Peptic Ulcer Disease

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Peptic Ulcer Disease in Children ]oyce D. Gryboski, MD*

Since the advent of endoscopy, peptic ulcer disease in children is being diagnosed with increasing frequency. Estimates of ulcer frequency in children seen at large centers have doubled or tripled from the earlier reports of one to two per year. 2~ With the frequent use of pharmaceutical and particularly nonsteroidal anti-inflammatory agents, the number of children with secondary gastritis and ulcers has risen dramatically. GENETICS AND HEREDITY A history of peptic ulcer disease is present in families of 20% to 50% of adult patients and in 33% to 62% of those of children. 8. 9. 2.5. 51. 79. 80. 85 Genetic studies suggest higher heritability (0.91) in children than in adults (0.37).59 In one study of 50 children, 25% had an affected first degree relative in comparison to 8.7% in control families. 97. 98 Generally, fathers (32.6%) are affected more often than mothers (8.7%), siblings, or grandparents (10.2%). Concordance is higher for monozygotic (50%) than for dizygotic twins. 36. 9:3 As in the adult, there is an increased incidence in those with blood group O. However, children with ulcer do not have an increased number of salivary nonsecretors. 60 Genetic heterogeneity has been suggested in patients with peptic ulcer disease since it has been associated with some inherited disease states or with increases in certain biochemical markers. 95. 96 One study of early-onset duodenal ulcer patients with a strong family history of ulcer has identified two groups of patients: one with a normal postprandial gastrin response and increased maximal acid output, and the other with increased postprandial gastrin, but normal maximal acid output. 69 Other studies have identified elevated pepsinogen I values in families with ulcer disease and note that levels elevated above 130 f.Lg/L are helpful in predicting members who are at particular risk for developing ulcer. 52. 103 In a study of children with duodenal ulcer and their parents, 6 of 14 children had increased pepsinogen *Professor of Pediatrics, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut

Medical Clinics of North America-Vo!' 75, No. 4, July 1991

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I (>90 ng/mL) and all had at least one parent with similarly elevated levels (only two had ulcers).sl Of eight children with normal levels, parents of four had an ulcer history. The study also separated children into two groups and suggested those with hyperpepsinogenemia inherited it as an autosomal dominant trait. However, the data in a study by Tam do not document such clear-cut inheritance; although hyperpepsinogenemic patients have hyperpepsinogenic parents, the reverse is largely, but not always so. He, therefore, suggests autosomal dominant inheritance in association with incomplete penetration. 103

PSYCHIATRIC FACTORS Emotional stress of some form is identified in up to 39% of children with peptic ulcer disease. 66 Several studies have examined the psychologic profiles of children with duodenal ulcer. Many children were described as quiet, intelligent, overachieving, but passive with underlying anger, frustration, and hostility. Many interacted poorly with family and peers. Others have identified in these children feelings of inadequacy, oven-eliance, usually upon the mother, and a fear of loss or separation from an important person in the child's life.102 In two other reports, loss or separation of an important figure has been stressed as a precipitating factor in the development of ulcer symptoms. I. 115 The role of stress impacted upon this author when caring for a 20-year-old man with Down's syndrome who suHered upper gastrointestinal bleeding 3 weeks after being transferred from sanding chair rungs in a workshop to a supervisory position.

GASTRIC SECRETION Although the gastric contents of the neonate are alkaline, these become increasingly more acid during the first hour of life, with pH falling from 3.6 to 2.5.10.37.110 Studies have shown gastric hyposecretion during the first 5 hours, with attainment of levels seen in older children by 6 to 8 hours of life. ~o In a few infants, achlorhydria or hypochlorhydria is noted. By 48 hours, the gastric pH varies between 3 and 1, but eventually stabilizes at 3.2. Miller, in a longitudinal study of gastric acidity, noted a gradual decrease in pH from birth to 10 days, stability for 3 to 4 weeks, and thereafter a gradual increase in acidity.74 Studies of histamine stimulation further confirm a period of early decreased acidity. One-third of premature infants have alkaline gastric contents for 6 to 12 hours, and one-fifth do not produce acid for 10 days.s. 54.114 The majority, however, reach maximal gastric acidity by 4 days, with acidity decreasing gradually over the next 4 weeks. Cord arterial and venous gastrin levels are elevated above those of the mother, having a mean value of 135 pg/mL, with 13% being greater than 200 pg/mL. ~1 Cord gastrin levels have not shown any correlation to the type of delivery or Apgar score of the infant, although they are highest in infants born to brothers with sickle cell anemia. l8 In contrast to the adult,

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gastrin levels do not decrease after fasting more than 8 hours. Levels gradually decrease to 76 to 155 pg/mL between 3 and 5 hours, to 1.51 pg/ mL between 1 and 3 days, and to 101 pg/mL between 1.4 and 22 months, although they remain higher than those of the adult throughout this period. Although plasma pepsinogen is elevated in the neonate and then falls, pepsin is present in gastric secretions in only minute amounts. Both increase during infancy and childhood, but do not reach adult levels until puberty.3 1i2 Therc are limited studies of gastric secretion in inf~mts and children. In one large study by Agunod et a1,3 output of hydrochloric acid, pepsin, and intrinsic factor is low on the first day, increases until the third week, declines briefly between 3 and 4 weeks, and thereafter rises gradually. Basal and pentagastrin-stimulated secretion in 1- and 2-day-old infants shows mean volumes of 7 and 6.9 mLlhour, basal acid output (BAO) of 0.1 and maximal acid output (MAO) of 0.12 and 0.13 mLlkg/hour. 41 , 44 Stimulation does not increase gastric secretion significantly beyond basal levels until 3 months of age. Gastric output correlates best with age, being 0.0.31 mEq/kg/hour at 1 month and 0.122 mEg/kg/hour at 3 months. After that age it best correlates with weight, as shown in a study of 10 children 21 months old; the ~AO was 0.88 in small children, 1.62 in medium-weight children, and 2.02 mEq/kg/hour in large-weight children. 31 Studies of older children 3 months to 12 years old show maximal acidity to increase from 0.239 to 0.262 mEg/kg/hour. 39 , 40, 6,5, 94 Gastric secretion studies show increased MAO in most children with peptic ulcer disease, but there is considerable overlap in values from patients and from normal children, 17, 19, ,0, 77. 94 Although increased MAO often portends a poor prognosis, it does not always correlate with disease severity. Increased BAO (64 ± 20 and 80 ± 10 /-lEg/kg/hour, as compared with normal values in childhood of 35 ± 10 and 40 ± 10 /-lEg/kg/hour) is more unusual in children, but it has been reported in three children 8, 11, and 15 years old. 58, 59, 106 In those children, symptoms were unresponsive to cimetidine or ranitidine. The basal acid hypersecretion was sensitive to atropine in two, and they had symptomatic response after addition of isopropamide to the therapeutic regimen, Mean fasting gastrin values in children with duodenal ulcer are 60.4 ± 9,7 pg/mL compared with normal control values of 3.8 ± 4.2 pg/mL, with stimulated values rising to 140 pg/mL. 1b , ,0 Although increased gastric emptying has been demonstrated in some adults with duodenal ulcer, studies have shown no difference in gastric emptying in children with ulcer compared with normal children. 10, SYMPTOMS The symptoms of peptic ulcer vary with the age of the child, becoming more specific in adolescence. 34, 42, 48, ,(;, 100 Primary peptic ulcers in children under 6 years are usually gastric and aflect boys and girls equally. 25, 85 Most are located in the antrum. In the neonate, the majority of ulcers are due to stress, but some are believed to

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be primary and to have no identifiable causc. Nonspecific symptoms such as vomiting or feeding difficulties often herald the onset, but the first sign may be upper gastrointestinal hemorrhage or perforation, usually along the greater curvature of the stomach. 2. 7. 27. 62. 67 Most specialists have encountered an infant who has not responded to medical management and who at surgery is fClUnd to have a large posterior duodenal ulcer that has eroded into a vessel. \Ve have encountered several infants 1 to 4 months old with a pyloric channel ulcer associated with projectile vomiting resembling that of pyloric stenosis. Toddlers and young children often complain of generalized abdominal, periumbilical, or, rarely, right lower quadrant pain. 49 . 50 The pain may occur in early morning, during the day, or at night and is not usually related to eating or fasting. In some children, the first sign may be the sudden onset of upper gastrointestinal bleeding manifest as hematemesis or hematochezia. '3 After 6 years, the majority of ulcers occur between 10 and 21 years and are seen more often in boys by a ratio of nearly 4 to 1. 6], 73 In a large study of llO children with duodenal ulcer, the mean age at diagnosis was 11.3 years, with 46% having symptoms before 10 years and 15% before 6 years of age. 78 Pain is more typically localized to the epigastrium and is described as sharp or gnawing. 1I3 It may be continuous or intermittent. It may awaken the child at night from sleep or in the early hours of the morning. Whereas 61 % of children with ulcer report nocturnal pain, only 7% of those with functional pain do SO.6 Pain often is reported to occur an hour or so after meals and is relieved by eating. Some children report an accentuation of pain with eating. A few may have only mild discomfort until they develop syncope from unrecognized anemia. In one surgical series, 49% of 50 patients had no history of pain until presentation, when 29 had bleeding, 15 had perforation, and 2 had gastric outlet obstruction. 107 Physical examination in the majority of patients reveals tenderness in the epigastrium or toward the right of the midline. DIFFERENTIAL DIAGNOSIS Numerous disorders can simulate the symptoms of peptic ulcer (Table 1). Infectious diseases include Helicobacter pylori infection, giardiasis, and even pneumonia. Gastritis and distal esophagitis, pancreatitis, and eosinoTable 1. Differential Diagnosis of Upper Abdominal Pain Gastritis Peptic ulcer Duodenitis Esophagitis Recurrent abdominal pain of childhood Giardiasis Eosinophilic gastroenteritis Pancreatitis

Biliarv tract disease Renal disease pyelonephritis ureteropelvic junction stricture Inflammatory bowel disease involving transverse colon Pneumonia Spinal cord lesion

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philic gastroenteritis may cause epigastric pain. Biliary tract disease and renal disease, particularly ureteropelvic junction stricture and high retrocecal appendix, are more often associated with right upper quadrant pain. Less common causes are spinal cord lesions, Henoch-Schonlein purpura, diabetes, and colitis involving the transverse colon. Recurrent abdominal pain of childhood is a major syndrome to be difFerentiated from peptic disease. (j. 82. 83 The adage "the closer the pain to the umbilicus, the less likely to identify an organic cause" applies in children. This type of pain is seen in the child who points directly to the umbilicus or draws a large circle about it. There is no documented weight loss or vomiting. The child may smile through the examination while describing pain or lie in apparent discomfort with eyes closed, cringing to abdominal palpation. A good differentiating sign in such patients is remaining exquisite tenderness when the abdomen is palpated and the head flexed to the chest. In such situations, one is actually palpating a tightened rectus and the pain of intra-abdominal origin should be decreased. Although most children probably deserve one good radiologic examination of the upper gastrointestinal tract and small bowel, time is well invested in searching out school difficulties or problems within the home. Only weeks later may the physician be told of family separations or losses, sexual abuse, or school failures. Since ulcer disease is more frequent in older children, Nord recommends endoscopic examination of the adolescent before making a diagnosis of recurrent abdominal pain. S2. 8:3 DIAGNOSIS Endoscopic examination is the most accurate method of establishing the diagnosis of peptic ulcer and can be performed safely even in the infant. Active bleeding may obscure an ulcer crater, and re-examination after the acute stage may be necessary in some children. 4. 53. 75 Radiologic examination will not detect superficial ulcerations and may miss a true ulcer. 101. 108 Conversely, barium trapped in a gastric or duodenal fold may give the appearance of an ulcer. In one study of symptomatic children, radiologic examination identified peptic ulcer in 47%, although the diagnosis was established in 88% by endoscopic examination.109 However, endoscopy is not considered necessary if radiologic studies demonstrate an obvious crater with radiating folds. Deformity of the pylorus or bulb, although suggesting an ulcer, does not prove it. Endoscopy is indicated for those symptomatic children in whom radiologic findings are negative or equivocal, and when used selectively it has a high positive yield. PEPTIC ULCER AND DISEASE Peptic ulcers may occur in association with specific disease states. Children with cystic fibrosis are at risk because of decreased bicarbonate secretion into the duodenum and in some cases because of gastric hypersecretion. Children with systemic mastocytosis or mastocytoma with attendant

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histamine release may develop duodenal ulcers. Duodenal ulcer with normal gastric secretion has been reported in patients with sickle cell anemia. 91 Although rare in the child, Zollinger-Ellison syndrome may present with either peptic ulcer disease or diarrhea. A 1982 review of 28 children in the Zollinger- Ellison registry followed up to 21 years suggested that malignant gastrinomas in children are slow-growing and compatible with life. 117 Six of seven children with less than total gastrectomy (before use of H 2 -antagonists) died from complications of gastric hypersecretion and tumor growth; 16 had total gastrectomy, with one dying from tumor extension. Tumors were located primarily in the pancreas, although two involved the stomach wall. In 12 children, a primary tumor site was not identified, although 14 children had evidence of metastatic disease. Gastrinoma has been identified in the kidney of one child having the syndrome. A pseudoZollinger-Ellison syndrome has occurred in a 7-year-old boy with antral Gcell hyperplasia who was later found to have Helicobacter pylori infection. 119 At our center, G-cell hyperplasia is being found in two to three children per year who are evaluated for upper abdominal pain.

DRUG-RELATED ULCER All drugs that cause peptic ulcer or gastritis in the adult do so in the child, with aspirin and other nonsteroidal anti-inflammatory agents being the major offenders. Infants with pulmonary hypertension treated with tolazoline (which stimulates histamine release and gastric secretion) must be monitored carefully for gastrointestinal bleeding due to ulcer. 12

STRESS ULCERS Stress ulcers occur in infants and children. In infants, they are most often related to traumatic delivery, respirator or cardiac distress, sepsis, hypoglycemia, or dehydration. In older children, ulcers are caused by trauma or severe, life-threatening illness. As in adults, such ulcers are asymptomatic until presentation with hemorrhage or perforation and carry a high mortality rate. 2. 7 In a 1984 review by Kumar et aI, who reviewed the disease in 54 children, 67 30 presented with hemorrhage, 8 with perforation, 6 with shock, and only 5 with pain. Mortality rates have varied from 10.4% to 77.7%. Stress ulcer occurs equally in males and females and some studies show a predominance in the stomach, whereas others report an equal distribution. Although usually singular, they may be multiple. The Cushing ulcer is associated with elevated intracranial pressure and occurs at about 1 week after trauma. 99 The Curling ulcer, which is associated with burns, occurs in 0.05% to 13% of such patients. 10. 28 The diagnosis of stress ulcer is to be suspected in any critically ill child who has evidence of blood in nasogastric return or in the stool. Unfortunately, the diagnosis is often made by the radiologic demonstration of free air in the abdomen after perforation has occurred.

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In a study involving cimetidine treatment, Lacroix et al GK randomized 40 children, mean age 1.5 years, admitted to a pediatric intensive care unit. Although drug decreased the gastric pH, it did not prevent upper gastrointestinal bleeding, which occurred in nine of 19 of treated and in eight of 21 non treated children. In our experience, sucralfate is an effective agent for the treatment of stress ulceration.

COMPLICATIONS The major complications of peptic ulcer are perforation and hemorrhage. Gastric outlet obstruction is recognized in Indian children, and one 9-year-old has been reported with outlet obstruction. 43 Failure to thrive and malabsorption often respond to medical therapy. 8. 82

PROGNOSIS Gastric ulcers do not tend to recur. Primary duodenal ulcer is a chronic disease that carries a 50% to 71% incidence of upper gastrointestinal symptoms in adult life. ZO. 29. 90. 116 In earlier studies, 4% to 43% have had gastrointestinal bleeding and one-third have required surgical intervention. 20 21. 90. 116 Endoscopy has identified relapse in eight of nine children within 4 years of diagnosis. Children with gastric ulcer are not likely to suffer recurrence after healing. 85 In a long-term review of 19 children followed for 14 to 27 years, Murphy, Eastham, et aF9 found a high incidence of morbidity in adult life. Six (31 % of patients) were well, 10 (53%) no longer had recurrent pain, but four (21%) had a persistently proven ulcer. More than half of the patients had experienced serious complications with eight (42%) having gastrointestinal bleeding; one, perforation; one, pyloric stenosis; and one, a penetrating ulcer. A 20-year review of 31 children by Collins et aPO showed only three to have a proven recurrence of ulcer after 16 years. In attempting to predict course by chemical markers, Odera et al 86 found that initial serum mean pepsinogen I levels in 30 children with ulcer were not significantly greater than in controls (67.5 versus 58.4 ng/mL). However, children who relapsed after discontinuing ranitidine therapy had significantly higher pepsinogen I levels (83.6 ng/mL) than those who did not relapse (57.2 ng/mL) or controls.

TREATMENT As in the adult, antacids may be used but problems arise with the need to take medications during school. If used, we recommend administration midmorning, midafternoon, and before bedtime. Magnesiumcontaining antacids tend to cause diarrhea, whereas aluminum-containing ones are constipating. Alternating them will often control these complications. Anticholinergics are not particularly useful, although a few children

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with symptoms refractory to ordinary Hz-receptor antagonists and showing increased BAO have improved with their administration. To avoid side effects (dry mouth, constipation, sleepiness, tachycardia, blurred vision), a new medication, pirenzepine, which has effects localized to secretory tissue, may be tried. H 2 -receptor antagonists are the preferred treatment in children. We favor ranitidine because it rarely competes or affects metabolism of other drugs. Along with complications in the hepatic P450 system, there have been reports of treatment failures with cimetidine in children. Thompson et al found no improvement in five of 16 children. A few infants have developed cholestasis and cerebral symptoms. 13.45.71. III The general doses used in children are cimetidine, 20 to 40 mg/kg/day in four divided doses; and ranitidine, 2 to 4 mglkg/day in two divided doses. Tolerance may develop within several weeks of H 2 -antagonist therapy in some patients and increased frequency of administration of drug may be necessarv. ,,7 We' have had little experience with famotidine and nizatidine, both potent Ilz-antagonists, in children. Sucralfate'is eflective in relieving ulcer symptoms and may be used with an Hz-receptor antagonist. The two drugs must be given at least 1 hour apart. Sucralfate has been particularly helpful in our hands in stressed children who develop gastrointestinal bleeding and in those with rheumatoid arthritis who become symptomatic while taking nonsteroidal antiinflammatory drugs. There are as yet no useful studies using prostaglandin E2 analogs in children. In a review of response to therapy, Chiang et al found good shortterm response, whatever the agent, with 83% of children with ulcer responding to antacid alone, 94% to sucralfate, and 87% to H 2-antagonists. However, 1 year later, 12% of the sucralfate group, 28% of the H 2 antagonist group, and 70% of the antacid-treated group had recurrent disease. l6

SURGICAL INTERVENTION Immediate surgery is necessary in children with perforation or hemorrhage which cannot be controlled by medical management. For the very few with unremitting symptoms and those with gastric outlet obstruction, vagotomy and pyloroplasty remain the procedures of choice. 82. 92

HELICOBACTER PYLORI-INDUCED DISEASE H elicobacter pylori is now an accepted cause of gastritis and peptic ulcer disease in children. 13.22.24.30,32,47,53,64.81,89,118 It has even been reported as a cause of transient protein-losing enteropathy. 56 The infection is most

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common in underdeveloped countries, where more than two-thirds of children are estimated to have had at least onc infection by 5 years of age. 14 In the United States, H. pylori is probably present in 5% of children under 9 years and in England in 5% of those 5 to 16 years old. H . 63 The history is usually one of epigastric pain in 83%, vomiting in 51 %, and hematemesis in 17%.64 The duration of symptoms is 1 to 6 months with a mean of 3 months. Radiologic examination may be indeterminate, show hypertrophic folds in the antrum or body of the stomach, or reveal gastric or duodenal ulcers. Pathologic changes resemble those seen in the adult, with superficial antral inflammation and mixed inflammatory cell infiltrate. Nodularity with lymphoid hyperplasia and decreased polymorphonuclear response have also been reported. 11. 26, 81 All studies stress the lack of correlation between endoscopic appearance and histology and the frequency of finding histologic gastritis in biopsies of normal-appearing antrum. In a retrospective review by Drumm et al of 53 children who underwent panendoscopy for upper gastrointestinal complaints, antral biopsy specimens of 19 showed inflammation. Six of these had H. pylori infection, and all had primary gastritis. 29 Hclicohactcr pylori was not found in those with secondary gastritis due to Crohn's disease, drug ingestion, eosinophilic gastroenteritis, or only duodenitis. The same authors found antral gastritis in a prospective study of 71 children with upper gastrointestinal complaints. Seven of 10 with primary gastritis and none with secondary gastritis or normal histology showed H. pylori infection. Five children had duodenal ulcers associated with antral gastritis, but duodenal tissue did not contain H. pylori. 31 Although the above studies suggest that H. pylori is specific to primary gastritis, it has been identified in tissue from one patient who was taking nonsteroidal anti-inflammatory drugs III and in one of our patients with gastric Crohn's disease. The relationship between true peptic ulcer and H. pylori is less convincing. Using serologic testing, Eastham et al found that 25 of 100 children ~ith elevated titers to H. pylori had gastritis and 12 had duodenal ulcer.J4 3; Only half of those with duodenal ulcer had associated gastritis. In a 7 -year review by Kilbridge et aI, 80% of children with duodenal ulcer had associated antritis and all of those had H. pylori infection. 64 However, the majority (84%) of children with gastric ulcer showed no evidence of H.

pylori.

More recently, serologic techniques have been used to identify children with H. pylori infection. However, these have drawbacks in that they may not differentiate recent from earlier infection or the antibody response may not have developed in those acutely infected. 23, 63, ][2 Despite these problems, there seems to be a good correlation between the presence of antibody and Hclicohactcr colonization of the mucosa. Tolia et al compared the enzyme-linked immunosorbent assay (ELISA) test using extract antigen, the rapid urease test, and histologic examination in 47 children and found H. pylori infection in 23% of those with dyspeptic symptoms. 1l2 They believed the combination of ELISA and urease test to be superior to histologic examination. In a prospective study of 60 children with chronic abdominal pain, Glassman et al correlated histologic examination, culture, and urease

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production test with IgA and IgG antibodies to H elicohacter. 46 Thirty-four (56%) children had histologic gastritis, with eight (13.3%) having Helicohacter by at least one criterion. Of the eight children, seven had IgG and six had IgA antibodies. . Several investigators have found that treatment with H 2 -antagonists alone will eliminate symptoms in more than half of affected children and therefore reserve therapy with bismuth and antibiotics for those who have not responded after 4 weeks of therapy. 22.24 Although amoxicillin alone has been shown to clear the infection in 85%, three-quarters of those children will suffer a relapse after 3 months. 87 Conventional therapy using bismuth and amoxicillin for 6 weeks has shown short-term clearance of the organism and improvement in gastritis in three-quarters of the patients studied 1 week after treatment. 3 ! Another study of 14 children examined 1 to 6 months after treatment showed that although two-thirds had no infection, gastritis was still present. 26 The combination of amoxicillin and tinidazole for 6 weeks has resulted in clearance of the organism in 94%, resolution of gastritis in 84%, and improved gastritis in 16% at 1 month. 88 Serum IgG antibodies, pepsinogen 1, and gastrin levels decreased with clearance of the organism, and of those assessed at 6 months, IgG antibody proved a good indicator of clearance or recurrence. 88

SUMMARY Primary duodenal ulcer disease occurs in children of all ages, but is most often seen in those over 10 years. As in the adult, it often pursues a chronic course. Primary gastric ulcer is seen in children under 6 years, is more unusual, and does not tend to recur. Stress ulcers are seen most often in infants and in critically ill children and are asymptomatic until the complications ofhemorrhage or perforation appear. Drug-related ulcers are being seen more frequently as the use of nonsteroidal anti-inflammatory agents increases. With the use of new therapeutic agents, management has been simplified and surgical intervention has become a rarity. Helicobacter pylori is now a recognized cause of antral gastritis and ulceration in the child.

REFERENCES 1. Ackerman SH, Manaker S, Cohen Ml: Recent separation and the onset of peptic ulcer disease in older children and adolescents. Psychosom Med 43:305-310, 1981 2. Adeyemi SO, Ein SH, Simpson JS: Perforated stress ulcer in infants. Ann Surg 190:206-

208, 1979

3. Agunod M, Yamaguchi !\i, Lopez R, et al: Correlative study of hydrochloric acid, pepsin and intrinsic factor secretion in newborns and infants. Am J Dig Dis 14:400-414, 1969 4. Ament ME, Christie DL: Upper gastrointestinal fiberoptic endoscopy in pediatric patients. Gastroenterology 72:1244-1248, 1977 5. Ames MD: Gastric acidity in the first ten days of life of the prematurely born baby. Am J Dis Child 100: 122-126, 1960 6. Apley J: The Child With Ahdominal Pain, ed 2. Oxf()[d, Blackwell Scientific Publications, 1975, pp 1-81

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7. Bell MJ, Keating JP, Ternberg JL, et al: Perforated stress ulcers in infants. J Pediatr Surg 16:998-1002, 1987 8. Benkov KJ, Becker H, Rose J, et al: Failure to thrive associated with chronic ulcer disease in a 9-year-old boy. Am J Gastroenterol 80:524-526, 1985 9. Blodgett MD, Morris N, Lurie HJ: Children with peptic ulcers and their families. J Pediatr 62:280-281, 1963 10. Bruck HM, Pruitt BA: Curling's ulcer in children: A 12-year review of 63 cases. Trauma 12:490-496, 1972 11. Bujanover Y, Konikoff F, Baratz M: Nodular gastritis and Helicobacter pylori. J Pediatr Gastroenterol Nutr 11:41-44, 1990 12. Butt W, Auldist A, McDougall P, et al: Duodenal ulceration: A complication oftolazoline therapy. Aust Paediatr J 22:221-223, 1986 13. Cadranel 5, Goossens H, DeBoeck M, et al: Campylobacter pyloridis in children. Lancet 1:735-736, 1986 14. Calva H, Ruiz-Palacios GM, Lopez-Vidal AB, et al: Cohort study of intestinal infection with Campylobacter in Mexican children. Lancet 1:503-506, 1988 15. Chhattriwalla Y, Colon AR, Scanlon JW: The use of cimetidine in the newhorn. Pediatrics 65:301-304, 1980 16. Chiang BL, Chang MH, Lin MI, et al: Chronic duodenal ulcer in children: Clinical observation and response to treatment. J Pediatr Gastroenterol Nutr 8:161-165, 1989 17. Christie DL, Ament ME: Diagnosis and treatment of duodenal ulcer in infancy and childhood. Pediatr Ann 5:672-677, 1976 18. Christie DL, Ament ME: Gastrin response to a protein meal in children with duodenal ulcer. Pediatr Res 10:353, 1976 19. Christie DL, Ament ME: Gastric acid hypersecretion in children with duodenal ulcer. Gastroenterology 71:242-244, 1976 20. Collins JSA, Glasgow JFT, Tronton TG, et al: Twenty-year review of duodenal ulcer. Arch Dis Child 61:407-408, 1986 21. Curci MH, Little K, Sieber WK, et al: Peptic ulcer disease in childhood reexamined. J Pediatr Surg 11:329-33.5, 1976 22. Czinn SJ, Speck WT: Campylobacter pylori: A new pathogen. J Pediatr 114:670-672, 1989 23. Czinn 5, Carr H, SchefRer L, et al: Serum IgA antibody to the outer membrane proteins of' Campylobacter pylori in children with gastroduodenal disease. J Infect Dis 1.59:.586.589, 1989 24. Czinn SJ, Dahms BB, Jacobs GH, et al: Campylobacter-like organisms in association with symptomatic gastritis in children. J Pediatr 109:80-83, 1986 2.5. Deckelbaum HJ, Roy CC, Lussier-Lazaroff J, et al: Peptic ulcer disease: A clinical study in 73 children. Can ~Ied Assoc J 111:22.5-228, 1974 26. DeGiacomo C, Maggiore G, Licardi G, et al: Effects of' antimicrobial treatment of Campy/obacter pylori-associated gastritis in children. Gastroenterology 9.5:1699, 1988 27. Denavit MF, Guerin J, Caldera R, et al: Ulcere duodenal chez un nourveauive. Ann Paediatr 2.5:49.5-498, 1978 28. Dimick S: Sixth National Burn Seminar: Gastrointestinal ulceration: Bleeding in children. J Trauma 7:119-120, 1967 29. Drumm B, Hhoads JM, Stringer DA, et al: Peptic ulcer disease in children: Etiology, clinical findings and clinical course. Pediatrics 82:410-414, 1988 30. Drumm B, Sherman P: Gastritis in childhood. In Walker WA, Durie P, Hamilton JH, et al (eds): Pediatric Gastrointestinal Disease. Philadelphia, BC Decker, 1991, pp 426437 31. Drumm B, Sherman P, Chiasson D, et al: Treatment of Campylobacter pylori-associated antral gastritis in children with bismuth sub salicylate and ampicillin. J Pediatr 113:908912, 1988 32. Drumm B, Sherman P, Cutz E, et al: Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children, N Engl J Med 316:1.5.57-1.561, 1987 33. Dunn S, Weber T, Grosfeld JL, et al: Acute peptic ulcer in childhood. Arch Surg 118:6.56-660 34. Eastham E: Peptic ulcer. In Walker WA, Durie PR, Hamilton R, et al (eds): Pediatric Gastrointestinal Disease. Philadelphia, BC Decker, 1991, pp 438-4.51

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Address reprint requests to Joyce D. Gryboski, MD Department of Pediatrics Yale University School of 1\1edicine 333 Cedar Street ;'\Jew Haven, CT 06.510

Peptic ulcer disease in children.

Primary duodenal ulcer disease occurs in children of all ages, but is most often seen in those over 10 years. As in the adult, it often pursues a chro...
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