Human Epididymis Protein 4 Reference Intervals in a Multiethnic Asian Women Population

Abstract

Background: Ovarian cancer is ranked as the fifth most common cause of cancer death in women. In Malaysia, it is the fourth most common cancer in females. CA125 has been the tumor marker of choice in ovarian cancer but its diagnostic specificity in early stages is only 50%. Hence, there is a critical need to identify an alternative tumor marker that is capable of detecting detect ovarian cancer at an early stage. HE4 is a new tumor marker proposed for the early diagnosis of ovarian cancer and disease recurrence. Currently, none of the normal ranges of HE4 quoted in the literature are based on data for a multiethnic Asian population. Therefore, the aim of this study was to determine reference intervals for HE4 in an Asian population presenting in University Malaya Medical Centre, a tertiary reference hospital. Materials and Methods: 300 healthy women were recruited comprising 150 premenopausal and 150 postmenopausal women, aged from 20-76 years. All women were subjected to a pelvic ultrasonograph and were confirmed to be free from ovarian pathology on recruitment. Serum HE4 levels were determined by chemiluminescent microparticle immunoassay (CMIA, Abbott Architect). The reference intervals were determined following CLSI guidelines (C28-A2) using a non-parametric method. Results: The upper limits of the 95 th percentile reference interval (90%CI) for all the women collectively were 64.6 pmol/L, and 58.4 pmol/L for premenopausal) and 69.0 pmol/L for postmenopausal. The concentration of HE4 was noted to increase with age especially in women who were more than 50 years old. We also noted that our proposed reference limit was lower compared to the level given by manufacturer Abbott Architect HE4 kit insert (58.4 vs 70 pmol/L for premenopausal group and 69.0 vs 140 pmol/L in the postmenopausal group). The study also showed a significant difference in HE4 concentrations between ethnic groups (Malays and Indians). The levels of HE4 in Indians appeared higher than in Malays (p<0.05), while no significant differences were noted between the Malays and Chinese ethnic groups. Conclusions: More data are needed to establish a reference interval that will better represent the multiethnic Malaysian population. Probably a larger sampling size of equal representation of the Malay, Chinese, Indians as well as the other native ethnic communities will give us a greater confidence on whether genetics plays a role in reference interval determination.

HE4 Tissue Expression and Serum HE4 Levels in Healthy Individuals and Patients with Benign or Malignant Tumors: A Systematic Review

“…So far, no optimal cutoff exist, as well as there is no consensus for correct parameters to include in the examination. Bolstad and colleagues (21) have suggested a set of baseline serum HE4 concentrations for men and women adjusted for age, and two recent studies (36,38) have suggested reference intervals of serum HE4 in healthy women at 65.87 pmol/L for premenopausal and 90.76 pmol/L for postmenopausal measured in the study with the largest group included (N ¼ 1,515 healthy women; ref. 38).…”

“…In healthy individuals, serum HE4 significantly varies between sexes with a pronounced age-related increase (13,21,(34)(35)(36). In a multivariate analysis with 1,591 samples comprising 801 women and 790 men of ages 18 to 86 years, age was shown to be the main determinant of serum HE4 level, and age-dependent reference limits were determined for men and women excluding all smokers.…”

“…Furthermore, significantly higher median HE4 levels in serum are measured in postmenopausal women compared with premenopausal (P < 0.001; refs. 36,38), and serum HE4 varies within the different phases of the menstrual cycle (39,40).…”

Physiopathological factors affecting the diagnostic value of serum HE4-test for gynecologic malignancies

“…Among these factors, age at blood draw and age of menarche were the most significant ones affecting HE4 levels. Other investigators have studied the potential contribution to HE4 levels by demographical factors such as age, gender, race, smoking habit, menstrual cycle, body mass index (BMI), and pregnancy [33,34]. The information and major findings of these studies were shown in Table 1.…”

HE4 as a Serum Biomarker for ROMA Prediction and Prognosis of Epithelial Ovarian Cancer

“…Currently, carbohydrate antigen 125 (CA125) is the established biomarker for detecting ovarian cancer recurrence and monitoring therapeutic response. However, this glycoprotein is not expressed in up to 20% of ovarian cancer patients and can be elevated in various benign conditions (Rosen et al, 2012;Maggino et al, 2013 (Devan et al, 2013;Hellstrom et al, 2003;Bouchard et al, 2006;Drapkin et al, 2005;Mokhtar et al, 2013). Our previous study suggested that the detection of HE4 could be helpful for the diagnosis of ovarian cancer, especially in postmenopausal patients (Lu et al, 2009).…”