Human Epididymis Protein 4 (HE4) is a naturally occurring glycoprotein, a protein molecule with sugar chains attached to its structure. First identified in the epididymis, a tube located at the back of the testicle, HE4 is also produced in various other bodily tissues.
The Normal Function of HE4
HE4 is present in several bodily tissues beyond the epididymis, including the female reproductive tract, such as the fallopian tubes, endometrium, and endocervix. It is also found in the respiratory tract, particularly in the trachea, and in the oral cavity. The widespread presence of HE4 suggests it plays diverse biological roles.
One proposed function of HE4 involves innate immunity, contributing to the body’s natural defense mechanisms. This protein also exhibits anti-protease activity, inhibiting enzymes that break down other proteins. Such a role could be significant in maintaining tissue integrity and regulating physiological processes. Additionally, HE4 is thought to be involved in cell differentiation and sperm maturation.
HE4 as a Clinical Indicator
HE4 is a significant biomarker, particularly in the context of ovarian cancer. It is used for monitoring disease progression, assessing how well a patient responds to treatment, and sometimes in the initial evaluation of cancer risk. Regulatory bodies, such as the FDA, have approved HE4 for specific clinical uses related to ovarian cancer.
The utility of HE4 often involves its comparison with another commonly used ovarian cancer biomarker, CA-125. HE4 can be elevated in certain types of ovarian cancer, such as serous and endometrioid epithelial ovarian carcinomas, even when CA-125 levels are not. This complementary nature allows for a more comprehensive assessment, as HE4 is overexpressed by 93% of serous and 100% of endometrioid epithelial ovarian carcinomas. Its ability to detect some cases that CA-125 might miss makes it a valuable tool in managing ovarian cancer.
Understanding HE4 Test Results
Interpreting HE4 test results involves understanding typical and elevated levels. Normal HE4 levels can vary, but generally, values below a certain cutoff are considered within the expected range: typically around 70 picomoles per liter (pmol/L) for premenopausal women and 140 pmol/L for postmenopausal women. Elevated HE4 levels, particularly above these cutoffs, can indicate an increased likelihood of ovarian cancer, especially in postmenopausal women with a pelvic mass.
However, a single elevated HE4 level does not definitively diagnose cancer. Healthcare professionals use HE4 levels in combination with clinical details, imaging results, and biomarkers like CA-125, often integrated into a risk assessment algorithm such as the Risk of Ovarian Malignancy Algorithm (ROMA) score. The ROMA score combines HE4 and CA-125 values with a woman’s menopausal status to estimate the probability of malignancy. A low ROMA score suggests a lower risk, while a high score indicates a higher risk, prompting further diagnostic evaluations.
Other Reasons for Elevated HE4 Levels
While HE4 is a recognized biomarker for ovarian cancer, its levels can also be elevated due to various non-cancerous conditions. Kidney dysfunction is a common reason for increased HE4 levels, as the kidneys play a role in clearing proteins from the bloodstream. When kidney function is compromised, HE4 may accumulate, leading to higher measured concentrations.
Certain benign gynecological conditions can also cause an increase in HE4. Endometriosis, a condition where tissue similar to the lining of the uterus grows outside the uterus, and uterine fibroids, non-cancerous growths of the uterus, have been associated with elevated HE4 levels. These increases are thought to be related to inflammation or cellular changes in these conditions. Therefore, an elevated HE4 result always requires a thorough medical evaluation to differentiate between benign and malignant causes.