Unit Converter
HE4 – Human epididymal protein 4
(Ovarian Cancer Biomarker – Especially for Epithelial Ovarian Cancer & ROMA Index)
Synonyms
- HE4
- Human epididymal protein 4
- WFDC2 (WAP four-disulfide core domain protein 2)
- Ovarian cancer marker HE4
- Epithelial tumor marker
Units of Measurement
- pmol/L
- nmol/L
Unit Conversions
(HE4 Molecular Weight ≈ 25 kDa)
1 nmol/L = 1000 pmol/L
1 pmol/L = 0.001 nmol/L
(Some assays report in pmol/L only; molar units are standard.)
Description
HE4 (WFDC2) is a secreted glycoprotein normally expressed in the:
- Epididymis
- Respiratory epithelium
- Renal tissue
Clinically, it is an important serum biomarker for epithelial ovarian cancer (EOC), especially serous and endometrioid subtypes.
HE4 is FDA approved with CA-125 as part of the ROMA (Risk of Ovarian Malignancy Algorithm).
Physiological Role
Physiologic function is not fully understood. Proposed roles:
- Protease inhibitor
- Innate immunity
- Sperm maturation in epididymis
However, clinical significance lies in its overexpression in ovarian tumors.
Clinical Significance
High HE4
Most clinically important: Ovarian cancer.
1. Epithelial Ovarian Cancer (EOC) – Primary Use
Elevated in:
- Serous carcinoma
- Endometrioid carcinoma
Advantages over CA-125:
- Higher specificity
- Less elevation in benign gynecological conditions
- Not elevated in endometriosis
2. Monitoring Cancer Treatment
- Tracks response to therapy
- Helps detect relapse/recurrence
- Often rises earlier than CA-125
3. Ovarian Mass Evaluation (ROMA Index)
HE4 + CA-125 + menopausal status = ROMA score
Used to:
- Stratify risk of malignancy
- Guide referral to gynecologic oncologist
4. Other Cancers
Elevated in some cases:
- Endometrial carcinoma
- Lung adenocarcinoma
- Pancreatic cancer
5. Renal Impairment
HE4 is cleared by kidneys - levels increase in:
- CKD
- AKI
Important to interpret with renal function (eGFR).
Low HE4
- Normal
- No clinical consequence
- Useful to rule out ovarian malignancy in appropriate context
Reference Intervals
(Mayo + ARUP + FDA ROMA + Tietz 8E)
Ranges vary by age, sex, renal function.
Adult Women (Premenopausal)
- < 70 pmol/L (typical)
Some labs use: <60–90 pmol/L
Postmenopausal
- < 140 pmol/L
Very High Levels
- >150–200 pmol/L → increased risk
- >300–500 pmol/L → highly suggestive of malignancy
- >1000 pmol/L → advanced ovarian cancer or renal failure
Diagnostic Uses
1. Risk Assessment of Ovarian Mass (ROMA Algorithm)
ROMA uses:
- HE4
- CA-125
- Menopausal status
Gives a predictive score for ovarian malignancy.
2. Diagnosis of Epithelial Ovarian Cancer
Particularly useful for:
- Serous tumors
- Endometrioid tumors
- Early-stage disease
3. Treatment Monitoring
- Falling HE4 → good treatment response
- Rising HE4 → relapse / progression
4. Distinguish Benign vs Malignant Masses
HE4 is less elevated in:
- Endometriosis
- Benign cysts
- Fibroids
Compared to CA-125.
5. Prognosis
High HE4 levels correlate with:
- Advanced stage
- Recurrence
- Poor survival
6. Endometrial Cancer
HE4 often elevated in:
- High-grade endometrial carcinoma
- Serous/clear cell endometrium cancers
Analytical Notes
- Serum or EDTA plasma
- Stable biomarker; fasting not required
- Renal impairment markedly increases levels
- Smoking slightly elevates HE4
- Use the same assay for serial monitoring
- Inter-assay variability exists
Clinical Pearls
- HE4 + CA-125 improves sensitivity for early ovarian cancer detection.
- Normal HE4 does not exclude ovarian cancer (mucinous tumors may be negative).
- Strongly independent of endometriosis - unlike CA-125.
- Correct interpretation requires considering renal function (creatinine).
- HE4 can predict recurrence earlier than CA-125 in many patients.
Interesting Fact
HE4’s receptor-binding biology is still under investigation—but its clinical performance in ovarian cancer exceeds early markers discovered decades ago.
References
- Tietz Clinical Chemistry & Molecular Diagnostics, 8th Edition - Tumor Markers.
- FDA-cleared ROMA Algorithm Documentation.
- Mayo Clinic Laboratories - HE4.
- ARUP Consult - Ovarian Cancer Markers.
- ESGO/ACOG Ovarian Cancer Evaluation Guidelines.
- NIH – HE4 in Oncology Research.