Role of acid and pepsinogen secretion

The bulk of our knowledge on acid secretion is derived from studies in adults. Gastric acid secretion begins in the newborn from the first day of life; it is not sensitive to gastrin, but rather to pentagastrin stimulation, which is the best way to evaluate it. Serum gastrin is usually elevated in the newborn period.35,36

Maximal acid output after pentagastrin stimulation increases from 0.031 mEq/kg per h at 1 month to 0.122 mEq/kg per h at 3 months, and up to 0.218 mEq/kg per h at 20 months, reflecting the increase of the mass of parietal cells.37 In another study, maximal acid output values were demonstrated not to change from 3 months to 12 years of life.38

Basal acid output has been found to be normal in children with PUD in all39-41 but one study.42 Although children with PUD have been shown to have a higher average maximal acid output compared to age-matched controls, the occasional child with peptic ulcer may well have a completely normal maximal acid output. Similarly, control children may occasionally show increased maximal acid output.39-42 This important overlap of values between children with or without ulcer is similar to that reported in adults. Interestingly, children with more severe PUD (requiring surgery, or presenting severe digestive bleeding) have been reported to have values of maximal acid output significantly higher than those with milder forms of disease or in remis-sion.40,42 Basal41 or meal-stimulated serum gastrin43 can be normal or slightly increased in children with ulcer.

Other disorders associated with severe gastric and duodenal ulcers secondary to increased gastric acid secretion are listed in Table 6.2. These situations are usually the consequence of an increased basal (Zollinger-Ellison syndrome, 'ZES') or stimulated (pseudo-ZES or antral G-cell hyperplasia/ hyperfunction syndrome)44 gastrin or histamine secretion.

Pepsins are proteolytic enzymes generated by the action of hydrochloric acid on their precursor pepsinogens. Pepsinogens are secreted by the principal cells of the gastric fundus (PGI) and by

Table 6.2 Causes of gastric acid hypersecretion

Zollinger-Ellison syndrome

Antral G-cell hyperplasia or hyperfunction


Chronic renal failure

Hypertrophic gastropathy

Small intestinal resection - short gut

Hyperparathyroidism the mucous cells of the remaining stomach and part of the duodenum (PGII). Seven molecular forms (Pg1-Pg5 for PGI and Pg6-Pg7 for PGII) can be identified electrophoretically. Only traces of pepsins have been demonstrated in neonatal gastric juice, and their increase with age is slow.37 In children with PUD, as well as in members of families with a high incidence of PUD, an increase of serum pepsinogen I has been demonstrated, and high serum pepsinogen I has been considered a marker of ulcerogenicity.45

Helicobacter pylori-related mechanisms

H. pylori may induce inflammation by two different pathways: direct toxicity mediated by secretion of specific toxins and other aggressive factors (Table 6.3); and immune-mediated toxicity secondary to stimulation of both innate and adaptive immune responses in the host.46

The gastric mucosa is a niche relatively resistant to bacterial infection. The main protective mechanism is the bactericidal activity of the gastric acid. However, H. pylori has developed some mechanisms to evade protection and to allow the colonization of the mucosa: urease production and motility. Urease activity is mediated by a unique pH-dependent urea channel, UreI, which works at low pH, and allows the influx of urea followed by hydrolysis into CO2 and ammonia, which buffers acid conditions close to the bacterium.47,48 By means of flagellar motility, H. pylori swims into the mucous layer, and attaches to epithelial cells by multiple bacterial-surface adhesins. The best characterized adhesin is Baba, a 78-kDa outer membrane protein, which binds to the fucosylated Lewis B blood-group antigen.49

Approximately half of the genomic variants of H. pylori are able to produce the thermolabile 95-kDa cytotoxin, called Vac-A, with a cytopathic effect induced by direct vacuolating action on epithelial cells (Figure 6.1).50 The toxin inserts itself into the epithelial cell membrane, forming a channel through which bicarbonate and organic anions can reach the bacterium. Other mechanisms involved in the Vac-A-mediated epithelial damage are the release of cytochrome C from mitochondria, and apoptosis.51 Even if the pathogenic role of Vac A is still under debate, it is relevant that Vac-A positive strains are isolated in 60% of patients with PUD, and in only 30% of patients with gastritis.52

Sixty-five to eighty per cent of strains of H. pylori have a chromosomal region called cag-PAI (37-kb genomic fragment containing 29 genes) which codifies a type IV secretory apparatus translocating the 120-128-kDa Cag-A protein inside the host cell.53,54 At the cellular level, a direct proliferative response and cytokine production are induced. Cag-A-positive strains are usually isolated from 80-100% of patients with more severe peptic lesions and in 60-75% of patients with milder forms of disease.

Even if the majority of strains isolated from patients with PUD are positive for both Cag-A and Vac-A, it is not possible to distinguish ulcerogenic from non-ulcerogenic strains with certainty.

The second pathway involved in gastric injury is secondary to activation of an immune response. H. pylori produces gastric inflammation in virtually all infected persons.55 This inflammatory response is triggered by bacterial attachment to epithelial cells, followed by recruitment of neutrophils, macrophages, T and B lymphocytes,

Table 6.3 Virulence factors demonstrated

in Helicobacter pylori strains

Colonization factors

Toxicity factors

Urease (acidity inhibition)

vacuolizing cytotoxin (Vac-A)

Flagellins (motility)

cag pathogenicity island (cag-PAI)

Adhesins (adhesivity)

ammonium, lipopolysaccharide, phospholipase

Catalase, superoxide dismutase (phagocytosis resistance)

and plasma cells. In the inflamed gastric epithelium, a high concentration of proinflammatory cytokines has been found. Increased production of interleukin (IL)-8, a potent neutrophil-activat-ing cytokine, is induced by activation of NFKp from Cag-A-positive, more than Cag-A-negative, strains.56 IL-8 and other chemokines amplify the immune as well as the inflammatory response, producing severe epithelial damage. The multiplicity of possible pathogenic mechanisms is shown in Figure 6.2.

A systemic and mucosal immune response is elicited by H. pylori infection.57 This does not lead to eradication, but it may contribute to further damage. Immunological studies have demon strated that an IL-18-driven Th1 immune response, instead of the expected Th2, combined with Fas-mediated apoptosis of H. pylori-specific T-cell clones, may contribute to the persistence of the infection. Some patients produce autoantibodies against the H+/K+ ATPase of gastric parietal cells that play a role in the induction of gastric atrophy.58

In addition to the direct and inflammatory mechanisms of mucosal injury, H. pylori may play an ulcerogenic role by interfering with acid and pepsin secretion. In children, H. pylori infection seems to increase serum PGI59 and in some, but not all, children with H. pylori, a meal-induced hypergastrinemia secondary to G-cell hyperplasia

Pathogenesis Acid Secretion
Figure 6.2 Helicobacter pylori-host interactions in the pathogenesis of mucosal lesions from reference 46, with permission.

has been reported. Eradication of H. pylori usually normalizes pepsinogen and gastrin secretion59 as well as G- and D-cell hyperplasia.60 H. pylori infection may interfere in the gastrin-HCl axis increasing gastric acid secretion, which in turn results in duodenal ulceration: in adults, an increased maximal acid output has been demonstrated to differentiate ulcer from non-ulcer H. pylori-positive patients.61

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