Human Epididymis Protein 4 (HE4) Reference Limits in Polish Population of Healthy Women, Pregnant Women, and Women with Benign Ovarian Tumors

Abstract

Objectives. Defining precisely the normal range of HE4 protein is crucial for the proper interpretation of tumor marker results and for a more efficient diagnosis of ovarian malignancy. The aim of our study was to evaluate a reference limit of HE4 protein in a population to promote and facilitate the common use of HE4 protein assays. We also tried to identify potential association of HE4 levels with other conditions such as smoking, age, BMI, and creatinine levels. Methods. Blood samples were collected from 617 patients divided into three groups: healthy, pregnant, and with benign ovarian tumors. Serum HE4 concentrations were measured following a standard procedure. HE4 reference ranges for each group and association of HE4 levels with BMI, creatinine, and smoking were investigated. Results. HE4 reference limit for healthy patients equals 85 pmol/l, which becomes 73 pmol/l and 93 pmol/l for pre and postmenopausal subgroups, respectively. There is a statistically significant correlation between HE4 serum level and smoking (p=0.000001) and there is no correlation with creatinine. But if we take into account age and smoking, in multivariate analysis, there is a correlation. For pregnant, the upper limit values of normal HE4 levels are 55 pmol/l (median=40 pmol/l), 80 pmol/l (median=43 pmol/l), and 106 pmol/l (median=53 pmol/l) for the first, second, and third trimesters, respectively. Conclusions. HE4 protein value strongly depends on the patient’s age and smoking. The serum concentration of HE4 marker increases with the duration of pregnancy. Understanding the normal range of HE4 protein enables the correct interpretation of marker measurements. This may result in an earlier and more effective diagnosis of ovarian cancer.

May human epididymis 4 protein play a role in the etiopathogenesis of hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome?

“…On the other hand, Wang et al claimed in their study that HE4 protein levels in first‐ and second‐trimester pregnant women did not change significantly when compared with nonpregnant women, but increased significantly in the third trimester 21 . Gasiorowska et al found that HE4 protein levels were not significantly different in first‐ and second‐trimester pregnancies when compared with each other, while third‐trimester pregnancies had significantly higher HE4 protein levels when compared with the levels in first and second trimester 22 . In the same study, it was concluded that HE4 protein levels increased with increasing age 22 .…”

“…Gasiorowska et al found that HE4 protein levels were not significantly different in first‐ and second‐trimester pregnancies when compared with each other, while third‐trimester pregnancies had significantly higher HE4 protein levels when compared with the levels in first and second trimester 22 . In the same study, it was concluded that HE4 protein levels increased with increasing age 22 . In the study of Ratko Delic et al published in 2020, statistically, HE4 protein levels were found within the limits of normal reference values in the first, second, and third trimesters, and serum concentration of the HE4 protein was found to be significantly increased in the third trimester compared to the first and second trimesters 23 .…”

An SPRi Biosensor for Determination of the Ovarian Cancer Marker HE4 in Human Plasma

“…The non-fluidic array version of the SPRi technique enables the determination of approximately 20 biomarkers without signal enhancement or the preliminary preconcentration of analyte [16,17], which is the advantage of this technique over the fluidic version of SPR. Serous ovarian cancer samples exhibit an HE4 concentration above 150 pM, with maximal values above 850 pM [4], while the marker level for healthy premenstrual women ranges between 15 and 62 pM [18]. The cut-off value for HE4 in serum is recommended at between 70 and 87 pM for premenstrual and between 112 and 140 pM for postmenstrual women, depending on the method used for marker determination [6,7].…”

Influence of Pregnancy-Related Conditions on Human Epididymis Protein 4 Serum Levels in Comparison to CA 125 – a Prospective Cohort Trial

“…All of these studies only investigated healthy pregnant women, one group additionally looked at HE4 serum levels in cases of threatened first trimester miscarriage [16] and another investigated the ROMA index [15]. The results of these studies are partly conflicting as some authors report no difference in HE4 levels in pregnancy [17] or even lower levels than in premenopausal women [13] whereas others confirmed higher HE4 levels with advancing gestation [16,19]. To date, no studies have been published to evaluate interferences of HE4 and CA 125 levels with regard to pregnancy-related conditions and postpartum.…”

“…Seven studies have investigated HE4 serum levels in pregnant women 13 , 14 , 15 , 16 , 17 , 18 , 19 . All of these studies only investigated healthy pregnant women, one group additionally looked at HE4 serum levels in cases of threatened first trimester miscarriage 16 and another investigated the ROMA index 15 .…”