Overview
The HE4 (Human Epididymis Protein 4) Test is a tumor-marker test mainly used for the diagnosis, monitoring, and risk assessment of ovarian cancer, especially epithelial ovarian cancers. HE4 is a protein that is present at normal levels in some tissues of the body, but it becomes overexpressed (produced in higher amounts) in certain ovarian cancers. Doctors often use HE4 alongside CA-125 to improve diagnostic accuracy and to detect high-risk cases earlier.
HE4 is considered a more specific and reliable marker than CA-125 because it is less likely to rise due to benign conditions like endometriosis, fibroids, or pelvic inflammatory disease.
Where HE4 Is Produced in the Body
In healthy individuals, HE4 is normally produced in:
- The epididymis (in males)
- The respiratory tract
- The female reproductive tract, especially fallopian tubes and endometrium
However, in women with ovarian cancer, cancerous epithelial cells begin producing HE4 at higher levels. This excess HE4 enters the bloodstream, which is why elevated levels can be detected in a blood test.
Why the HE4 Test Is Important
Even though HE4 has no natural helpful function in the body, measuring its levels is extremely important for medical diagnosis. HE4 helps in:
1. Early Detection of Ovarian Cancer
It is one of the most sensitive markers for epithelial ovarian cancer.
2. Risk Assessment (ROMA Score)
When combined with CA-125, HE4 is used to calculate the ROMA (Risk of Ovarian Malignancy Algorithm), which predicts whether a pelvic mass is likely to be cancerous.
3. Monitoring Treatment Response
HE4 levels can show if cancer treatment (surgery or chemotherapy) is working.
4. Detecting Recurrence
Rising HE4 levels after treatment may indicate that cancer has returned.
5. Differentiating Benign vs Malignant Tumors
HE4 gives clearer differentiation compared to CA-125 because benign gynecological diseases rarely elevate HE4.
Causes of Low or Negative HE4 Levels
Low or normal HE4 levels may be due to:
- No ovarian cancer present
- Benign (non-cancerous) gynecological conditions
- Early-stage ovarian cancer that does not produce HE4
- Ovarian cancer subtypes like mucinous tumors that do not elevate HE4
A negative HE4 test does not guarantee no cancer, but it makes ovarian malignancy less likely.
Symptoms of Low or Normal HE4 Levels
If HE4 levels are normal, there are no symptoms related to HE4 itself. It simply indicates:
- No tumor activity
- No abnormal HE4-producing cells
- Likely absence of ovarian cancer
Causes of High or Positive HE4 Levels
HE4 levels become high due to:
1. Epithelial Ovarian Cancer
Especially:
- Serous subtype
- Endometrioid subtype
These cancers commonly overproduce HE4.
2. Endometrial Cancer
Some uterine cancers may also elevate HE4.
3. Other Cancers (Less Common)
Includes:
- Lung cancer
- Pancreatic cancer
4. Rare Benign Causes
Though uncommon, slight elevations may appear in kidney disease or some inflammatory conditions, but this is much less frequent compared to CA-125.
Symptoms When HE4 Levels Are High
High HE4 levels indicate possible cancer, not symptoms caused directly by HE4 itself. Common symptoms seen in ovarian cancer include:
- Persistent abdominal bloating or swelling
- Pelvic or lower abdominal pain
- Feeling full quickly or loss of appetite
- Frequent urination or urinary pressure
- Unexplained weight loss
- Fatigue and weakness
These symptoms are often vague, which is why tumor-marker testing is useful.
Reference Ranges for HE4 Test
The reference range depends on the woman’s age and menopausal status:
- Premenopausal women: < 70 pmol/L
- Postmenopausal women: < 140 pmol/L
Different labs may have slight variations in their reference ranges because of the equipment or testing methods used.
Sample Type Used for the HE4 Test
- Blood sample (serum or plasma)
- No tissue sample is required for this test
- Often paired with CA-125 for ROMA score calculation
Test Preparation
Generally, no fasting or special preparation is required. However:
- Avoid smoking before the test
- Inform your doctor about hormonal medications
- If you have kidney disease, tell your doctor (it may affect values)
- If you have an ovarian mass, both HE4 and CA-125 may be ordered together
When to Consult a Doctor
You should consult a doctor if:
- You have symptoms like persistent bloating, pelvic pain, or early satiety
- You have a family history of ovarian or breast cancer
- You have an ovarian cyst that looks suspicious on ultrasound
- You are undergoing treatment for ovarian cancer and want to monitor progress
- You notice symptoms returning after treatment
Immediate medical attention is needed if severe abdominal pain or sudden swelling occurs.
Important Word Explanations
- Tumor Marker: A substance made by cancer cells or by the body in response to cancer.
- Epithelial Ovarian Cancer: The most common type of ovarian cancer, starting in the tissue covering the ovary.
- ROMA Score: A calculation using HE4 + CA-125 to determine cancer risk.
- Benign: Non-cancerous condition.
- Malignant: Cancerous growth capable of spreading.
- Overexpression: Producing much higher amounts than normal.
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