS who respond best to prokinetic therapy. PPIs provide the strongest evidence of effectiveness without difference in efficacy between different PPIs and no dose effect (52,53). Acid reduction therapy is the most common treatment prescribed in children, although the specific mechanism of action remains unclear. In a pediatric double-blind, placebo-controlled trial, the superiority of famotidine over placebo in clinical improvement in children with FD has been demonstrated (54). Dehghani et al (55) have shown that omeprazole had no benefit over ranitidine or famotidine in the relief of symptoms in children with dyspepsia, in a large pediatric cohort. Therapy to increase gastrointestinal motility and emptying include prokinetic agents that stimulate gastric contractility, and agents primarily targeting 5-HT (5-HT3 antagonists and 5-HT4 agonists), dopamine, and motilin receptors. It was shown they have more beneficial effects in adult patients with meals-related symptoms (PDS). There is a lack of pediatric data regarding agents targeting 5-HT receptors. In pediatric patients with dyspepsia, cisapride, a 5-HT4 receptor agonist, may normalize gastric emptying (56) but data on clinical effects are not available. Because of the potentially fatal cardiac arrhythmias, cisapride was withdrawn from the United States and European markets, but there is no evidence that these effects are common in otherwise healthy children and the medication can still be used in limited capacity with close supervision (27). Metoclopramide is a dopamine antagonist and its effectiveness is noted as a promotility agent in reducing dyspeptic symptoms, but adverse effects may include irreversible extrapyramidal symptoms. In pediatric FD, the long-term use of metoclopramide should be limited because of a lack of proven efficacy, and significant potential adverse effects. Domperidone is a dopamine-2 receptor antagonist and does not cross the blood-brain barrier, even if there is a possible occurrence of arrhythmias with QT interval prolongation in long-term therapy. Acotiamide (Z-338 or YM443) is a novel experimental drug that enhances gastric emptying and gastric accommodation. It is a cholinesterase inhibitor, inhibiting muscarinic type 1 and type 2 (M1/M2) receptors on cholinergic nerve endings and, thus, stimulates acetylcholine release from enteric neurons (57). This drug could be useful, as many studies conducted in Japan and Europe have demonstrated, in postprandial fullness and early satiation improvement, without much effect on epigastric pain confirming the differential therapeutic effect in EPS and PDS in FD (58). Another potential therapeutic target is represented by impaired gastric accommodation, which is one of the major pathophysiological mechanisms of FD. This effect is determined by various agents such as nitrates, sildenafil (phosphodiesterase-5 inhibitor) and antimigraine drugs (5-HT receptors agonists) but they are high in cost and low in tolerability and for this reason are not beneficial in patients with FD (52). Cyproheptadine has been shown to be effective in improving symptoms in children with FD, in a retrospective open-label study (59,60). It is an antagonist of serotonin, histamine H1, and muscarinic receptors with physiologic effects due to increased gastric accommodation or decreased gastric hypersensitivity to distension. Psychotropic drugs, such as anxiolytics and antidepressants, are used in the treatment of FD mainly based on evidence obtained in IBS, reducing visceral hypersensitivity and central pain perception. They include tricyclic antidepressants, selective serotonin uptake inhibitors (SSRIs), and related medications, and have potential adverse effects including cardiac dysrhythmias and anticholinergic effects. Selective serotonin reuptake inhibitors may enhance gut transit and gastric accommodation. In a systematic review, it has been shown that anxiolytics and antidepressants reduce pain in FD with efficacy comparable to antisecretory and prokinetic agents (61). Limited data exist regarding treatment of pediatric FD with tricyclic antidepressants and SSRIs. In a retrospective study, it has been demonstrated, although with several limitations, that tricyclic antidepressant drugs, amitriptyline and imipramine, are effective in treating pediatric patients with FGIDs, such as FD, for a long duration (62). There are no published placebo-controlled, randomized controlled trials of SSRIs for treatment of pediatric FGIDs in general, or FD in particular (Table 2).
Further investigations are needed, such as placebo-controlled trials on therapy targeting pathophysiological mechanisms to improve directed medical therapy for children with FD.
Complementary and Alternative Therapy
Because of the limited efficacy of conventional medical therapy, new forms of treatment are used in FD, such as acupuncture and homeopathy. A study has demonstrated that acupuncture may improve gastric emptying and accommodation in adult patients (63). Pediatric data on the use of complementary and alternative therapy in the treatment of FD are poor compared with adult populations. Some patients use herbal supplements, such as STW5 (9-herb combination product Iberogast) with relief of symptoms, which acts by relaxing the gastric fundus (64). Other agents, including capsaicin, a component of red pepper, or a combination of peppermint oil and caraway oil, have shown some benefit in small adult studies (65). At pharmacologic doses, melatonin, acting as a partial 5-HT antagonist, delays gastric emptying and may also have a direct effect on visceral sensitivity (66). In a double-blind, randomized, placebo-controlled crossover trial Zybach et al (67) have studied the effectiveness of 2 weeks’ treatment with melatonin compared with placebo in children ages 8 to 17 years, diagnosed with FD based on Rome III criteria, after failure of 4 weeks’ acid suppression therapy. A positive clinical response (based on self-reported pain) was achieved in 42% of children on melatonin compared with 50% on placebo, but the short-term (2 weeks) use of melatonin does not appear to have efficacy in relieving pain in contrast to the previous study of FD in adults (68). Future studies should consider FD subtypes, pathophysiologic mechanisms, and baseline sleep disturbances. Pasalar et al (69) have evaluated, in a double-blind, randomized clinical trial, the efficacy of a traditional Persian medicine, jollab, in reducing FD symptoms. One hundred sixty adult patients with a diagnosis of FD were enrolled and treated with either jollab or placebo. The response rate, in terms of reducing frequency and severity of symptoms, was higher in the treatment group (78%) than in the placebo group (31%), with jollab appearing to be more effective than the placebo.
FD is a complex, heterogeneous disorder in children with an increased incidence in recent years, and with high demands for specialist visits. In many cases, it may be associated with other FGIDs. The symptoms of FD are not easily recognizable in the pediatric population. If symptoms are persistent or more severe, esophagogastroduodenoscopy can be recommended to exclude organic causes. A correct approach would result in proper identification of the typical symptoms and in the choice of a conservative approach with reassurance and, eventually, symptom-based therapy.
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