Observational Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 21, 2025; 31(31): 108977
Published online Aug 21, 2025. doi: 10.3748/wjg.v31.i31.108977
Age- and gender-specific dynamics and next-generation reference intervals for pepsinogen in northern China
Miao-Miao Zhang, Dong Zhu, Hai-Bin Zhao, Xiu-Ying Zhao
Miao-Miao Zhang, Dong Zhu, Hai-Bin Zhao, Xiu-Ying Zhao, Department of Laboratory Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing 102218, China
Co-first authors: Miao-Miao Zhang and Dong Zhu.
Author contributions: Zhang MM was responsible for data curation, conducted formal analysis, and drafted the original manuscript; Zhu D conceived and designed the study, performed statistical analysis, supervised the research process, and contributed to manuscript review and editing; Zhao HB performed laboratory testing and contributed to data curation; Zhao XY provided clinical expertise and advice relevant to study interpretation.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Beijing Tsinghua Changgung Hospital (Approval No. 24791-6-01).
Informed consent statement: The study was conducted using de-identified retrospective data from routine health examinations, with no direct patient interaction or intervention. Informed consent was waived by the Ethics Committee of Beijing Tsinghua Changgung Hospital.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Data sharing statement: The data presented in this study are available from the corresponding author upon request at zhudongcherish@163.com.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dong Zhu, Associate Chief Technologist, Department of Laboratory Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing 102218, China. zhudongcherish@163.com
Received: April 27, 2025
Revised: July 1, 2025
Accepted: July 24, 2025
Published online: August 21, 2025
Processing time: 113 Days and 18.8 Hours
Abstract
BACKGROUND

Pepsinogen (PG) and the PG I/II ratio (PGR) are critical indicators for diagnosing Helicobacter pylori infection and chronic atrophic gastritis, and assessing gastric cancer risk. Existing reference intervals (RIs) often overlook age, sex, and demographic variations. Partitioned RIs, while considering these factors, fail to capture the gradual age-related physiological changes. Next-generation RIs offer a solution to this limitation.

AIM

To investigate age- and sex-specific dynamics of PG and establish next-generation RIs for adults and the elderly in northern China.

METHODS

After screening, 708 healthy individuals were included in this observational study. Serum PG was measured using chemiluminescence immunoassay. Age- and sex-related effects on PG were analyzed with a two-way analysis of variance. RI partitioning was determined by the standard deviation ratio (SDR). Traditional RIs were established using a non-parametric approach. Generalized Additive Models for Location, Scale, and Shape (GAMLSS) modeled age-related trends and continuous reference percentiles for PG I and PG II. Reference limit flagging rates for both RI types were compared.

RESULTS

PG I and PG II levels were influenced by age (P < 0.001) and sex (P < 0.001), while PGR remained stable. Age-specific RIs were required for PG I (SDR = 0.366) and PG II (SDR = 0.424). Partitioned RIs were established for PG I and PG II, with a single RI for PGR. GAMLSS modeling revealed distinct age-dependent trajectories: PG I increased from a median of 39.75 μg/L at age 20 years to 49.75 μg/L at age 60 years, a 25.16% increase, after which it plateaued through age 80 years. In contrast, PG II showed a continuous rise throughout the age range, with the median value increasing from 5.07 μg/L at age 20 years to 8.36 μg/L at age 80 years, corresponding to a 64.89% increase. Continuous reference percentiles intuitively reflected these trends and were detailed in this study. Next-generation RIs demonstrated superior accuracy compared to partitioned RIs when applied to specific age subgroups.

CONCLUSION

This study elucidates the age- and sex-specific dynamics of PG and, to our knowledge, is the first to establish next-generation RIs for PG, supporting more individualized interpretation in laboratory medicine.

Keywords: Pepsinogen; Reference intervals; Next-generation reference intervals; Age dynamics; Gastric biomarkers; Personalized medicine

Core Tip: This study pioneers the establishment of next-generation reference intervals (RIs) for pepsinogen (PG) in Chinese adults and elderly populations using Generalized Additive Models for Location, Scale, and Shape. We identified age- and sex-specific dynamics: PG I and PG II levels increased with age (PG I plateaued post-60 years; PG II rose continuously), with males exhibiting higher values. Partitioned RIs based on age were established, but next-generation RIs demonstrated superior accuracy. By capturing continuous physiological trends, next-generation RIs could potentially reduce diagnostic misinterpretation.