What are the implications and management of elevated Alpha-Fetoprotein (AFP) levels in pregnant and non-pregnant individuals?

Elevated Alpha-Fetoprotein (AFP): Clinical Implications and Management

In Pregnancy

Elevated maternal serum AFP (MSAFP) between 16-18 weeks gestation requires immediate systematic evaluation starting with ultrasound to confirm gestational age, exclude multiple gestation and fetal demise, followed by level II ultrasound and amniocentesis with acetylcholinesterase testing if the elevation persists after these benign causes are excluded. 1

Screening Protocol and Timing

• Optimal screening window is 16-18 weeks gestation, with acceptable range of 15-20 weeks 1, 2
• AFP is synthesized by fetal yolk sac and liver, passing into maternal circulation, serving as the primary screening marker for open neural tube defects (ONTDs) 2, 3
• Detection rates reach 95% or greater for anencephaly and 75-90% for open spina bifida using a 2.0 MoM (multiples of median) cutoff 2

Differential Diagnosis of Elevated MSAFP

Fetal causes:

• Neural tube defects (anencephaly, open spina bifida) - most common serious etiology 1, 2, 4
• Ventral abdominal wall defects (gastroschisis, omphalocele) 5, 4
• Fetal demise 1, 4
• Other structural anomalies: renal abnormalities, sacrococcygeal teratomas, intestinal atresias 5, 4

Benign causes requiring exclusion first:

• Incorrect gestational age dating 1, 2
• Multiple gestation (typically 2.3 MoM in twins) 5
• Fetal blood contamination 3

Placental causes:

• Abnormal placental barrier allowing increased fetal-maternal transfer 6
• This explains most unexplained elevations where amniotic fluid AFP remains normal 6

Systematic Evaluation Algorithm

Step 1: Initial Assessment

• Confirm gestational age with level I ultrasound 1
• Exclude multiple gestation and fetal demise 1
• Adjust for maternal factors: weight, race, and diabetes mellitus (AFP levels are lower in women with IDDM) 1, 2

Step 2: Repeat Testing (if indicated)

• Second MSAFP specimen is most appropriate when first result is minimally elevated and time permits 1
• Skip repeat testing when result is very elevated and expert sonography is available, or pregnancy is relatively advanced 1

Step 3: Advanced Evaluation

• Prompt referral to center with level II ultrasound capability performed by experienced sonographers 1
• Amniocentesis for amniotic fluid AFP and acetylcholinesterase (AChE) assay 1, 2
• Genetic counseling throughout the process 1, 2

Low MSAFP Implications

• Low values (e.g., 0.12-0.17 MoM) may indicate chromosomal abnormalities, particularly Down syndrome 2, 5
• Also associated with congenital diaphragmatic hernia and duodenal atresia 4
• The cutoff for low values should consider the Down syndrome risk of a 35-year-old woman (1/270 in second trimester) 1

Critical Pitfalls to Avoid

• Never interpret AFP results in isolation - always consider gestational age, maternal weight, race, and IDDM status 2
• Do not rely solely on AFP without confirmatory testing when results are abnormal 2
• Failing to establish separate normative values for different patient populations (especially IDDM) affects accuracy 1, 2
• Inadequate counseling before and after testing impacts patient care 2

Informed Consent Requirements

• MSAFP screening must be voluntary with documented informed consent 1, 2
• Patients should be fully informed about procedures, implications, and available options before specimen collection 1
• Some couples may decline testing for religious or ethical reasons 1

In Non-Pregnant Individuals

Elevated AFP in non-pregnant adults warrants immediate evaluation for hepatocellular carcinoma (HCC), particularly in patients with chronic liver disease, using multiphasic contrast-enhanced CT or MRI, as AFP >400 ng/mL has high positive predictive value for HCC when combined with imaging showing a growing liver mass. 1

Clinical Context and Interpretation

• AFP is not sensitive or specific for HCC - only 18% of HCC patients have values >400 ng/mL and 46% have normal AFP <20 ng/mL 1
• Imaging findings of classic enhancement are more definitive than AFP level alone in the diagnostic setting 1
• AFP >200-400 ng/mL should be tested as prognostic factors of poor outcome 1

Differential Diagnosis in Adults

Malignant causes:

• Hepatocellular carcinoma (primary concern in chronic liver disease) 1
• Intrahepatic cholangiocarcinoma 1
• Germ cell tumors 1
• Metastases from colon cancer 1
• Lymphoma 1

Non-malignant causes:

• Chronic hepatitis B or C infection 1
• Chronic liver disease without malignancy 1

Evaluation Protocol

When AFP is elevated without identified liver mass:

• Perform multiphasic abdominal contrast-enhanced CT or MRI to determine enhancement characteristics, extent and number of lesions, vascular anatomy, and extrahepatic disease 1
• Gadolinium contrast is preferred for MRI 1
• Additional imaging studies are recommended for rising serum AFP in absence of liver mass 1

When liver mass is detected:

• Multidisciplinary team management is associated with improved outcomes including higher rates of treatment, higher rates of curative treatments in early stages, and prolonged survival 1
• Biopsy may be considered when lesion is suspicious for malignancy but imaging does not meet HCC criteria 1
• A growing mass with negative biopsy does not rule out HCC - continual monitoring with multidisciplinary review is required 1

Prognostic Significance

• Elevated AFP is associated with poorer prognosis across multiple scenarios 1
• Predicts risk of tumor recurrence after resection 1
• Predicts risk of drop-out in liver transplant waiting list 1
• Predicts survival and recurrence risk after liver transplantation 1
• Predicts response to loco-regional therapies and survival in advanced HCC 1

Normal Physiologic Context

• AFP is the major protein of fetal serum, produced by fetal liver 3
• Pregnancy is the only normal situation where AFP is present after birth 3
• Small amounts continue to be produced in adults, but marked elevation always requires investigation 3, 7