Test Catalog

Test ID: HE4    
Human Epididymis Protein 4, Serum

Useful For Suggests clinical disorders or settings where the test may be helpful

Aiding in monitoring patients with treated epithelial ovarian cancer for recurrence or progression


This test should not be used as a screening test for ovarian cancer or for monitoring patients with mucinous or germ cell ovarian cancer.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Human epididymis protein 4 (HE4) belongs to the family of whey acidic four-disulfide core (WFDC) proteins. Currently, the biologic function of HE4 is unknown.


HE4 has been shown to be overexpressed in 93% of serous, 100% of endometrioid, and 50% of clear cell ovarian carcinomas. In a study of 233 patients with a pelvic mass, including 67 with epithelial ovarian cancer, HE4 had a higher sensitivity for ovarian cancer detection than cancer antigen 125 (CA 125), 72.9% versus 43.3%, respectively, at a specificity of 95%. Researchers also found HE4 to be elevated in more than half of the ovarian cancer patients who did not have elevated CA 125 levels; therefore, the combination of markers provided slightly improved cancer diagnostic sensitivity for the detection of ovarian cancer.


The main established application of HE4 is in post-therapy monitoring of ovarian cancer patients, who had elevated pretreatment levels. In this setting, it complements CA 125 measurement and facilitates follow-up of patients with little or no CA 125 pretreatment elevations.


Certain histological types of ovarian cancer (mucinous or germ cell tumors) rarely express HE4, therefore the use of HE4 is not recommended for monitoring of patients with these types of ovarian cancer.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Females: < or =140 pmol/L

Males: Not applicable

Interpretation Provides information to assist in interpretation of the test results

Increase in human epididymis protein 4 (HE4) suggests recurrence or disease progression, while a decrease suggests therapeutic response. A change in serum HE4 concentration of greater than or equal to 20% is considered significant.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Results cannot be interpreted as absolute evidence of the presence or absence of malignant ovarian disease, because mild elevations of human epididymis protein 4 (HE4) might also be present in individuals with benign gynecologic conditions (ovarian cysts, cystadenomas, leiomyomas, myomas, fibromas, and endometriosis), hypertension, congestive heart failure, and renal or liver disease.


Serial testing for patient HE4 results should be used in conjunction with other clinical methods for monitoring ovarian cancer.


The use of this test in disease states other than ovarian cancer has not been clinically validated.


Serum markers are not specific for malignancy and values may vary by method. Values obtained with different assay methods cannot be used interchangeably. Correlation studies between this method and the previous ELISA method show good correlation (correlation coefficient =0.92). However this method will, on average, give 28% higher HE4 concentrations and individual patient results may vary more than would be calculated from the correlation equation.


Ideally, when changing methods, parallel testing using the old and new method allows for establishing the patient's HE4 baseline levels with the new method (rebaseline).


In rare cases, interference due to extremely high titers of antibodies to analyte-specific reagents (human anti-mouse or heterophile antibodies, streptavidin, or ruthenium) can occur. The laboratory should be alerted if the result does not correlate with the clinical presentation.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Moore RG, Brown AK, Miller MC, et al: The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol 2008 Feb;108(2):402-408

2. Ferraro S, Braga F, Lanzoni M, et al: Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review. J Clin Pathol 2013 Apr;66(4):273-281