Clinical Information

Worldwide, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death.(1) While HCC can be treated effectively in its early stages, most patients are not diagnosed until they are symptomatic and at higher grades and stages, which are less responsive to therapies. Alpha-fetoprotein (AFP) is the standard serum tumor marker utilized in the evaluation of suspected HCC. However, increased serum concentrations of AFP might be found in chronic hepatitis and liver cirrhosis, as well as in other tumor types (eg, germ cell tumors),(2) decreasing the specificity of AFP testing for HCC. Furthermore, AFP is not expressed at high levels in all HCC patients, resulting in decreased sensitivity, especially in potentially curable small tumors.

AFP-L3:

AFP is differentially glycosylated in several hepatic diseases. For example, alpha-(1,6)-fucosyltransferase is differentially expressed in hepatocytes following malignant transformation.(3) This enzyme incorporates fucose residues on the carbohydrate chains of AFP. Different glycosylated forms of AFP can be recognized following electrophoresis by reaction with different carbohydrate-binding plant lectins. The fucosylated form of serum AFP that is most closely associated with HCC is recognized by a lectin from the common lentil (Lens culinaris). This is designated as AFP-L3 (third electrophoretic form of lentil lectin-reactive AFP). AFP-L3 is most useful in the differential diagnosis of individuals with total serum AFP of 200 ng/mL or less, which may result from a variety of benign pathologies, such as chronic liver diseases.

Des-gamma-carboxy prothrombin:

Des-gamma-carboxy prothrombin (DCP), also known as the protein induced by vitamin K absence or antagonist II (PIVKA-II), is an abnormal form of the coagulation protein, prothrombin. DCP is a nonfunctional prothrombin resulting from a lack of carboxylation of 10 glutamic acid residues in the N-terminal portion of the molecule. In normal liver, prothrombin undergoes post-translational carboxylation before release into the peripheral blood. The carboxylation converts specific amino-terminal glutamic acid residues to gamma-carboxyglutamic acid. The vitamin K-dependent carboxylase responsible for the carboxylation is absent in many HCC cells, and an abnormal prothrombin with all or some unconverted glutamic acid is secreted. Therefore, this non-carboxylated form (DCP) has been used as an HCC biomarker.

DCP is considered a complementary biomarker to AFP and AFP-L3 for assessing the risk of developing HCC. Elevations of both AFP-L3 and DCP indicate progression of HCC, albeit they reflect different features of the progression. In a prospective study of patients in the United States with an established diagnosis of HCC, sensitivities for AFP, AFP-L3, and DCP were 68%, 62%, and 73%, respectively. When the 3 markers were combined, the sensitivity was 86%. In another study, DCP levels were shown to correlate with tumor size and metastatic HCC. In this study, compared to AFP and AFP-L3, DCP had the highest sensitivity (87%) and the highest positive predictive value (87%) in patients with HCC due to chronic hepatitis B and C infections. A number of studies have shown that elevated serum DCP is significantly related to portal vein invasion or intrahepatic metastasis, which significantly affect prognosis for patients with HCC.

DCP can be elevated in other conditions besides HCC. Conditions such as obstructive jaundice, intrahepatic cholestasis causing chronic decrease in vitamin K, and ingestion of drugs such as warfarin or wide-spectrum antibiotics can result in high concentrations of DCP. In addition, 25% to 50% of patients with HCC will have a DCP value within the reference range. Because of this, a normal DCP value does not rule out HCC.

Gender, Age, AFP-L3, AFP, DCP (GALAD) Score:

Biomarkers of HCC include AFP, AFP-L3, and DCP. The GALAD model combines these three biomarkers with the patient's gender and age to estimate the risk of HCC in patients with chronic liver disease based on the following equation Z = -10.08 + 0.09 x age + 1.67 x sex + 2.34 log(10) (AFP) + 0.04 x AFP - L3 + 1.33 x log(10) (DCP), where sex = 1 for males, 0 for females.

The GALAD score is calculated using the lower limit of quantitation (LLOQ) when one or more of the following values are below the lower limit of quantitation: %L3, Total AFP, or DCP. In the event this occurs, the GALAD score is resulted as (<)GALAD score.

The GALAD model has been demonstrated to have higher diagnostic accuracy for the detection of HCC when compared to the use AFP, AFP-L3, and DCP markers alone or in combination. The performance of the GALAD score has also been reported to be superior to ultrasound for HCC detection.