Overview
Human Epididymis Protein 4 (HE4), also known as WFDC2, is a small glycoprotein belonging to the whey acidic four-disulfide core (WAP) protein family. It was originally identified in the epithelial cells of the human epididymis but is now recognized for its significant role in oncology. HE4 is encoded by the WFDC2 gene located on chromosome 20q13.12, and circulates in a mature glycosylated form of approximately 25 kDa.
HE4 is involved in processes such as protease inhibition, immune modulation, and cellular regulation. Overexpression of HE4 has been documented in several malignancies, including ovarian, endometrial, lung, and breast cancers. Among these, its most established and clinically relevant role is in epithelial ovarian cancer. HE4 is widely used as a biomarker for early detection, monitoring treatment response, assessing recurrence, and evaluating disease progression in ovarian cancer patients.
Symptoms
HE4 elevation itself does not cause specific symptoms. Patients undergoing HE4 testing usually present with symptoms related to underlying ovarian or gynecological pathology rather than symptoms directly attributable to the biomarker.
Clinical features prompting HE4 testing may include abdominal pain, pelvic discomfort, bloating, unexplained weight loss, or other signs suggestive of ovarian malignancy. In many cases, HE4 testing is performed as part of a diagnostic evaluation for pelvic masses or during follow-up of previously diagnosed ovarian cancer.
Causes
Elevated HE4 levels are primarily caused by malignant transformation of epithelial cells, particularly in ovarian cancer. Increased expression of the WFDC2 gene contributes to tumor progression, invasion, and metastasis.
HE4 expression is also observed in other malignancies such as endometrial, lung, and breast cancers. Certain physiological conditions, including pregnancy and increasing age, may lead to higher HE4 levels, but these elevations generally remain within defined reference limits. Renal dysfunction may also influence HE4 concentrations and should be considered during interpretation.
Risk Factors
Risk factors associated with abnormal HE4 levels largely reflect the risk factors for ovarian and gynecological cancers. Postmenopausal women typically have higher baseline HE4 values compared to premenopausal women, requiring separate reference ranges.
Age, tumor size, disease stage, higher parity, and parametrial invasion are associated with increased HE4 levels. Smoking status and renal function may also affect serum and urinary HE4 concentrations. Patients with suspected pelvic masses, known ovarian cancer, or those undergoing post-treatment surveillance are considered high-risk groups for HE4 elevation.
Prevention
There are no direct preventive measures for elevated HE4 levels, as HE4 functions as a biomarker rather than a causative agent. Prevention focuses on early detection and timely clinical management of ovarian cancer.
The use of HE4 in combination with CA-125 and imaging techniques improves diagnostic accuracy and supports early intervention. Early identification of malignancy through biomarker evaluation allows appropriate treatment planning and helps reduce disease progression and recurrence.
Clinical Importance
HE4 has emerged as a highly valuable biomarker in ovarian cancer diagnostics. It is particularly useful in differentiating benign from malignant pelvic masses, especially when used alongside CA-125 as part of the Risk of Ovarian Malignancy Algorithm (ROMA).
Compared to CA-125, HE4 shows higher specificity and is less influenced by benign gynecological conditions such as endometriosis, fibroids, and menstruation. This makes HE4 especially useful in postmenopausal women, where CA-125 often yields false-positive results. Elevated HE4 levels correlate with advanced disease stage, increased tumor burden, and poorer prognosis.
Methods of Detection and Sample Handling
HE4 can be measured using enzyme-linked immunosorbent assay, chemiluminescent microparticle immunoassay, bead-based array systems, and immunohistochemistry. Serum and urine HE4 levels are more closely associated with carcinogenesis than with non-malignant pathological conditions.
Blood samples are collected in plain or EDTA tubes, with prompt separation of serum or plasma. Urine samples and formalin-fixed paraffin-embedded tissue are also used for specific diagnostic applications. Patients are advised to avoid biotin-containing supplements before testing, as biotin may interfere with immunoassay results.
Prognostic Significance and Limitations
HE4 has demonstrated prognostic value in ovarian and uterine cervical cancers. Increased HE4 expression is associated with advanced-stage disease, larger tumor size, and poorer survival outcomes. Rising HE4 levels during follow-up may indicate disease recurrence earlier than imaging or clinical symptoms.
Despite its advantages, HE4 is not a standalone diagnostic test. Elevated levels may occur in non-ovarian malignancies and certain physiological states. Results must always be interpreted in conjunction with CA-125 levels, imaging findings, clinical history, and renal function. When used as part of a combined diagnostic strategy, HE4 significantly enhances the accuracy of ovarian cancer detection and monitoring.
