Functional disorders of the gastrointestinal (GI) tract are those characterized by symptoms in the absence of structural or biochemical disease. These are a common problem in pediatrics. In 1999, the Rome II Committee set out to develop a symptom-based classification of functional GI disorders, including recurrent abdominal pain. The goal of this classification is to promote criteria-based diagnosis rather than diagnosis based on excluding organic diseases, thereby reducing the cost and suffering of these patients.1 Dyspepsia, a category identified under functional abdominal pain in the Rome II criteria, refers to the symptom of pain or discomfort in the upper abdomen. The definition provided in this review is from Rome III, defined in 2006.2
Dyspepsia is a widely prevalent problem in adults and children. It has an annual prevalence of up to 25% of adults in Western countries and accounts for 2% to 5% of primary care visits. Prevalence of 3% to 27% is described in children, depending upon community or school-based studies.3,4 Twelve percent to 16% of children referred to tertiary care clinics in the U.S. have dyspepsia.5,6
Functional dyspepsia (FD) is defined, per the Rome III criteria, as a clinical syndrome characterized by chronic and recurrent pain or discomfort centered in the upper abdomen, not related to bowel movements, in the absence of underlying organic disease that may be the likely explanation for the symptoms (Table 1). In this definition, the duration of symptoms was shortened to 2 months from 3, as this was considered sufficient for resolution of most acute diseases. Endoscopy is no longer mandatory for making this diagnosis because, unlike adults, children are less likely to have mucosal abnormalities in the context of dyspepsia.4 Finally, also unlike adults, subtype categories of dyspepsia, ulcer-like, and dysmotility-like were eliminated, as the symptoms of pain and discomfort are often not differentiable in children. There are also no data to suggest that different pathophysiologic mechanisms underlie the causation of the two subtypes in children. 5,6
Definition of Functional Dyspepsia
The main pathophysiological mechanisms proposed for FD are motor dysfunction, visceral sensory abnormalities, and psychosocial factors. Several motor abnormalities have been documented in adults and children with FD. These include delayed gastric emptying, impaired initial distribution of a meal within the stomach, impaired accommodation, antral hypomotility, gastric dysrhythmia (tachygastria, bradygastria, and mixed dysrhythmia), and altered duodenojejunal motility.7 Abnormal gastric emptying or electogastrography abnormality is found in up to 70% of children with FD.8,9 Abnormal sensory perception has also been noted in FD. In particular, hypersensitivity to gastric distension, labeled as “irritable stomach syndrome,” has been seen in FD but not in organic dyspepsia and is thought to be akin to rectal hypersensitivity in irritable bowel syndrome — an entity that is often associated with FD.10 Finally, psychosocial factors have a significant impact on FD. The comorbidity between anxiety and FD is high. FD patients with gastric hypersensitivity were noted to have a significant negative correlation between anxiety level and threshold for pain and discomfort.11
A thorough history and examination is useful to screen for organic disease. History of “alarm symptoms” (Table 2) may justify diagnostic testing for organic disease; however, symptoms need to be taken in the context of the whole picture. For instance, nocturnal pain is not necessarily an alarm symptom. In fact, in a technical report, the American Academy of Pediatrics and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Subcommittee for Abdominal Pain concluded that postprandial or nocturnal pain does not help distinguish between organic and functional etiology.1 History of a viral illness may be present in post-infectious gastroparesis, which can present with symptoms of FD.12 A radionuclide gastric emptying test may be helpful in such cases. History of unexplained refractory iron deficiency anemia or first-degree relatives with gastric cancer should raise suspicion for Helicobacter pylori.13,14 The test for initial diagnosis of H. pylori should preferably be histopathology and rapid urease test or culture, and the use of serology either for initial diagnosis or for test of eradication is discouraged.15 Of note, there is inadequate evidence to support a causal relation between H. pylori gastritis and abdominal pain in the absence of ulcer; therefore, abdominal pain alone does not justify testing for H. pylori.15,16 History of severe abdominal pain or recurrent vomiting may prompt consideration of an upper-GI series to rule out an anatomical anomaly or mechanical obstruction, such as malrotation or duodenal web. History of discrete, acute episodic pain associated with food intake or localized to the right upper or periumbilical regions may prompt testing of serum amylase, lipase, and obtaining an abdominal ultrasound. Symptoms suggestive of gastroesophageal reflux disease (GERD) may be treated empirically; however, a pH probe or impedance test may be useful in case of abdominal pain in the absence of classic symptoms of GERD (eg, heartburn, waterbrash). Testing for celiac disease may be considered with positive family history, history of weight loss or stunting, or autoimmune endocrine diseases. Breath hydrogen tests may be used to evaluate symptoms of bloating or pain with or without dairy intake to screen for lactose intolerance or bacterial overgrowth. Table 3 lists potential differential diagnoses for FD.
Alarm Symptoms and Signs in Children with Functional Dyspepsia
Differential Diagnosis for Functional Dyspepsia
Role of Endoscopy
Esophagogastroduodenoscopy (EGD) is helpful in identifying mucosal lesions, including erosive esophagitis, eosinophilic esophagitis, peptic ulcer, and H. pylori infection, among others. However, mucosal abnormalities do not preclude a diagnosis of FD. In fact, mild histologic gastritis or duodenitis without macroscopic lesions on endoscopy, and in the absence of NSAIDs intake, may be consistent with a diagnosis of FD. These findings have been described in asymptomatic adults and in patients with irritable bowel syndrome. The Rome Committee suggests that history of dysphagia or recurrence of symptoms after stopping acid suppression or persistence of symptoms despite acid suppression may prompt an EGD.2 The majority of patients with dyspepsia do not have mucosal lesions on endoscopy. In one prospective study of children with dyspepsia symptoms, 44% had an EGD at a mean of 39 days from initial exam, and 62% of the EGDs were normal.4 Only 9% of the EGDs were notable for H. pylori. This is in contrast to an adult study in which 58% of patients had clinically significant endoscopic findings, and 30% had H. pylori.17 Hence the “test and treat” strategy (performing a non-invasive test for H. pylori and administering treatment), which has been validated in adults, is not encouraged in children.18
Beyond Rome III
Pediatric Rome classification of functional GI disorders is continuing to evolve. The current definition of FD does not specifically include the symptom of nausea, but it can be included under discomfort. Evidence suggests that nausea is a frequent and disabling complaint in children that can be present in up to 60% of children with pain-associated functional GI disease, including FD.19 In the adult Rome III classification, nausea and vomiting disorders is a separate category under functional gastroduodenal disorders. Whether the formation of further categories and subcategories would be helpful is a matter of debate. It is well-known that there is considerable overlap between the various categories of functional GI disorders. One possible approach, which has been described in the literature, is to view some of the categories as part of a broad continuous spectrum. For instance, FD and gastroparesis could be considered to lie in various points along a spectrum ranging from rapid gastric emptying to severely delayed gastric emptying.20 Some of these issues may be addressed in Rome IV, which is in the pipeline.
The Rome criteria provide the framework for making a positive diagnosis of FD. This is a critical step because it helps the patient and the family to shift their focus from pursuing further investigations to treating symptoms and improving quality of life. In patients with mild, intermittent symptoms, reassurance and lifestyle modification may be sufficient. Patients who do not respond to those measures may require medications. The most commonly used first-line medications for dyspepsia are anti-acid therapy and prokinetics. These should ideally be combined with psychological and complementary therapies for a comprehensive, biopsychosocial approach.
Omeprazole was shown in a large, randomized controlled trial in adults to be modestly superior to placebo in the treatment of functional dyspepsia. Both standard (20mg) and low-dose (10mg) therapy was found to be effective in patients with FD, especially those with ulcer-like rather than dysmotility-like symptoms.21 The therapeutic benefit of omeprazole was demonstrated after 4 weeks of treatment. At 3 months following therapy, patients taking omeprazole had fewer days on medication, fewer clinic visits, and higher quality-of-life scores compared to those taking placebo.22 Data from adult studies suggest that proton pump inhibitors (PPI) are more efficacious than histamine antagonists, and that starting empirical therapy with PPI rather than H2 blockers may be more cost-effective.23,24
The other group of medications used in FD is prokinetics. This group includes erythromycin, cisapride, domperidone, metoclopramide, trimebutine, mosapride, and itopride; there are no published studies for the latter two in children, and there are very limited data for the use of the others in the treatment of FD in children. These drugs have been shown to be superior to placebo in the treatment of FD in adults.25 Erythromycin, a motilin receptor agonist, has been found to be effective and safe for use in children.26 Cisapride, which is a 5HT4 agonist, is a powerful prokinetic agent, effective in gastroparesis; however, it carries a black box warning for arrhythmia due to QT prolongation and requires cautious use with close monitoring.27
Cyproheptadine, a serotonin 5HT 2A and 2B antagonist, has been shown to be effective for treating dyspeptic symptoms in children.28 The mechanism of action is thought to be fundic relaxation and improvement in gastric accommodation. It was effective in patients who were refractory to prokinetic therapy. It was particularly effective in treating vomiting that occurred within an hour of ingestion of a meal, but was also helpful in treating nausea, early satiety, and abdominal pain.
There are limited data comparing the efficacy of antisecretory therapy versus prokinetics for FD. A single randomized trial comparing use of mosapride (prokinetic) and lansoprazole found no difference in their relative efficacies.29 Antisecretory therapy is frequently used as first-line when the predominant symptom is epigastric pain syndrome, whereas prokinetics may be used if the predominant symptom is postprandial distress with fullness and early satiety. There is a paucity of literature on duration of therapy with these medications, particularly given that symptoms of FD are chronic.
Tricyclic antidepressants (TCA)
Amitriptyine has been used in the treatment of FD. In a multicenter, randomized clinical trial in children, low-dose amitriptyline (10mg for weight < 35 kg and 20 mg for weight > 35 kg) was not superior to placebo; however, both amitriptyline and placebo had excellent therapeutic responses, underscoring the power of placebo in pediatric functional GI disorders.30 Based on this study, it seems reasonable to reserve TCAs for anxious children with FD who fail non-pharmacological therapy or are unwilling to consider it.
Botulinum toxin A, which has been used for treating spasticity in cerebral palsy, can be injected intrapylorically for treatment of gastroparesis. It has been used in children for treating gastroparesis refractory to medical therapy.31 It was found to be safe and effective in treating symptoms of nausea, vomiting, abdominal pain, and distension. It may be considered in the setting of failed medical therapy, prior to more invasive surgical procedures such as gastrostomy.
There is increasing literature to support the use of non-pharmacologic therapy in pediatric functional GI disorders. Cognitive behavior therapy is useful when there is history of anxiety. Guided imagery and progressive relaxation have been shown to be effective in pain-related functional GI disorders.32 Biofeedback-assisted relaxation training, or BART, is a promising adjunctive tool to medications.33
Dietary Interventions and Supplements
Ginger root and STW (Iberogast) — an herbal preparation containing iberis, peppermint, and chamomile — have been shown in adult studies to be effective for relief of dyspepsia symptoms.34,35 There is limited evidence to support minimizing fatty, gaseous, and spicy food intake.
FD, which is characterized by pain or discomfort of the upper abdomen, may be diagnosed using the Rome III criteria. Several treatment options exist, with emphasis on a comprehensive bio-psychosocial model.
- Di Lorenzo C, Colletti RB, Lehmann HP, et al. Chronic abdominal pain in children: a technical report of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40:249–261. doi:10.1097/01.MPG.0000154661.39488.AC [CrossRef]
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- De Giacomo C, Valdambrini V, Lizzoli F, et al. A population-based survey on gastrointestinal tract symptoms and Helicobacter pylori infection in children and adolescents. Helicobacter. 2002;7:356–363. doi:10.1046/j.1523-5378.2002.00109.x [CrossRef]
- Hyams JS, Davis P, Sylvester FA, et al. Dyspepsia in children and adolescents: a prospective study. J Pediatr Gastroenterol Nutr. 2000;30:413–418. doi:10.1097/00005176-200004000-00012 [CrossRef]
- Caplan A, Walker L, Rasquin A. Development and preliminary validation of the questionnaire on pediatric gastrointestinal symptoms to assess functional gastrointestinal disorders in children and adolescents. J Pediatr Gastroenterol Nutr. 2005;41:296–304. doi:10.1097/01.mpg.0000172748.64103.33 [CrossRef]
- Walker LS, Lipani TA, Greene JW, et al. Recurrent abdominal pain: symptom subtypes based on the Rome II Criteria for pediatric functional gastrointestinal disorders. J Pediatr Gastroenterol Nutr. 2004;38:187–191. doi:10.1097/00005176-200402000-00016 [CrossRef]
- Thumshirn M. Pathophysiology of functional dyspepsia. Gut. 2002;51Suppl 1:i63–66. doi:10.1136/gut.51.suppl_1.i63 [CrossRef]
- Friesen CA, Lin Z, Hyman PE, et al. Electrogastrography in pediatric functional dyspepsia: relationship to gastric emptying and symptom severity. J Pediatr Gastroenterol Nutr. 2006;42:265–269. doi:10.1097/01.mpg.0000189367.99416.5e [CrossRef]
- Riezzo G, Chiloiro M, Guerra V, et al. Comparison of gastric electrical activity and gastric emptying in healthy and dyspeptic children. Dig Dis Sci. 2000;45:517–524. doi:10.1023/A:1005493123557 [CrossRef]
- Mertz H, Fullerton S, Naliboff B, Mayer EA. Symptoms and visceral perception in severe functional and organic dyspepsia. Gut. 1998;42:814–822. doi:10.1136/gut.42.6.814 [CrossRef]
- Van Oudenhove L, Vandenberghe J, Geeraerts B, et al. Relationship between anxiety and gastric sensorimotor function in functional dyspepsia. Psychosom Med. 2007;69:455–463. doi:10.1097/PSY.0b013e3180600a4a [CrossRef]
- Sigurdsson L, Flores A, Putnam PE, Hyman PE, Di Lorenzo C. Postviral gastroparesis: presentation, treatment, and outcome. J Pediatr. 1997;131:751–754. doi:10.1016/S0022-3476(97)70106-9 [CrossRef]
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- Koletzko S, Jones NL, Goodman KJ, et al. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr. 2011;53:230–243.
- Gold BD, Colletti RB, Abbott M, et al. Helicobacter pylori infection in children: recommendations for diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2000;31:490–497. doi:10.1097/00005176-200011000-00007 [CrossRef]
- Thomson AB, Barkun AN, Armstrong D, et al. The prevalence of clinically significant endoscopic findings in primary care patients with uninvestigated dyspepsia: the Canadian Adult Dyspepsia Empiric Treatment — Prompt Endoscopy (CADET-PE) study. Aliment Pharmacol Ther. 2003;17:1481–1491. doi:10.1046/j.1365-2036.2003.01646.x [CrossRef]
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- Kovacic K, Williams S, Li BU, Chelimsky G, Miranda A. High prevalence of nausea in children with pain-associated functional gastrointestinal disorders: are Rome criteria applicable?J Pediatr Gastroenterol Nutr. 2013;57:311–315. doi:10.1097/MPG.0b013e3182964203 [CrossRef]
- Lacy BE. Functional dyspepsia and gastroparesis: one disease or two?Am J Gastroenterol. 2012;107:1615–1620. doi:10.1038/ajg.2012.104 [CrossRef]
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Definition of Functional Dyspepsia
|Diagnostic Criteria* for Functional Dyspepsia:
|Must include all of the following:
Persistent or recurrent pain or discomfort centered in the upper abdomen (above the umbilicus).
Not relieved by defecation or associated with the onset of a change in stool frequency or stool form (ie, not IBS).
No evidence of an inflammatory, anatomic, metabolic, or neoplastic process that explains the subject’s symptoms.
Alarm Symptoms and Signs in Children with Functional Dyspepsia
Persistent right upper- or right lower-quadrant pain.
Gastrointestinal blood loss.
Family history of inflammatory bowel disease.
Involuntary weight loss.
Deceleration of linear growth.
Differential Diagnosis for Functional Dyspepsia
Gastric or duodenal ulcer with or without Helicobacter pylori.
Infection: Giardia, bacterial overgrowth.
Inflammatory bowel disease.
Malrotation with or without volvulus.
Ureteropelvic junction obstruction.