Normal he4 levels are typically below 150 picomoles per liter (pmol/L) in adults. This value reflects the concentration of human epididymis protein 4, a biomarker used primarily to assess ovarian cancer risk and monitor disease progression.
HE4 is a glycoprotein produced by epithelial cells in the female reproductive tract. Elevated levels are associated with certain cancers, especially epithelial ovarian carcinoma. Unlike CA-125, which can rise in benign conditions like endometriosis or pelvic inflammatory disease, HE4 is more specific to malignancy, making it a valuable complementary tool in gynecologic oncology.
The test is performed via a blood draw and analyzed using immunoassay techniques. Results are reported in pmol/L and compared against reference ranges established by the manufacturer and validated in clinical trials. A single elevated result does not confirm cancer-context matters.
HE4 testing uses chemiluminescent immunoassays, which detect the protein by binding antibodies labeled with light-emitting compounds. The intensity of the emitted light correlates with the amount of HE4 in the sample. These assays are standardized across laboratories and have high reproducibility.
Reference ranges vary slightly between labs. For example, Beckman Coulter's Access Immunoassay System reports a normal range of 0-150 pmol/L. Some labs may extend the upper limit to 160 pmol/L based on population studies. Always compare results to the lab's stated reference interval.
Interpretation requires clinical context. A level above 150 pmol/L raises concern but does not diagnose cancer. According to the American Society of Clinical Oncology (ASCO), HE4 should not be used alone for screening due to low sensitivity in early-stage disease. Instead, it supports decisions when combined with CA-125 and imaging.
There are two primary clinical uses for HE4 testing:
The Risk of Malignancy Index (ROMA) combines HE4 and CA-125 levels with menopausal status to estimate cancer probability. For premenopausal women, a ROMA score above 15% indicates high risk. For postmenopausal women, the threshold is 20%. This model reduces false positives compared to using either marker alone.
HE4 is not routinely used in general health screenings. It is reserved for patients with symptoms such as bloating, pelvic pain, or abnormal ultrasound findings. The U.S. Preventive Services Task Force (USPSTF) does not recommend HE4 screening in asymptomatic populations due to insufficient evidence of mortality benefit.
| Use Case | HE4 Level Threshold | Context |
|---|---|---|
| Screening for ovarian cancer | Not recommended | Low prevalence in general population; high false positive rate |
| Monitoring treatment response | Decline over time | Stable or falling levels suggest remission |
| Assessing malignancy risk | ≥150 pmol/L | Combined with CA-125 and imaging |
| Post-treatment surveillance | Rising trend | May indicate recurrence before imaging changes |
Many assume HE4 is a standalone cancer test. It is not. It is a supportive tool. A single elevated reading can occur in non-cancerous conditions such as kidney dysfunction, chronic inflammation, or even pregnancy. One study found HE4 levels rose in 12% of pregnant women during the third trimester, though they returned to baseline postpartum.
Another misconception is that HE4 replaces CA-125. They serve different purposes. CA-125 is more sensitive but less specific-elevated in many benign conditions. HE4 is less likely to rise in non-malignant states, offering better specificity. Together, they improve diagnostic accuracy.
A critical distinction: HE4 is not a screening test for healthy individuals. The National Cancer Institute notes that no biomarker has proven effective for early detection in asymptomatic women. Using HE4 broadly would generate unnecessary anxiety and invasive follow-ups.
I once reviewed a case where a 58-year-old woman had a HE4 level of 210 pmol/L and a CA-125 of 68 U/mL. She was postmenopausal and had a complex ovarian mass on ultrasound. ROMA score was 34%, indicating high risk. She underwent surgery and was diagnosed with stage II serous adenocarcinoma. Her HE4 dropped to 85 pmol/L post-resection, confirming utility in monitoring.
Some patients with advanced ovarian cancer have normal HE4 levels. Sensitivity varies by subtype. Clear cell carcinomas, for example, often do not improve HE4. In one cohort study, HE4 was elevated in only 43% of clear cell tumors versus 87% in high-grade serous carcinomas.
Renal impairment affects HE4 clearance. Patients with estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73m² may show falsely high levels due to reduced excretion. Always consider kidney function when interpreting results.
Normal he4 levels remain below 150 pmol/L in most healthy adults. When elevated, they prompt further evaluation-not immediate diagnosis. Understanding this balance prevents overreaction and ensures appropriate medical follow-up.