Human Epididymis Protein 4 (HE4) is a protein marker that is measured in the blood to provide information relevant to women’s health. Originally identified in the male reproductive tract, its presence in the bloodstream has become primarily associated with certain gynecological conditions. The HE4 blood test quantifies the concentration of this protein in a patient’s serum, offering a numerical value that clinicians use as part of a larger diagnostic picture. Understanding what constitutes a “normal range” for this test is important for any patient receiving these results, as the interpretation depends heavily on individual factors. This article clarifies the established numerical benchmarks and the clinical context required to properly evaluate the test result.
Understanding the HE4 Test
The HE4 protein is naturally produced by cells in several parts of the body, including the glandular epithelium of the reproductive tract, the respiratory epithelium, and the distal renal tubules. The main reason this protein is measured in a clinical setting is its tendency to be overexpressed in certain types of cancer cells, particularly epithelial ovarian cancer. The test itself is a simple blood draw, and the concentration of the protein in the serum is measured using a laboratory assay.
While HE4 is not a screening test for the general population, its measurement acts as a tumor marker, aiding in the assessment of risk in women who already present with a pelvic mass. Its use complements other markers, such as CA-125, which has historically been the primary tool for this purpose. Research has shown that HE4 is often elevated in cases where CA-125 levels are not, making the combined use of both markers more informative.
Defining the HE4 Normal Range
The concept of a “normal range” for an HE4 blood test is not a single, fixed number but rather a threshold that is highly dependent on a patient’s menopausal status. The concentration is typically measured in picomoles per liter (pmol/L), and the upper limit of what is considered normal differs significantly between pre- and postmenopausal women. This variation reflects the biological changes that occur in the reproductive system after menopause, which naturally cause HE4 levels to rise.
For women who are premenopausal, the upper limit of the normal range is generally lower, often cited around 70 pmol/L to 90 pmol/L. Conversely, for women who are postmenopausal, the upper limit is higher, frequently set in the range of 120 pmol/L to 140 pmol/L. One large United States-based study, for instance, established the 95th percentile as 89 pmol/L for premenopausal women and 128 pmol/L for postmenopausal women.
It is important to recognize that these values represent the 95th percentile, meaning 95% of healthy women fall below that concentration. Slight differences in these cutoff points can exist between different laboratories because the reference ranges are sometimes calibrated based on the specific population they serve or the particular assay technology they use. Therefore, a patient’s laboratory report will typically provide the specific reference range used for their result, which should be the primary guide for interpretation.
Common Non-Cancerous Causes of Elevated HE4
An HE4 level that exceeds the established normal range does not automatically indicate the presence of a malignancy; several non-cancerous conditions can lead to an elevated result. One of the most common and significant causes of an elevated HE4 level is chronic kidney disease or any form of renal impairment. The HE4 protein is normally cleared from the bloodstream by the kidneys, so when kidney function is diminished, the protein accumulates, causing the blood concentration to rise.
Beyond kidney issues, the patient’s age is a biological factor that correlates with increasing HE4 levels, particularly in postmenopausal women. Certain benign gynecological conditions can also cause mild to moderate elevations in HE4, though this is less frequent than with the traditional CA-125 marker. While conditions like endometriosis and uterine fibroids often result in high CA-125 levels, HE4 is generally less affected by these benign diseases. This lower rate of false-positive elevation in benign conditions is a clinical advantage of the HE4 test.
Interpreting HE4 Results in Clinical Practice
When an HE4 result is elevated, physicians use it not in isolation, but as one component of a structured clinical evaluation. The most common application for an elevated HE4 result is within the Risk of Ovarian Malignancy Algorithm (ROMA). This algorithm combines the patient’s HE4 value, their CA-125 value, and their menopausal status into a single numerical score that estimates the probability of a pelvic mass being malignant.
The primary purpose of the ROMA score is to facilitate the appropriate triage of patients who have a pelvic mass requiring surgery. Patients classified as having a high likelihood of malignancy are referred to a specialized gynecologic oncologist for treatment at a tertiary care center. This process helps ensure that complex cases are managed by specialized teams from the outset, which is associated with better patient outcomes.
For patients already diagnosed with epithelial ovarian cancer, the HE4 test serves the function of monitoring. A rising HE4 level after successful treatment may indicate a recurrence of the disease, while a declining level during chemotherapy suggests a positive response to treatment. HE4 is not suitable for general population screening because its predictive value is only high in the context of a pre-existing clinical concern, such as an ovarian mass or a history of the disease. The final interpretation of any HE4 result must always integrate the patient’s full clinical history, physical examination findings, and imaging results.