Age- and gender-specific dynamics and next-generation reference intervals for pepsinogen in northern China

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