Recurrent abdominal pain in childhood is common, affecting 10% to 15% of school-aged children.1,3 While the majority have functional pain, approximately 10% have an organic etiology.3-5 Children with recurrent abdominal pain demonstrate significant clinical heterogeneity.6 Recent descriptions of recurrent abdominal pain in children have identified three broad subsets of children: (1) those with periumbilical pain, which is usually functional in nature (the term functional implies that there is no structural, infectious, inflammatory, or biochemical cause for the patient's symptoms), (2) those with pain associated with altered bowel habits suggestive of irritable bowel syndrome, and (3) children with dyspepsia. Distinguishing between these groups of patients is important clinically because the evaluation and management may differ. However, it is possible for more than one type of pain to occur simultaneously in an individual patient.
Dyspepsia is denned as pain or discomfort centered in the upper abdomen. Dyspepsia may be associated with meals, nausea, waterbrash, chest pain, belching, postprandial distention, and early satiety. The differential diagnosis of dyspepsia includes gastroesophageal reflux, esophagitis, gastritis, duodenitis, peptic ulcer disease, and Helicobacter pylori gastritis, as well as hepatobiliary and pancreatic disorders. Although only a small percentage of children with abdominal pain require invasive diagnostic tests, the increased use of esophagogastroduodenoscopy in the evaluation of recurrent abdominal pain has allowed the identification of a treatable subset of children with acid-peptic disease whose disease was not identified previously by contrast radiography. This article discusses the pathophysiology, clinical presentation, evaluation, and management of children with dyspepsia due to acid-peptic disease.
Acid-peptic inflammation and intestinal dysmotility are two major pathophysiologic contributors to dyspepsia in children. Although evidence of both may coexist in a given patient, the interaction of acid-peptic inflammation and gut dysmotility is poorly understood.
Intestinal dysmotility is associated with organic causes of dyspepsia such as gastroesophageal reflux, in addition to being implicated in functional dyspepsia. Evidence suggesting that dysmotility is associated with functional dyspepsia includes delayed intestinal transit time observed in children with abdominal pain triggered by emotional stress.7 More sophisticated analyses have described high amplitude duodenal contractions and more frequent migrating motor complex activity with slower propagation velocities in children with recurrent abdominal pain.8 Although dysmotility may cause dyspeptic symptoms in children, a causal relationship has not been firmly established due to the lack of age-matched controls in these studies.7,8
Gastroesophageal reflux also may cause dyspepsia and is associated with altered motility. The distal esophagus is composed of smooth muscle and is controlled by the autonomie nervous system. A peristaltic wave of contraction in the external circular muscle layer generates a mechanical force that propels ingest' ed food from the mouth to the stomach. The lower esophageal sphincter, which is an area of tonically contracted circular muscle, relaxes to allow passage of food into the stomach. The theory that gastroesophageal reflux disease results from a low-resting lower esophageal sphincter pressure is no longer favored by most experts. More recent evidence suggests that patients with gastroesophageal reflux may have abnormal episodes of transient lower esophageai sphincter relaxation, which allow reflux of gastric contents into the esophagus.
The factors that contribute to acid-peptic inflammation in children with dyspepsia are presumably similar to those involved in the pathogenesis of peptic ulcer disease. Acid-peptic inflammation is thought to occur when there is an imbalance between the offensive and defensive factors in the upper gastrointestinal mucosa. The offensive factors include acid, pepsin, medications, infection with H pylori, and possibly bile acids. The defensive factors include the mucus layer, local bicarbonate secretion, and mucosal blood flow.
Gastric Acid Secretion
Gastric acid secretion occurs in three phases: cephalic, gastric, and intestinal. The cephalic phase occurs when the sight, taste, smell, and thought of food stimulates gastric parietal cell acid secretion through vagai pathways. In the gastric phase, the ingestion of food, gastric distension of the fundus, and specific foods stimulate acid secretion. The release of the gastric contents into the small intestine causes gastrin release, which stimulates acid secretion in the intestinal phase. Three secretagogues can stimulate acid secretion from the gastric parietal cell:
* histamine via a paraendocrine pathway,
* acetylcholine via a neuroendocrine pathway, and
* gastrin by an endocrine pathway.
The proton pump (H+/K+-ATPase) is the final common pathway for acid secretion within the parietal cell. A chloride ion is secreted along with each H+ secreted by the proton pump.
Pepsins are enzymes that hydrolyze protein at a pH <5 and are irreversibly inactivated at alkaline pH. Pepsin secretion is stimulated by agents that also stimulate acid secretion. Pepsinogen, the precursor of pepsin, is secreted from the gastric chief cells and is converted to an active form at an acid pH. There are two distinct types of pepsinogen: pepsinogen I and pepsinogen II. Pepsinogen I is the major human pepsinogen found in the chief cells and mucous neck cells of the gastric fundus. Pepsinogen II is produced in the gastric antrum, pylorus, and Brunner's glands of the duodenum, and is often found in increased concentration in the serum of patients with antral gastritis.
Helicobacter pylon infection causes chronic gastritis and is a major contributing factor to the development of peptic ulcers. Helicobacter pylori may colonize any region of the stomach, but the antrum is affected most often, while colonization of the fundus alone rarely occurs. The prevalence of H pylori colonization increases with advancing age and is uncommon in children from developed countries. Helicobacter pylori colonization is increased in African Americans and Hispanics, individuals in underdeveloped countries, and in lower socioeconomic groups. Acute infection with H pylori produces a transient hypochlorhydria, while chronic infection is associated with increased basal and postprandial plasma gastrin concentrations as well as increased gastrin response to gastrinteleasing peptide.9 Furthermore, patients infected with H priori have decreased levels of somatostatin, which inhibits the synthesis and release of gastrin, when compared with uninfected controls subjects.9
Evidence linking H pylori to peptic ulcer disease includes the following:
* eradication of H fryiori alone increases ulcer healing compared to placebo,
* eradication of H pylori combined with antisecretory medications increases ulcer healing compared with antisecretory therapy alone; and
* antagonists to the mechanism of injury of H pylori infection blocks its ulcerogenic effects.
A National Institutes of Health consensus conference on treatment of H pylori recommends eradication in patients with peptic ulcer disease but does not recommend treatment in the absence of an ulcer.
Mucus is secreted by superficial epithelial cells and mucus cells from glands throughout the stomach. Mucus secretion is stimulated by cholinergic agonists, prostagiandins, and cytokines. The thick mucus layer retards acid diffusion from the lumen to the mucosal surface, thus protecting the gastric epithelium from the adverse effects of luminal gastric acid.
Gastric Bicarbonate Secretion
Gastric bicarbonate secretion is stimulated by prostagiandins E2 and F2, cyclic guanosine monophosphate, cholecystokinin, and calcium, and is inhibited by nonsteroidal antiinflammatory drugs or acetazolamide. Bicarbonate secretion at the mucosal surface produces a pH grathent with decreasing acidity on the epithelial cell membrane, minimizing the deleterious effects of acid to the cell and increasing acidity in the gastric lumen, where an acid pH is important in the digestive process.
Many other factors with less clearly defined pathophysioiogic roles are associated with dyspepsia in children. Patients may identify dietary factors in connection with dyspepsia. Caffeine stimulates gastric acid secretion, but has not been proven to play a role in peptic ulcer formation. Alcohol can damage gastric mucosa, leading to gastritis. Medications such as nonsteroidal antiinflammatory drugs, aspirin, and corticosteroids also can cause gastric mucosal damage and gastric ulcers. Cigarette smoking is associated with duodenal ulcers, slows ulcer healing rates, and increases ulcer recurrence. A recent epidemiologie study demonstrated an increased risk of esophagttis in infants and children passively exposed to tobacco smoke.10 Stress is another factor commonly associated with dyspepsia in children, and the contribution of this factor should be considered in the management of these patients.
Recurrent abdominal pain localized to the epigastric region is a symptom of acid-peptic disease and is less likely functional in origin.11 Therefore, the physician evaluating the child with upper abdominal pain should consider esophagitis, gastritis, duodenitis, or peptic ulcer disease in the differential diagnosis. In addition, children with these disorders also may present with periumbilical pain, but usually have associated symptoms that would suggest an underlying acidpeptic disease.
Figure 1. Esophageal pH study in a 7-month-old female. The infant awoke crying after a prolonged episode of acid reflux (arrow) and returned to steep after feeding (open arrow).
The presenting symptoms of dyspepsia vary with the age of the patient. Infants and toddíers may exhibit vomiting, feeding resistance, postprandial "fussiness," unexplained irritability, poor weight gain, or gastrointestinal bleeding. Many of these symptoms also are associated with more common illnesses such as upper respiratory infections or otitis media, and therefore a high index of suspicion is required to diagnose acid'peptic disease in this age group. Figure 1 depicts an esophageal pH tracing in an infant demonstrating a temporal association between gastroesophageal reflux and nocturnal irritability.
The signs and symptoms of older children and adolescents with acid-peptic disease are similar to those associated with dyspepsia in adults. Signs and symptoms typically associated with dyspepsia in children include epigastric tenderness, nocturnal pain that awakens the child from sleep, postprandial pain that occurs 1 to 3 hours after eating, waterbrash ("sour burps"), vomiting, a family history of peptic ulcer disease, weight loss, fecal occult blood, and gastrointestinal bleeding. Symptoms associated with esophagitis, gastritis, duodenitis, or peptic ulcer disease in children are depicted in Figure 2. As shown in Figure 2, epigastric pain, nocturnal pain, postprandial pain, and waterbrash were the most common symptoms in children with acid'peptic disease.11 The presence of fecal occult blood, weight loss, or hematemesis was specific for acid-peptic disease, but occurred less frequently. Therefore, the absence of fecal occult blood or weight loss does not rule out the presence of acid-peptic disease in children.
Interestingly, the incidence of vomiting was similar in children with acid-peptic disease and those with functional abdominal pain, and thus was not a predictive symptom for the presence of an underlying organic etiology in this study.11 However, other studies have found vomiting more frequently in children with suspected acid-peptic disease and no difference in the presence of postprandial pain between children with acid-peptic or functional pain.12 Finally, the presence of periumbilical pain was more common in children with functional pain, although approximately 20% of children with acid-peptic disease reported pain in a periumbilical location.11 All of these patients experienced other dyspeptic symptoms in addition to abdominal pain. Therefore, even if a child complains of periumbilical pain, the clinician should consider possibilities other than functional pain if symptoms associated with acid-peptic disease are present.
Figure 2. Symptoms in 296 children with acidpeptic disease. The percentage of patients with each symptom and abnormal esophagogastroduodenoscopy (EGD) biopsy findings (EGD+) are shown in solid bars; those with normal EGD biopsy findings (EGD-) are in open bars (Abbreviation: FOB=fecal occult blood).
Hyams et al12 evaluated a wide variety of symptoms in children with recurrent abdominal pain to distinguish those that were suggestive of irritable bowel syndrome from those associated with dyspepsia. Pain occurring within 1 hour of awakening, pain radiating from the epigastric region to the chest, and regurgitation were suggestive of acid-peptic disease. In contrast, cramping pain, lower abdominal pain, and increased flatus were reported more frequently in children whose recurrent abdominal pain was associated with irritable bowel syndrome.12 A summary of symptoms suggestive of acid-peptic disease versus those associated with irritable bowel syndrome in children with recurrent abdominal pain is listed in Table 1.
A thorough history and complete physical examination are useful in distinguishing children with functional abdominal pain from those with possible acid-peptic disease who warrant more extensive diagnostic evaluation. As discussed above, the history should include inquiring about symptoms of epigastric pain, nocturnal pain, waterbrash, chest pain, early morning pain, weight loss, hematemesis, or melena. Patients should be asked about the use of medications such as nonsteroidal antiinflammatory drugs or corticosteroids, as well as alcohol or tobacco use. A family history of peptic ulcer disease should be elicited. Dietary history should identify specific foods that produce an exacerbation of symptoms. Unusual emotional stress at home or school and its relationship to symptoms should be a part of the social history.
Due to the wide availability of antacids and overthe-counter H2-receptor antagonists, many children may have been given these agents at home prior to evaluation by a physician. The use of these agents and the degree of response should be included in the patient's history of present illness. Relief of symptoms with antacids or antisecretory agents may indicate acid-peptic disease, but also could represent a placebo response. Finally, the lack of pain relief with antacids or over-the-counter H;-receptor antagonists does not rule out the possibility of acid-peptic disease because these medications may not have been given in adequate doses or frequently enough to be effective.
Symptoms Associated With Recurrent Abdominal PaIn In Children
The physical examination begins with obtaining vital signs, including a comparison of weight and height to previous measurements. Inspection of the oropharynx may reveal dental enamel erosion in children with chronic gastroesophageal reflux. A fundoscopic examination to rule out papilledema should be performed in children with chronic vomiting. Wheezing may be heard on auscultation of the chest in children with bronchospasm associated with gastroesophageal reflux. The abdomen should be palpated carefully in all regions to identify those children with localized epigastric tenderness from those with diffuse, periumbilical, or lower abdominal pain. The fingers should be inspected during examination of the extremities for changes associated with selfinduced vomiting. A careful neurological examination is important in children with chronic vomiting to screen for central nervous system disorders.
Laboratory, radiographie, and other diagnostic tests that may be useful in evaluating the child with abdominal pain are listed in Table 2. The evaluation can be tailored in most children according to the presenting symptoms, thus avoiding unnecessary diagnostic tests. Stool guaiac, complete blood cell count, erythrocyte sedimentation rate, urinalysis, and stool ova and parasite examination are useful screening tests for nearly all patients with recurrent abdominal pain. Children with structural lesions of the upper gastrointestinal mucosa may have mild anemia. An elevated erythrocyte sedimentation rate suggests inflammatory bowel disease or other systemic inflammatory conditions. An abnormal urinalysis may signal an underlying renal disorder. Hypoproteinemia or hypoalbuminemia may be associated with inflammatory bowel disease, or rarely with protein-losing enteropathy in patients with erosive esophagitis. Elevations of serum aminotransferase or amylase concentrations indicate hepatobiliary or pancreatic etiologies of dyspepsia. In patients with these laboratory abnormalities, an abdominal ultrasound is indicated. In the absence of laboratory or physical findings suggestive of hepatobiliary or pancreatic disease, the diagnostic yield of abdominal ultrasound is low in recurrent abdominal pain of childhood.13
Figure 3. Erosive esophagitis diagnosed by esophagogastroduodenoscopy in a 7-year-old female with dysphagia unresponsive to ranitidine therapy.
The clinician often is faced with determining which children should have an upper gastrointestinal series with small-bowel follow through or should be referred for possible esophagogastroduodenoscopy. Factors influencing this decision include the availability of these diagnostic tests and the clinician's suspicion that an upper gastrointestinal mucosal lesion is present. An upper gastrointestinal series with small-bowel follow through is useful in ruling out obstructive lesions in patients with recurrent vomiting and in evaluating the distal small intestine in children with suspected Crohn's disease. However, upper gastrointestinal contrast radiographs are not as sensitive as esophagogastroduodenoscopy in detecting upper gastrointestinal mucosal lesions such as esophagltis or gastritis. Figures 3 through 5 demonstrate examples of conditions diagnosed by esophagogastroduodenoscopy that were not identified on upper gastrointestinal series.
Figure 4. Duodenal ulcer in a 14-year-old male with dyspepsia unresponsive to famotidine therapy.
Generally accepted indications for esophagogastroduodenoscopy in children include evaluation of gastrointestinal bleeding, dysphagia, odynophagia, refusal to eat, persistent chest pain, weight loss, anemia, persistent unexplained vomiting, or investigation of an abnormality present on upper gastrointestinal series. In addition, esophagogastroduodenoscopy may be indicated in children with abdominal pain associated with significant morbidity such as excessive school absenteeism or in children with dyspepsia that persists despite therapy for suspected acid-peptic disease. Esophagogastroduodenoscopy also may be useful in preschool-aged children with persistent abdominal pain and vomiting because functional disorders are less common in this age group.
Other diagnostic tests that may be useful in the evaluation of children with dyspepsia include esophageal pH monitoring and esophageal manometry. Esophageal pH monitoring is almost never required to diagnose reflux but may be helpful in correlating symptoms such as chest pain, wheezing, or coughing with gastroesophageal reflux. Dysphagia, which is the sensation of food being obstructed during passage from the mouth to the stomach, strongly suggests esophageal disease. In patients without a definite structural cause of dysphagia, esophageal manometry may be used to rule out esophageal motor disorders.
Diagnostic Evaluation of Dyspepsia in Children
An important goal in managing children with dyspepsia is to distinguish patients with functional pain from those with acid-peptic disease. If a diagnosis of functional pain is established, reassurance, support, and patient education should be the goals of therapy. Acknowledging that the pain is real and not "all in his or her head" may earn the trust of the patient and develop a foundation for future management. Identifying emotional or dietary factors associated with symptoms is important, as is resumption of normal daily activities, including school attendance.
Therapeutic agents available for treatment of children with dyspepsia due to acid-peptic disease are listed in Table 3. Broad categories of pharmacologie agents prescribed for dyspepsia include antacids, H2receptor antagonists, proton-pump inhibitors, prokinetics, and cytoprotective agents.
Antacids neutralize gastric acidity and are a lowcost, effective means of treating acid-peptic inflammation. Antacids composed of aluminum and magnesium hydroxides or calcium carbonate are used most commonly. Some preparations add simethicone, a surfactant, or alginate, which layers over the air-fluid level in the stomach, either of which may reduce gastroesophageal reflux. For treatment of acid-peptic disease, antacids should be given 1 and 3 hours after eating and at bedtime. Due to the large number of doses required, compliance is a problem in treating acidpeptic disease with antacids. However, antacids may be recommended as adjunctive therapy for relief of symptoms or for empirical treatment of mild symptoms of dyspepsia. A consistent relief of symptoms with antacids may suggest underlying acid-peptic disease for which further diagnostic evaluation or treatment would be considered.
Medications for Acid-Peptic Disease
Antisecretory agents include H2-receptor antagonists and proton-pump inhibitors. As a group, the H2receptor antagonists cimetidine, ranitidine, famotidine, and nizatidine are the most frequently used medications for treatment of acid-peptic disease. These agents are highly selective, reversible, competitive antagonists to the action of histamine on H2 receptors. They decrease both the volume of gastric fluid and the amount of gastric acid secreted. The proton-pump inhibitors, omeprazole and lansoprazole, are irreversible inhibitors of H+/K*-ATPase, an enzyme that is unique to gastric parietal cells. These drugs are potent inhibitors of gastric acid secretion and are used for the treatment of peptic ulcer disease, erosive esophagitis, or esophagitis that is unresponsive to treatment by H2-receptor antagonists. Experience is limited in the use of proton-pump inhibitors in young children.
Sucralfate is a sucrose octasulfate and polyaluminum hydroxide complex that acts as a cytoprotective agent. Sucralfate forms a sticky, viscid gel at a pH <4 and adheres to gastrointestinal epithelial cells and injured mucosa. Even though the pH of the duodenum is >4, the gel formed by sucratfate retains its adherent properties. Sucraífate is used for treatment of duodenal and gastric ulcers, but is less effective than antisecretory agents for management of gastroesophageal reflux.
The prokinetic agents metoclopramide and cisapride are benzamide derivatives. These drugs increase lower esophageal sphincter tone, improve gastric emptying, and stimulate esophageal peristalsis. Metoclopramide may cause central nervous system (CNS) side effects such as drowsiness, dizziness, or extrapyramidal symptoms. Cisapride does not cause CNS side effects, but may cause abdominal cramping or diarrhea. In older children and adolescents, prokinetic agents are useful as adjunctive therapy in treating symptoms of vomiting, dysphagia, or waterbrash, but are less effective than antisecretory agents when used alone.
Figure 5. Candida esophagitis In an immunocompetent 14month-old female with a normal barium swallow; vomiting persisted despite treatment with ranitidine and metoclopramide.
When compared with the number of studies in adults, relatively few studies have reported treatment outcomes of children with acid-peptic disease with this problem. One study evaluated the response to treatment in children with histologie evidence of esophagitis, gastritis, or duodenitis.14 Patients ranged in age from 1 to 18 years (mean: 1 1 years). The clinical presentation of these patients was similar to the symptoms of dyspepsia listed in Table 1 . The abdominal pain resolved in more than 85% of patients following treatment with H2-receptor antagonists (usually ranitidine 4 mg/kg/day up to 300 mg/day or famotidine 1 to 2 mg/kg/day up to 40 mg/day) for 8 weeks. One hundred thirty-one patients responded to therapy, 85 (65%) of whom achieved symptomatic resolution without subsequent relapse, while 46 (35%) experienced a recurrence of symptoms that again responded to therapy with H2-receptor antagonists. During a follow-up period of up to 4 years, 44% of children with esophagitis relapsed, more common than the relapse rate of those with gastritis or duodenitis. It should be noted that patients in this study were a select group with histologie evidence of acidpeptic disease who may have been more likely to benefit from pharmacologie therapy. Other children with dyspepsia may have functional pain and are probably analogous to adults with nonulcer dyspepsia. Nonulcer dyspepsia is a diagnosis of exclusion in patients with upper abdominal pain without upper gastrointestinal mucosal lesions or other structural abnormalities. The benefit of pharmacologie therapy in these patients is unclear.
Studies of adults with nonulcer dyspepsia commonly exclude patients with reflux esophagitis. Adults with gastroesophageal reflux tend to improve with antisecretory therapy in contrast to those with nonulcer dyspepsia. Furthermore, the rate of recurrent symptoms in adults with gastroesophageal reflux is high, reportedly up to 75% in some studies.15 In the study described above,14 the rate of recurrent symptoms in children with esophagitis was much lower than that reported in adults.
Another subset of children with acid-peptic disease that may represent a unique group are those with H priori gastritis. In many North American cities, H pylori infection is found in fewer than 15% of children who undergo esophagogastroduodenoscopy for diagnostic evaluation of recurrent abdominal pain.16 Thus, H pylori infection is not commonly associated with recurrent abdominal pain of childhood, an observation that also has been made by other investigators.17 However, other pediatrie studies report that H pylori gastritis is a cause of recurrent abdominal pain in children even in the absence of peptic ulcer disease.18 There is general agreement that investigation for and treatment of H pylori infection is indicated in children with clearly demonstrable peptic ulcer disease. A large number of treatment protocols have been proposed, many of which appear efficacious. A review of these is beyond the scope of this discussion. The optimum management of H pylori infection in other clinical situations merits further investigation.
The physician treating a child who presents with typical mild symptoms of dyspepsia may consider empiric therapy with antacids or H2-receptor antagonists. Treatment also should include stress management, changes in dietary patterns, and avoidance of foods or medications associated with acid-peptic disease. If the symptoms resolve, the medication may be discontinued after 4 to 8 weeks. If the symptoms recur or if the symptoms persist despite therapy, subspecialty referral should be considered. However, if more severe symptoms such as weight loss or gastrointestinal blood loss develop, subspecialty consultation should be sought at that time.
The management of recurrent abdominal pain in children can be challenging for clinicians. Recognizing children with dyspepsia is important for arriving at appropriate diagnostic and treatment plans. Consultation with a pediatrie gastroenterologist may be helpful in children with atypical presentations and severe symptoms, in patients in whom a diagnosis is not established after initial evaluation, or in those who fail to respond to empiric therapy.
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Symptoms Associated With Recurrent Abdominal PaIn In Children
Diagnostic Evaluation of Dyspepsia in Children
Medications for Acid-Peptic Disease