What is the accuracy of alpha-fetoprotein (AFP) for diagnosing hepatocellular carcinoma (HCC)?

Alpha-Fetoprotein (AFP) Accuracy for Hepatocellular Carcinoma Diagnosis

Alpha-fetoprotein (AFP) alone is an inadequate test for hepatocellular carcinoma (HCC) screening or diagnosis, with limited sensitivity of only 60% at the commonly used cut-off of 20 ng/mL, meaning it would miss 40% of HCC cases. 1

Diagnostic Performance of AFP at Different Cut-off Values

• At a cut-off of 20 ng/mL, AFP has a sensitivity of approximately 60% and specificity of 80-94% for detecting HCC at any stage, but sensitivity drops to only 32-49% for early-stage tumors 1
• When the cut-off is raised to 200 ng/mL, sensitivity decreases to 22.4% while specificity improves to 66-97% 1
• Further increasing the cut-off to 400 ng/mL reduces sensitivity to 17.1% with specificity of 60-96% 1
• The positive predictive value (PPV) of AFP is highly dependent on HCC prevalence in the population being tested:
  • With HCC prevalence at 50%, the PPV of AFP at 20 ng/mL is 84.6% 1
  • With HCC prevalence at 5% (more typical in liver clinics), the PPV drops to only 41.5% 1
  • Even at a cut-off of 400 ng/mL with 5% prevalence, the PPV is only 60% 1

Clinical Utility of AFP in HCC Diagnosis

• AFP has greater diagnostic value in specific clinical scenarios:
  • In cirrhotic patients with a liver mass, an AFP >200 ng/mL has a very high positive predictive value for HCC 1, 2
  • AFP accuracy varies by underlying liver disease etiology - it is more accurate in HCV-negative patients (c-statistic 0.89) than in HCV-positive patients (c-statistic 0.83) 3
  • Different optimal cut-offs have been suggested based on etiology: 59 ng/mL for HCV-positive patients and 11 ng/mL for HCV-negative patients 3
  • AFP has significantly higher accuracy for detecting HCC in HIV-positive patients with cirrhosis compared to HIV-negative patients (c-statistic 0.81 vs 0.59) 3

AFP in Surveillance vs. Diagnosis

• AFP is considered inadequate as a standalone surveillance test due to its limited sensitivity 1, 4
• When combined with ultrasound for surveillance, AFP increases sensitivity for early HCC detection from 45% to 63%, providing some additional benefit 1, 5
• For diagnosis (rather than surveillance), AFP still has value when significantly elevated:
  • In cirrhotic patients with a liver mass, AFP >200 ng/mL has high specificity for HCC 1, 2
  • A persistently elevated AFP has been shown to be a risk factor for HCC development 1

Comparison with Other Diagnostic Modalities

• Ultrasound has a specificity >90% but insufficient sensitivity to detect HCC in many cirrhotic patients 6
• CT scanning shows sensitivity of 68% and specificity of 93% for HCC detection 6
• MRI demonstrates superior sensitivity (81%) compared to both ultrasound and CT for HCC detection 6, 7
• Combining AFP with other biomarkers can improve diagnostic accuracy:
  • Des-gamma-carboxy prothrombin (DCP/PIVKA-II) and AFP-L3 (a fucosylated variant of AFP) can enhance diagnostic performance when used with AFP 1, 2, 8
  • The GALAD model (incorporating Gender, Age, AFP-L3, AFP, and DCP) has shown sensitivity >60% for early HCC detection 1

Pitfalls and Limitations

• AFP can be elevated in non-HCC conditions, including:
  • Acute and chronic liver diseases with significant hepatic inflammation 8
  • During periods of active hepatocyte regeneration 8
  • In some non-HCC malignancies such as cholangiocarcinoma 1
• The diagnostic performance of AFP varies significantly based on:
  • Tumor size and aggressiveness 1
  • Underlying liver disease etiology 3, 8
  • Activity of underlying liver disease 1, 8
  • Different laboratory measurement methods 8

In conclusion, while AFP has limitations as a standalone test for HCC, it retains clinical value when significantly elevated (>200 ng/mL) in patients with liver masses, and when used in combination with appropriate imaging studies. For optimal diagnostic accuracy, AFP should be interpreted in the context of imaging findings and patient-specific factors.