When should Alpha-Fetoprotein (AFP) levels be checked in patients with a history of liver disease, such as hepatitis B or C, or cirrhosis, and in pregnant women?

When Should AFP Be Checked?

AFP should be checked every 6 months in combination with liver ultrasound for all patients at high risk for hepatocellular carcinoma, including those with chronic hepatitis B or C infection, cirrhosis of any etiology, and specific high-risk populations based on age, ethnicity, and family history. 1, 2

High-Risk Populations Requiring AFP Surveillance

Patients with Chronic Hepatitis B

• All HBsAg-positive patients age 20 and older should undergo AFP testing every 6 months, regardless of cirrhosis status 1
• Asian men over age 40 and Asian women over age 50 require surveillance 1, 2
• African and African American patients with hepatitis B over age 20 need screening 1
• Any HBsAg-positive person with a family history of HCC should be screened every 6 months regardless of age 1
• Patients over age 40 with persistent ALT elevation and/or HBV DNA >2,000 IU/ml require surveillance 1

Patients with Cirrhosis

• All cirrhotic patients of any etiology require AFP testing every 6 months, including those with hepatitis C, NASH, alcoholic cirrhosis, primary biliary cholangitis, genetic hemochromatosis, and alpha-1 antitrypsin deficiency 2
• The surveillance interval should be every 6 months, not 6-12 months, as the more frequent interval improves early detection 1

Patients with Chronic Hepatitis C

• All patients with chronic hepatitis C and cirrhosis require surveillance every 6 months 1, 2
• Non-cirrhotic patients with chronic hepatitis C and advanced fibrosis (≥F3) should undergo surveillance 1

Surveillance Protocol

Standard Approach

• AFP should always be combined with liver ultrasound, never used alone 1, 2
• The combination of ultrasound plus AFP increases early-stage HCC detection from 45% to 63% compared to ultrasound alone 2
• Testing interval is every 6 months for standard risk patients 1, 2

Enhanced Surveillance for Extremely High-Risk Patients

• In Japan, patients with HBV/HCV-related cirrhosis (extremely high-risk group) undergo surveillance every 3-4 months 1
• This more frequent interval may be considered for patients with multiple risk factors 1

Interpreting AFP Results

Diagnostic Thresholds

• AFP ≥200 ng/mL has high specificity (97-99%) but low sensitivity (22-36%) for HCC diagnosis 2
• At the 20 ng/mL cutoff, sensitivity is 50-75% for small HCC with specificity >90% 2
• Normal AFP does not exclude HCC—up to 46% of HCC patients have AFP <20 ng/mL 2

Critical Pattern Recognition

• A rising AFP in a step-like manner strongly suggests HCC, even if absolute values remain below 200 ng/mL 2
• Serial 3-6 month AFP increase ≥10% combined with AFP ≥20 ng/mL increases HCC risk 22-42 fold within 6 months 3, 2
• Progressive AFP elevation ≥7 ng/mL per month has 71.4% sensitivity and 100% specificity for HCC diagnosis 2
• Trajectory analysis shows that patients in the "AFP-increase group" have 24-fold increased HCC risk compared to those with stable AFP 3

Special Considerations and Pitfalls

When AFP Alone Is Insufficient

• AFP has poor sensitivity (39-65%) for HCC diagnosis overall, particularly in early-stage disease 2
• AFP can be elevated in patients with active hepatitis or cirrhosis without HCC 1
• Fluctuating AFP levels in cirrhotic patients may reflect hepatitis flares rather than HCC development 1

When to Escalate Imaging

• Patients with rising AFP but normal ultrasound should undergo MRI, which is more sensitive for tumors <1 cm 1
• MRI is also preferred for patients with cirrhosis, obesity limiting ultrasound quality, heterogeneous liver echotexture, or indeterminate lesions 1

Monitoring Patients Not Meeting Treatment Criteria

• HBeAg-positive patients with persistently normal ALT should have AFP checked every 3-6 months 1
• HBeAg-negative inactive carriers should have AFP tested every 3 months during the first year, then every 6-12 months 1
• More frequent AFP monitoring is warranted when ALT becomes elevated 1

AFP in Pregnancy

While the evidence provided focuses primarily on liver disease surveillance, AFP is also routinely checked in pregnancy as part of maternal serum screening, typically between 15-20 weeks gestation for neural tube defects and chromosomal abnormalities. However, this is a distinct clinical context from HCC surveillance and uses different reference ranges and interpretation algorithms.

Key Algorithmic Approach

1. Identify if patient is high-risk (chronic HBV/HCV, cirrhosis, specific demographics) 1, 2
2. If high-risk: AFP + ultrasound every 6 months 1, 2
3. If extremely high-risk (HBV/HCV cirrhosis): Consider every 3-4 months 1
4. Monitor AFP trends, not just absolute values—serial increase ≥10% over 3-6 months is highly concerning 3, 2
5. If AFP rising but ultrasound negative: Obtain MRI 1
6. Never rely on AFP alone—always combine with imaging 2