Serum human epididymis protein 4 and long-term mortality in U.S. women: a nationally representative cohort study

Serum Human Epididymal secretory protein E4 (HE4) is a biomarker in gynecologic oncology and is increasingly linked to fibrosis and adverse outcomes across organ systems; however, its population-level prognostic value beyond cancer and advanced organ failure remains unclear.

We analyzed women aged ≥ 20-years in the National Health and Nutrition Examination Survey (NHANES) 2001-2002 cycle with serum HE4 (unweighted n = 2200; weighted population ≈46.9 million) linked to mortality outcomes through 2019.

Over a median 199.3-months of follow-up, 466 deaths occurred. Higher ln-HE4 levels were strongly associated with Chronic Kidney Disease (CKD) (Odds Ratio [OR = 2.07], 95% CI: 1.38-3.12) and history of lung disease (OR = 1.34, 95% CI: 1.06-1.71). In fully adjusted models, higher ln-HE4 was associated with all-cause mortality (Hazard Ratio [HR = 1.29], 95% CI: 1.03-1.63) and cancer mortality (HR = 1.60, 95% CI: 1.02-2.49). Chronic lower respiratory disease mortality showed a positive but imprecise association because of limited events (n = 25; HR = 3.16, 95% CI: 1.26-7.91). For diabetes mortality, the estimate was also imprecise and not statistically significant (n = 18; HR = 3.84, 95% CI: 0.92-16.00). Trends across quartiles were significant for all-cause (p for trend = 0.001) and cancer mortality (p for trend = 0.006). Sensitivity analyses were broadly consistent, although estimates for outcomes with few events should be interpreted cautiously.

In a nationally representative cohort of U.S. women, higher serum HE4 was associated with increased risks of all-cause and cancer mortality. Associations with chronic lower respiratory disease and diabetes mortality were based on few events and should be interpreted cautiously. These results support HE4 as a potential population-level prognostic biomarker beyond oncology, warranting validation in other cohorts and mechanistic studies.