Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors

J Gastroenterol Hepatol. 2005 Aug;20(8):1266-78. doi: 10.1111/j.1440-1746.2005.03867.x.


Background: Gastric neoplasia is common in humans, yet controversy remains over contributions of chronic achlorhydria, gastrinemia and hyperplasia, to cancer risk. To study this, mice lacking the gastric H/K-ATPase (Atp4a(-/-) mice) were used to determine whether chronic loss of acid secretion, with attendant hypergastrinemia, predisposes to cancer phenotype.

Methods: Atp4a(-/-) and Atp4a(+/+) mice, paired for age and gender, were examined at 3, 8, 12 and 20 months for histopathology, and for expression of the trefoil factor family (TFF)1-3, Reg IIIbeta, gamma and delta, osteopontin, CD44, chromogranin A, Crp-ductin, and galectin, all of which are important in cell growth.

Results: By 8 months, the glandular stomach of the Atp4a(-/-) mice doubled in weight and thickness, and several modulators of growth were increased. Female Atp4a(-/-) mice were more hyperplastic than Atp4a(-/-) males at 12 and 20 months. By 1 year, severe mucocystic hyperplasia, incomplete intestinal metaplasia, ciliated metaplasia, a shift in mucins from neutral to acidic, and inflammation were widespread. Cells in the mucus pit zone developed a pyloric-type appearance, containing large hyaline-like, periodic acid-Schiff (PAS)-negative/alcian blue-negative inclusions. But critical characteristics of gastric neoplasia, such as nuclear atypia, invasion into the muscularis mucosa, and metastases were absent. In Atp4a(-/-) mice, chromogranin A and histidine decarboxylase, RegIIIgamma and delta, TFF3, osteopontin and CD44 were upregulated while Reg IIIbeta, and TFF1 were reduced.

Conclusions: Chronic achlorhydria and hypergastrinemia in aged Atp4a(-/-) mice produced progressive hyperplasia, mucocystic and incomplete intestinal metaplasia, and the upregulation of growth factors without histological evidence of neoplasia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Achlorhydria / metabolism*
  • Achlorhydria / pathology
  • Age Factors
  • Animals
  • Disease Models, Animal
  • Endometrial Hyperplasia / pathology
  • Female
  • Gastric Mucosa / metabolism*
  • Gastric Mucosa / pathology
  • H(+)-K(+)-Exchanging ATPase / deficiency*
  • H(+)-K(+)-Exchanging ATPase / genetics
  • Hyperplasia
  • Male
  • Metaplasia
  • Mice
  • Mice, Knockout
  • Sex Factors
  • Stomach / pathology


  • H(+)-K(+)-Exchanging ATPase