Peptic Ulcer Disease in Children Gisela Chelimsky and Steven Czinn Pediatrics in Review 2001;22;349 DOI: 10.1542/pir.

22-10-349

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2001 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.

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Article

gastroenterology

Peptic Ulcer Disease in Children

Gisela Chelimsky, MD,* and Steven Czinn, MD

Objectives

After completing this article, readers should be able to:

1. Describe the different mechanisms involved in the pathogenesis of peptic ulcer disease. 2. Recognize the presenting symptoms of peptic ulcer disease and the differential diagnosis of those symptoms in children. 3. Clarify the role of endoscopic procedures in pediatric peptic ulcer disease. 4. Describe the role of Helicobacter pylori in the pathogenesis of peptic ulcer disease. 5. Review the medications and dosages commonly used in the treatment of peptic ulcer disease and H pylori infection in children.

Introduction
During the past decade, it has been estimated that peptic ulcer disease has affected more than 4 million people in the United States annually. For much of the last century, the pathogenesis of this disease was believed to be due to a number of predisposing factors, the most important of which was the hypersecretion of gastric acid. The development of pediatric exible beroptic endoscopes that allowed the gastroenterologist to obtain gastric biopsies and identication of the microorganism Helicobacter pylori have changed our understanding of gastritis in children.

Pathogenesis
Acid-peptic inammation is believed to occur when there is an imbalance between cytotoxic and cytoprotective factors in the upper gastrointestinal tract. The toxic mechanisms include acid, pepsin, medications such as aspirin and nonsteroidal anti-inammatory drugs, bile acids, and infection with H pylori. The defensive or cytoprotective mechanisms include the mucous layer, local bicarbonate secretion, and mucosal blood ow. Acid secretion from the parietal cells can be stimulated by three secretagogues: histamine via the paraendocrine pathway, acetylcholine via the neuroendocrine pathway, and gastrin via the endocrine pathway. Each employs a different mode of delivery to its target, the oxyntic cell. Acethylcholine is released at the vagal cholinergic terminals near the oxyntic cells (or parietal cell). Gastrin is released by the G cells in the antral and duodenal mucosa and is carried by the blood to the oxyntic cells. Histamine is released by mast-like cells of the lamina propria of the oxyntic (acid-secreting) mucosa into the extracellular uid, through which it diffuses to the adjacent oxyntic cells. The nal common pathway for all acid secretion within the parietal cell is the proton pump (H/K ATPase). With each proton (H) secreted into the gastric lumen by the proton pump, a chloride ion also is secreted. The secretion of pepsin, enzymes that hydrolyze proteins, also is stimulated by factors that promote gastric acid secretion. The precursor of pepsin, pepsinogen, is secreted by the chief cells and is converted to the active form at an acidic pH (5). Finally, medications such as nonsteroidal anti-inammatory drugs and acetazolamide inhibit the bicarbonate secretion. The primary mechanism by which the host prevents the development of peptic ulcer disease is secretion of mucus by supercial epithelial cells and mucus cells from glands throughout the stomach. The thick mucous layer retards the diffusion of acid from the lumen to the gastric mucosal surface, thereby protecting the gastric epithelium. In addition
*Department of Pediatrics. Chief, Division of Pediatric Gastroenterology, Department of Pediatrics, Rainbow Babies and Childrens Hospital and Case Western Reserve University, Cleveland, OH. Pediatrics in Review Vol.22 No.10 October 2001 349

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gastroenterology peptic ulcer disease

to secretion of mucus, protection is increased by the secretion of bicarbonate, which produces a pH gradient, with decreasing acidity on the epithelial side that minimizes the deleterious effect of the low pH. The stomach and duodenum produce bicarbonate. The mechanisms involved in bicarbonate secretion include vagal-mediated stimulation as well as HCO3 secretion stimulated by acid in the lumen, both in the stomach and duodenum.

Major and Minor Criteria for the Diagnosis of Dyspepsia

Table 1.

Major Criteria Epigastric abdominal pain Recurrent vomiting (at least 3/mo) Minor Criteria Symptoms associated with eating (anorexia/weight loss) Pain awakening the child at night Heartburn Oral regurgitation Chronic nausea Excessive belching/hiccuping Early satiety Periumbilical abdominal pain Family history of peptic ulcer disease, dyspepsia, or irritable bowel syndrome

Clinical Presentation
Recurrent epigastric abdominal pain is the hallmark symptom of acid-peptic disease, and in many cases, there is a family history of peptic ulcer disease. Other associated but less specic symptoms include nocturnal pain that awakens the child from sleep, postprandial pain, oral regurgitation, and vomiting. Less frequently, the child may present with upper gastrointestinal bleeding, occult blood in the feces, and weight loss. Finally, although primarily associated with functional abdominal pain, periumbilical abdominal pain, when seen with other symptoms, may be a presentation of peptic ulcer disease. Unfortunately, the symptoms described previously may not indicate a specic etiology of acid-peptic disease; they also can result from other medical conditions such as parasitic infections, pancreatitis, Crohn disease, biliary/ hepatic disease, lactose intolerance, or H pylori infection. In this era of medical cost containment, it is critical to develop a systematic approach for the evaluation of a child who has recurrent abdominal pain that can discriminate between functional and organic etiologies. Dyspepsia is a syndrome of nonspecic symptoms related to the upper gastrointestinal tract that are intermittent or continuous for at least 2 months duration. We have developed major and minor criteria that we believe will help the physician determine which child who has symptoms of dyspepsia should undergo further evaluation (manuscript in preparation). Two major and nine minor clinical criteria have been identied (Table 1). A child who has abdominal pain must have a constellation of signs or symptoms that includes either both major criteria, one major and two minor criteria, or four minor criteria to justify an extensive medical evaluation and possible referral to a pediatric gastroenterologist for identication of an organic etiology. A child who has met the criteria for the diagnosis of dyspepsia as dened previously has a high likelihood of having an organic etiology for the abdominal pain. Such children are ideal candidates for referral to the pediatric gastroenterologist.
350 Pediatrics in Review Vol.22 No.10 October 2001

Evaluation
A careful history should focus particularly on symptoms such as epigastric abdominal pain, nocturnal pain, oral regurgitation, heartburn, weight loss, hematemesis, and melena. In addition, a dietary history should be obtained in an effort to identify specic foods that increase the pain (fatty meals, spicy foods, lactose, and caffeine-containing beverages). The child and family should be asked about the use of potentially causative medications (eg, nonsteroidal anti-inammatory drugs, corticosteroids), alcohol, tobacco, and acid-suppressive medications. Many children already are being treated with over-the-counter antacids or histamine2 (H2)-receptor antagonists. It is important to review the doses of acid-suppressive medications being used because a lack of response may be due to inadequate dosing or frequency of administration. On the other hand, relief of symptoms may indicate acidpeptic disease or functional dyspepsia. Finally, particularly in teen-age females, abdominal pain, heartburn, regurgitation, weight loss, vomiting, and hematemesis can be sentinel signs of unsuspected eating disorders.

Physical Examination
The physical examination begins with the vital signs and weight and height. Anthropometric measurements should be plotted on age- and gender-appropriate growth curves, and current parameters compared with previous ones if available. A funduscopic examination should be performed in children whose predominant complaint is emesis. Examination of the mouth and oropharynx may demonstrate the presence of aphthous

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gastroenterology peptic ulcer disease

Additional Diagnostic Studies Based on the Primary Presenting Signs and Symptoms
Table 2.

Symptom/Signs Vomiting Vomiting and abdominal pain Right upper quadrant pain Elevated erythrocyte sedimentation rate, blood in feces, anemia, weight loss Bloating, increased burping, or atus

Test Upper gastrointestinal series Amylase and lipase Liver function tests/ultrasonography of the liver and gallbladder Upper gastrointestinal series with small bowel follow-through and colonoscopy Lactose hydrogen breath test

Condition Evaluated Gastric outlet obstruction, malrotation Pancreatitis Hepatobiliary disease Inammatory bowel disease or other systemic inammatory conditions Lactose intolerance and small bowel bacterial overgrowth

ulcers (in some instances an early manifestation of Crohn disease) or dental enamel erosion, a manifestation of chronic gastroesophageal reux in children. Examination of the lungs can reveal wheezing (bronchospasm can be due to or exacerbated by gastroesophageal reux). The abdomen should be palpated carefully to determine areas of tenderness. The liver span should be measured (to determine hepatomegaly) and the presence of an enlarged spleen documented (portal hypertension). A rectal examination also should be performed to evaluate for perianal disease, a common nding in Crohn disease, and occult blood in feces. The ngers should be examined for clubbing (Crohn disease) and for changes associated with self-induced vomiting.

endoscopy include the evaluation of gastrointestinal bleeding or an abnormality found on upper gastrointestinal radiographic series, odynophagia, refusal to eat, and persistent unexplained vomiting. When an upper endoscopy is performed, biopsies always should be obtained from the esophagus, duodenum, and gastric antrum. If the child already has been treated with H2-blockers or proton pump inhibitors, biopsies of the body of the stomach should be obtained to evaluate for the presence of H pylori. The nding of mild nonspecic inammation in the absence of H pylori infection should allow the physician to diagnose nonulcer dyspepsia if the remainder of the evaluation is unremarkable.

Role of H pylori Infection Laboratory Studies

Laboratory evaluations should be based on the presenting symptoms and ndings on physical examination. The initial evaluation should include a complete blood count with differential count, erythrocyte sedimentation rate, liver function test, measurement of electrolytes, and examination of the stool for ova and parasites. Finally, particularly for females who have abdominal pain, a urinalysis and urine culture should be obtained. Further tests are performed as indicated by the associated clinical symptoms (Table 2). Based on prevalence studies, H pylori is among the most common bacterial infections in humans. In 1982, Marshall and Warren successfully cultured H pylori from the gastric antrum and proved the association of H pylori infection with peptic ulcer disease. H pylori are gramnegative, S-shaped rods that are 0.5 3.0 micrometers in length and produce enzymes such as urease, catalase, and oxidase. H pylori require a microaerobic environment for culture, reecting their environmental niche in the semipermeable mucous layer overlying the gastric epithelium. Although all children infected with H pylori appear to develop chronic-active gastritis, most apparently have asymptomatic infections, which may never lead to clinically evident disease. Only a minority of children develops peptic ulceration or gastric cancer, the more severe manifestations of Helicobacter infection. The method of acquisition and transmission of H pylori is unclear, although the most likely mode of transmission is fecal-oral, which is supported by the nding of viable H pylori in feces. Risk factors, such as minimal
Pediatrics in Review Vol.22 No.10 October 2001 351

When Should Endoscopy Be Performed?

If dyspepsia is diagnosed based on the previous criteria, results of initial screening tests are normal, and the child has no history of hematemesis, melena, or occult blood in the stool, a trial of H2-receptor antagonists may be offered for 2 to 4 weeks. Lack of improvement or inability to wean the medication due to relapse in symptoms is an indication for upper endoscopy. Other indications for

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gastroenterology peptic ulcer disease

education and low socioeconomic status during childhood, inuence the prevalence. The mechanism by which H pylori causes gastric inammation is unclear, but one factor that may account for the gastric damage is the large amount of urease present in H pylori. Urease hydrolyzes urea to ammonia and bicarbonate at the gastric mucosal surface. Ammonia can be directly toxic to epithelial cells, and the concomitant increase in the mucosal surface pH might interfere with gastric epithelial function, such as production of mucus. In addition to urease, the H pylori vacuolating cytotoxin has been the focus of intense investigation for several years. Cytotoxin-producing strains tend to be more virulent than toxinnegative ones. H pylori not only produces chronic active gastritis and duodenal ulcers, but chronic colonization ultimately may predispose an individual to a signicantly increased risk of developing gastric cancer or mucosa-associated lymphoid tissue (MALT) lymphoma. H pylori has been classied as a group I carcinogen by the World Health Organization. The relative risk of gastric carcinoma is 2.3 to 8.7 times greater in infected adults compared with uninfected subjects. However, only 1% of H pylori-infected individuals ever develop gastric cancer. Finally, H pylori is only one of many risk factors in the cascade that leads to gastric cancer and, therefore, does not yet justify the eradication of H pylori in early life. The association of H pylori and recurrent abdominal pain is more controversial. With the exception of one study, there does not appear to be an association between H pylori infection and an increased prevalence of recurrent abdominal pain. Therefore, routine evaluation for H pylori in patients who do not have symptoms of acidpeptic disease is not warranted. There is no clear evidence that treatment of H pylori will alleviate symptoms in children who have recurrent abdominal pain and H pylori gastritis.

rology does not rule out infection in young children. Serology also is not useful for demonstrating successful eradication of H pylori infection. The 13C-urea breath test offers some important advantages over the serologic tests. It is noninvasive, easy to perform, and easy to repeat to evaluate response to treatment. This test measures bacterial colonization in gastric mucosa. It currently is not approved by the United States Food and Drug Administration for the pediatric population.

Recent guidelines for the diagnosis of H pylori infection in children only

recommend endoscopy with biopsy for evaluation of those who have symptoms consistent with peptic ulcer disease.
Recently, guidelines for the diagnosis and treatment of H pylori infection in children were endorsed by the American Academy of Pediatrics and published (Drumm, 2000). Based on the current available data, these guidelines do not recommend the use of serology or urea breath test for diagnosis of H pylori infection in children. The guidelines only recommend endoscopy with biopsy for the evaluation of children who have symptoms consistent with peptic ulcer disease. The purpose of the endoscopy is to identify organic etiologies for the dyspepsia, not simply to screen for H pylori.

Treatment of Acid-Peptic Disease

Treatment and dosing of medications are listed in Table 3. The medications prescribed for acid-peptic disease include H2-receptor antagonists, proton pump inhibitors, cytoprotective agents, and anticholinergic agents. The rst-line drugs used are H2-blockers, and proton pump inhibitors are prescribed when the patient has no response to H2-blockers. Cytoprotective agents are useful if mucosal lesions are present. Anticholinergic medications seldom are used.

Diagnostic Tests for H pylori Infection

Several enzyme-linked immunosorbent assay-based commercial kits that measure anti-H pylori serum immunoglobulin G (IgG) antibody titers are available for adults. The sensitivity and specicity of these tests in children are variable and seem to depend on the test used. Children younger than age 10 years seem to have more false-negative serologies. Therefore, a negative se352 Pediatrics in Review Vol.22 No.10 October 2001

H2-Receptor Antagonists
The most commonly used agents are cimetidine, ranitidine, and famotidine. These agents are highly selective, reversible, competitive antagonists to the action of histamine on H2-receptors. They decrease the volume of gastric secretions as well as the amount of gastric acid

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gastroenterology peptic ulcer disease

Table 3.

Medications Used in the Treatment of Acid-Peptic Disease

Pediatric Dose 20 to 40 mg/kg per day up to 400 mg twice daily 1 to 1.2 mg/kg per day up to 20 mg twice daily 2 to 4 mg/kg per day up to 150 mg twice daily 0.8 mg/kg per day 0.8 mg/kg per day, effective dosage range of 0.3 to 3.3 mg/kg per 24 hr has been reported 40 to 80 mg/kg per day up to 1 g four times/day How Supplied Syrup: 300 mg/5 mL; Tablets: 200, 300, 400, and 800 mg Syrup: 40 mg/5 mL; Tablets: 20 and 40 mg Syrup: 75 mg/5 mL; Tablets: 150 and 300 mg Capsules: 15 and 30 mg Capsules: 10 and 20 mg

Medication H2-receptor Antagonists Cimetidine Famotidine Ranitidine Proton Pump Inhibitors Lansoprazole Omeprazole Cytotoprotective Agents Sucralfate

Suspension: 1 g/5 mL; Tablets: 1 g

secreted. Possible side effects of cimetidine are diarrhea, rash, myalgias, confusion, neutropenia, gynecomastia, elevated liver function tests, and dizziness. Ranitidine may produce headache, gastrointestinal disturbance, malaise, insomnia, sedation, arthralgia, and hepatotoxicity. Famotidine may cause headache, dizziness, constipation, diarrhea, and drowsiness.

gastric secretion but no effect on the cardiovascular system in doses required for the treatment of acid hypersecretion. Imipramine, a tricyclic antidepressant agent that has anticholinergic effects, also has been used to inhibit gastric acid.

Proton Pump Inhibitors

The proton pump inhibitors, omeprazole and lansoprazole, are irreversible inhibitors of H/K ATPase. They are potent inhibitors of gastric acid secretion. Potential side effects include headache, diarrhea, nausea, and vomiting for omeprazole and headache and diarrhea for lansoprazole.

Three Recommended Combination Eradication Therapies for H pylori-associated Disease in Children

Table 4.

Medications Amoxicillin

Dose

Duration of Treatment 14 days 14 days 1 month 14 days 14 days 1 month 14 days 14 days 1 month

Cytoprotective Agents
Sucralfate is a sucrose octasulfate and polyaluminum hydroxide complex that acts as a cytoprotective agent. It forms a sticky gel that adheres to injured mucosa at a pH of less than 4. In the duodenum, where the pH is greater than 4, sucralfate maintains its adherent properties. It is contraindicated in children who have renal failure.

Anticholinergic Agents
Atropine and related anticholinergic agents have been used for decades in the treatment of peptic ulcer disease, but they usually are not effective as single agents. Lowdose anticholinergic agents in adults augment the effect of the H2-receptor antagonists on food-stimulated acid secretion in those who have duodenal ulcers. Piranzepine is a muscarinic antagonist agent that has selectivity for

50 mg/kg per day divided bid Clarithromycin 15 mg/kg per day divided bid Proton pump inhibitor 1 mg/kg per day divided bid Amoxicillin 50 mg/kg per day divided bid Metronidazole 20 mg/kg per day divided bid Proton pump inhibitor 1 mg/kg per day divided bid Clarithromycin 15 mg/kg per day divided bid Metronidazole 20 mg/kg per day divided bid Proton pump inhibitor 1 mg/kg per day divided bid

Pediatrics in Review Vol.22 No.10 October 2001 353

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Treatment of H pylori Infection

Compliance is a very important factor in achieving eradication of H pylori in children. Several regimens have been published, including 1-week therapy with colloidal bismuth subcitrate, clarithromycin, and metronidazole (eradication in 21/22 children [95%]) and 1-week treatment with lansoprazole, amoxicillin, and clarithromycin (eradication rate of 87%). Treatment for 2 weeks with metronidazole, clarithromycin, and omeprazole was successful in 93% of children treated. Although concerns have been expressed about the use of bismuth salts in children, none of the potential side effects has been reported when used for the treatment of H pylori infection. Table 4 summarizes the three recommended eradication therapies for H pylori-associated disease in children.

Suggested Reading
Ashorn M. Diagnosis and treatment of pediatric Helicobacter pylori infection. Are special guidelines needed? Ital J Gastroenterol Hepat. 1997;29:491 494 Black D, Haggitt R, Whitington P. Gastroduodenal endoscopichistologic correlation in pediatric patients. J Pediatr Gastroenterol Nutr. 1988;7:353358

Cadranel S, Bontems P, Snyder J. Consensus for the management of Helicobacter pylori infection in children: still searching for a paradigm. Acta Gastro-Enterologica Belgica. 1998; 61:316 320 Czinn S. Dyspepsia in children. J Pediatr Gastroenterol Nutr. 1993; 17:237238 Debas HT. Peripheral regulation of gastric acid secretion. In: Johnson LR II, ed. Physiology of the Gastrointestinal Tract. 2nd ed. New York, NY: Raven Press; 1986:931945 Drumm B, Koletzko S, Oderda G. Helicobacter pylori infection in children: a consensus statement. J Pediatr Gastroenterol Nutr. 2000;30:207213 Gremse D, Sacks A. Evaluation of dyspepsia. Pediatr Ann. 1997; 26:4:251259 Hua-Xiang X, Talley N. Helicobacter pylori eradication in patients with non-ulcer dyspepsia. Drugs. 1999;5:785792 Hyman P, Hassall E. Marked basal gastric acid hypersecretion and peptic ulcer disease: medical management with a combination H2 histamine receptor antagonist and anticholinergic. J Pediatr Gastroenterol Nutr. 1988;7:57 63 Kato S, Ritsuno H, Ohnuma K, Iinuma K, Sugiyama T, Asaka M. Safety and efcacy of one-week triple therapy for eradicating Helicobacter pylori in children. Helicobacter. 1998;3(4) Ranjan D, Hassall E, Jevon G, Dimmick J. Gastritis and gastropathy of childhood. J Pediatr Gastroenterol Nutr. 1999;29:378 394 Rowland M, Imrie C, Bourke B, Drumm B. How should Helicobacter pylori infected children be managed? Gut. 1999;45(suppl 1):I36 I39

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PIR Quiz
Quiz also available online at www.pedsinreview.org 6. A 6-year-old boy has had intermittent periumbilical abdominal pain for the past 2 months. The pain has awakened him frequently at night and has been associated with nausea and loss of appetite. These ndings are least suggestive of a diagnosis of: A. B. C. D. E. Acid-peptic disease. Biliary tract disease. Crohn disease. Eosinophilic gastroenteritis. Functional abdominal pain.

7. A 9-year-old girl is diagnosed with dyspepsia without hematemesis, melena, or occult blood in the stool. Results of screening tests are normal. The most appropriate next step is: A. B. C. D. E. Esophagogastroduodenoscopy. Trial of omeprazole. Trial of ranitidine. Trial of sulcralfate. Upper gastrointestinal radiographic series.

8. Helicobacter pylori infection in a child is most likely to result in: A. B. C. D. E. Chronic active gastritis. Duodenal carcinoma. Gastric carcinoma. Nonulcer dypepsia. Peptic ulcer.

9. According to the American Academy of Pediatrics, H pylori infection in children is diagnosed most accurately by: A. B. C. D. E. Biopsy. Hydrogen breath test. Serum immunoglobulin G (IgG) antibodies. Serum IgM antibodies. Urea breath test.

10. Triple therapy recommended for childhood H pylori infections always includes: A. B. C. D. E. Aminoglycosides. Beta-lactams. Histamine2 blockers. Macrolides. Proton pump inhibitors.

Pediatrics in Review Vol.22 No.10 October 2001 355

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Peptic Ulcer Disease in Children Gisela Chelimsky and Steven Czinn Pediatrics in Review 2001;22;349 DOI: 10.1542/pir.22-10-349

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