Pepsinogen IiEdit
Pepsinogen II is a digestive proenzyme (zymogen) that serves as the precursor to the proteolytic enzyme pepsin. In humans, pepsinogen exists as two major isoforms, pepsinogen I and pepsinogen II. Pepsinogen II is produced by cells in the gastric mucosa, including the mucous neck cells of the fundic glands and cells of the pyloric glands, and it is also produced by Brunner's glands in the duodenum; it is secreted into the gastric lumen and, to a lesser extent, into the bloodstream. When exposed to the acidic environment of the stomach, pepsinogen II is activated to pepsin, which participates in the digestion of dietary proteins.
Beyond its digestive role, pepsinogen II is detectable in the circulation and is used clinically as a biomarker of gastric mucosal health. Clinicians often measure both pepsinogen II and pepsinogen I, together with their ratio, as part of noninvasive assessments of gastric mucosal status and the risk of atrophic gastritis or gastric cancer. The interpretation of these tests depends on assay method, age, region, and concomitant factors such as inflammation or medication use.
Biochemistry and physiology
- Activation and function: Pepsinogen II is a proenzyme that is converted to the active protease pepsin upon acidification in the stomach. Pepsin then cleaves proteins into smaller peptides, contributing to the early stages of protein digestion. This process works in concert with pepsinogen I-derived pepsin and with other gastric enzymes.
- Distribution and secretion: Pepsinogen II is produced by multiple gastric mucosal cell types, particularly in the fundus, body, and pylorus, and also by Brunner's glands in the duodenum. It is secreted into the gastric lumen and can enter the circulation in measurable amounts.
- Regulation: Secretion of pepsinogens is influenced by neural and hormonal signals that regulate gastric acid and enzyme output, including vagal stimulation and gastrin-mediated pathways. Pharmacologic suppression of acid production can alter pepsinogen levels in serum and gastric juice.
Clinical significance
- Biomarker for gastric mucosal status: In clinical practice, the levels of pepsinogen I, pepsinogen II, and their ratio (PG I/PG II) are used to infer the condition of the gastric mucosa. A reduced PG I/PG II ratio can indicate corpus-dominant atrophic gastritis, a condition associated with elevated risk for gastric cancer. This approach is often used in conjunction with testing for Helicobacter pylori infection and other serologic markers.
- Noninvasive screening and risk stratification: Serologic panels that include pepsinogen I and II are used in some healthcare systems to stratify risk and determine whether patients should undergo endoscopic evaluation for gastric neoplasia. The usefulness and recommended cutoffs for these tests vary by population, region, and laboratory methodology, so clinicians rely on local guidelines and validated reference ranges.
- Interfering factors and limitations: Several factors can influence pepsinogen levels, including age, medication use (notably acid-suppressive therapy such as proton pump inhibitors and H2 receptor antagonists), inflammatory states, and Helicobacter pylori status. Variability among assay methods means that interpretation should be grounded in lab-specific reference ranges. Pepsinogen testing is most informative when used as part of a broader risk assessment rather than as a stand-alone diagnostic tool.
- Relation to gastric cancer risk: While low PG I and a low PG I/PG II ratio are associated with higher risk of gastric corpus atrophy and, by extension, gastric cancer, the tests are not definitive. They are best viewed as risk indicators that guide decisions about further investigation, such as endoscopy, especially in populations with high baseline incidence of gastric cancer.
Controversies and debates
- Utility and cost-effectiveness in different healthcare settings: Proponents argue that serologic pepsinogen testing can identify individuals at higher risk for serious gastric disease without the need for routine endoscopy in all patients. Critics point to variable test performance across populations, limited sensitivity and specificity, and the possibility of overdiagnosis or unnecessary procedures in some groups. The balance of benefits and harms is discussed differently in various national guidelines.
- Regional differences in practice: In several East Asian countries, serologic pepsinogen panels are incorporated into national screening programs or high-risk stratification strategies, whereas in many Western systems, endoscopy-based approaches or alternative risk stratification methods are emphasized. These differences reflect epidemiologic patterns, healthcare infrastructure, and cost considerations.
- Influence of gastric microbiota and inflammation: The interpretation of pepsinogen levels can be affected by infection with Helicobacter pylori and by ongoing gastritis or inflammation. Disentangling the effects of mucosal atrophy from concurrent inflammatory processes remains an area of active research, with implications for how tests are used in screening algorithms.
- Methodological variability: Assay differences, specimen type (serum vs. plasma), and pre-analytic conditions contribute to discordant results between laboratories. Standardization efforts and locally validated reference ranges are important to ensure reliable interpretation, which can complicate cross-population comparisons and meta-analyses.