Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma

Abstract

Background & aims: Alpha-fetoprotein (AFP) is widely used as a surveillance test for hepatocellular carcinoma (HCC) among patients with cirrhosis. Des-gamma carboxy-prothrombin (DCP) and lectin-bound AFP (AFP-L3%) are potential surveillance tests for HCC. The aims of this study were to determine performance of DCP and AFP-L3% for the diagnosis of early HCC; whether they complement AFP; and what factors affect DCP, AFP-L3%, or AFP levels.

Methods: We conducted a large phase 2 biomarker case-control study in 7 academic medical centers in the United States. Controls were patients with compensated cirrhosis and cases were patients with HCC. AFP, DCP, and AFP-L3% levels were measured blinded to clinical data in a central reference laboratory.

Results: A total of 836 patients were enrolled: 417 (50%) were cirrhosis controls and 419 (50%) were HCC cases, of which 208 (49.6%) had early stage HCC (n = 77 very early, n = 131 early). AFP had the best area under the receiver operating characteristic curve (0.80, 95% confidence interval [CI]: 0.77-0.84), followed by DCP (0.72, 95% CI: 0.68-0.77) and AFP-L3% (0.66, 95% CI: 0.62-0.70) for early stage HCC. The optimal AFP cutoff value was 10.9 ng/mL leading to a sensitivity of 66%. When only those with very early HCC were evaluated, the area under the receiver operating characteristic curve for AFP was 0.78 (95% CI: 0.72-0.85) leading to a sensitivity of 65% at the same cutoff.

Conclusions: AFP was more sensitive than DCP and AFP-L3% for the diagnosis of early and very early stage HCC at a new cutoff of 10.9 ng/mL.

Figure 1

Serum levels of alpha-fetoprotein (AFP), des-gamma carboxyprothrombin (DCP) and lectin-bound AFP among those with cirrhosis, early stage Hepatocellular carcinoma (HCC) and late stage of HCC (the latter defined as Intermediate and Advanced stages based on the Barcelona staging classification). The box refers to the 25^th to and 75^th percentile values with a line indicating the median levels, while the interquartile range extend outside the box. Points outside the interquertile range are outliers. Median levels are shown for each marker at the bottom of each. Both early and late stage HCC had higher levels (p<0.0001) compared to cirrhosis. Late stage HCC had higher levels compared to early stage HCC (p<0.05).

Figure 2

Receiver operating characteristics (ROC) curve evaluating those with early stage HCC (n=208) and cirrhosis controls (n=417). The area under the ROC curve is shown with its 95% confidence intervals. DCP is black, AFP is red, AFP-L3 is blue and combination of AFP and DCP is pink.

Figure 3

Scattered plot for alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP) according viral and non-viral etiology. Red = early stage HCC, green = cirrhosis controls.

Figure 4

Receiver operating characteristics (ROC) curve according to etiology of liver disease in those with early stage HCC (n=208) and cirrhosis controls (n=417). Panel A shows those with viral etiology and Panel B shows those with non-viral etiology The area under the ROC curve is shown with its 95% confidence intervals. DCP is black, AFP is red, AFP-L3 is blue and combination of AFP and DCP is pink.