PUD is thought to arise as a result of an imbalance between cytotoxic and cytoprotective factors in the upper gastrointestinal tract. Cytotoxic factors include hydrochloric acid; pepsin; bile acids; ethanol; smoking; medications such as salicylates, corticosteroids, and nonsteroidal antiinflammatory drugs; and infection with H. pylori. The cytoprotective factors include the unstirred mucous layer, local bicarbonate secretion, prostaglandins, mucosal blood flow, and epithelial cell renewal.

Acid production is essential to the development of PUD. Oxidative phosphorylation of glucose and fatty acids within the parietal cells produces hydrogen ions that are secreted actively across a concentration gradient into the gastric lumen. When the concentration of intraluminal acid is twice the normal concentration, the gastric mucosal barrier may be broken. Entities such as Zollinger-Ellison syndrome and antral G-cell hyperplasia, both of which are rare events in children, are associated with excess production of acid and ulcer disease. Substances such as pepsin, bile acids, alcohol, and salicylates, when placed in the stomach, further disrupt the mucosal cell barrier, thereby allowing back diffusion of hydrogen ions from the gastric lumen into the mucosal cells. Cellular destruction subsequently results in the release of histamine, which further stimulates parietal and chief cells to produce more acid and pepsin, respectively.

Secretion of acid is regulated by three factors: acetylcholine, gastrin, and histamine. Acetylcholine is released from vagal cholinergic fibers and directly stimulates the parietal cell mass. Gastrin is released by G cells in the antral and duodenal mucosa and is carried to parietal cells by the bloodstream. Gastrin is the most important stimulant of acid secretion and is released in the presence of an alkaline antrum, by direct contact with ingested peptides and amino acids, and by the intravenous administration of calcium. Histamine is released by mast-like cells of the lamina propria and diffuses through the extracellular fluid to the parietal cells. The final common pathway for acid secretion within the parietal cell is the proton (H⁺-K^+-ATPase) pump.

Acid secretion begins in infancy at 48 hours of life and achieves adult levels by age 6 months (Table 347.1). Basal and maximal acid output, the latter measured by pentagastrin stimulation, generally is higher in children with PUD than in healthy individuals, although overlap exists with normal values (Table 347.2).
Serum gastrin concentrations are normal in children with primary or secondary gastric ulcers and may be normal or moderately elevated (100 to 120 pg/mL) in children with primary duodenal ulcers (Table 347.3). Hypergastrinemia may be seen in other disease entities, such as the Zollinger-Ellison syndrome, antral G-cell hyperplasia, long-standing pyloric obstruction, renal failure, short-gut syndrome, hyperparathyroidism, multiple endocrine neoplasias, pheochromocytoma, neurofibromatosis, primary pernicious anemia, and atrophic gastritis.

Mucous secretion by the epithelial mucous glands protects the stomach from ulceration by retarding the diffusion of acid from the lumen to the mucosal surface. Bicarbonate secretion from the stomach and duodenum serves as a buffer that minimizes the deleterious effect of a low pH. Prostaglandins bind to receptors in parietal cells and block acid secretion. Prostaglandins also stimulate mucosal blood flow, thereby providing an adequate supply of oxygen and nutrients for epithelial cell renewal.

PUD is an uncommon occurrence in children. The prevalence is estimated to be less than 1% of pediatric hospital discharges and approximately 2% of children who undergo upper endoscopy for various complaints (Table 347.4). The median age of children with a diagnosis of primary ulcer disease is 9 years, but the age may range from infancy through adolescence. Most primary peptic ulcers occur in children older than 8 years of age, whereas secondary ulcers occur at all ages. The gender distribution of primary ulcer disease is 60% males and 40% females. In one report of primary peptic disease in children, duodenal ulcers occurred in 34% of cases and gastric ulcers occurred in 51%. H. pylori was found in 39% of children with duodenal ulcers and in 15% of those with gastric ulcers.

Primary peptic ulcers usually are solitary lesions located in the duodenum and less commonly in the gastric antrum. The lesions are round or oval, are less than 2 cm in size, and have a sharp, punched-out defect. The ulcer may be superficial, may erode into the muscularis mucosa, or may penetrate the entire wall into adjacent organs. Chronic ulcers underlying scarred mucosa may cause puckering of the gastric folds and result in a spoke-like appearance on gross examination. The histologic appearance of PUD is that of active necrosis. The base and margins of the ulcer have fibrinoid debris overlying an acute inflammatory infiltrate. In the base of the ulcer, granulation tissue infiltrated with mononuclear cells is present and rests on a more solid collagenous scar. With reepithelialization, the glands of the mucosal margins become mucous-secreting, a change called intestinalization. In a large proportion of pediatric PUD, the spiral shaped, gram-negative, urease-producing bacterium H. pylori can be found within the mucosal inflammation and ulceration. However, 20% of pediatric cases may be negative for H. pylori.

Secondary peptic ulcers occur as single or multiple lesions and are found primarily in the stomach. The lesions tend to be circular, are less than 1 cm in diameter, and involve the mucosa or superficial epithelium. The ulcer base appears brown due to acid digestion of the blood within the superficial erosion, but the lesion is not indurated. An acute inflammatory infiltrate may be found in the margins and base of the ulcer, but scarring of blood vessel walls is absent. Reepithelialization is rapid and demonstrates many mitotic nuclei.

H. pylori has been associated causally with PUD (Box 347.1). However, although all children infected with H. pylori develop
chronic-active gastritis, most appear to have asymptomatic infections that may never lead to clinically evident disease. Only a minority of children develop peptic ulceration. The factors that result in formation of ulcers in this setting are unknown.

H. pylori disease is a chronic infection that typically is acquired in childhood. The prevalence of H. pylori is related inversely to socioeconomic status. Seroprevalence of H. pylori gradually increases with age, suggesting that the rate of acquisition decreases with age in successive generations of children as the standard of living improves. The human is the only known host for H. pylori. Clustering of H. pylori infection occurs within families, suggesting a common source of infection, person-to-person transmission, or a genetic predisposition to infection. Although the mode of transmission probably is person to person, the route of transmission is controversial. Genetic factors may influence the susceptibility to acquire H. pylori infection, but environmental factors are more important. Breast-fed children have a lower rate of H. pylori infection than do those who are not breast-fed, regardless of the educational status of the mother. Children with H. pylori gastritis often are asymptomatic. Symptoms such as abdominal pain and vomiting do not differentiate children with H. pylori colonization of the gastric mucosa from those who are not colonized. Treatment of H. pylori gastritis may not resolve abdominal symptoms unless patients also have duodenal ulcer disease. The eradication of H. pylori is associated with a pronounced reduction in the relapse rate of duodenal ulcers. Ulcer relapse is associated with either reinfection or recrudescence of H. pylori infection in medically noncompliant patients. Chronic gastric colonization with H. pylori may predispose the child to the development of mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori also is one of many risk factors that may lead to gastric carcinoma.