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Test ID: HCCGS Hepatocellular Carcinoma Risk Panel with GALAD Score, Serum


Advisory Information


GALAD score testing (this test) should not be performed for pregnant patients as alpha-fetoprotein results are elevated during pregnancy.



Necessary Information


Gender and age are required.



Specimen Required


Container/Tube:

Preferred: Red top

Acceptable: Serum gel

Specimen Volume: 0.5 mL

Collection Instructions: Centrifuge and aliquot serum.


Useful For

Risk assessment for development of hepatocellular carcinoma in patients with chronic liver disease

Profile Information

Test ID Reporting Name Available Separately Always Performed
L3AFP AFP-L3% and Total AFP, S Yes Yes
DCP Des-Gamma-Carboxy Prothrombin, S Yes Yes
GAL1 GALAD Model Score No Yes
GAL2 Probability of HCC No Yes

Method Name

Isotachophoresis with Laser-Induced Fluorescence

Reporting Name

HCC Risk Panel with GALAD Score, S

Specimen Type

Serum

Specimen Minimum Volume

0.25 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Serum Frozen (preferred) 90 days
  Refrigerated  5 days

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, UDP-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 (DCP):

(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 of unconverted glutamic acid is secreted. Therefore, this noncarboxylated 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. The elevation 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, the 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 and Probability of HCC:

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 probability 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 probability estimate of HCC is calculated as follow Pr(HCC) = exp(Z)/(1 + exp[Z]).

 

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.

Reference Values

TOTAL ALPHA-FETOPROTEIN (AFP):

<4.7 ng/Ml

 

AFP L3-PERCENT:

<10%

 

DES-GAMMA-CARBOXY PROTHROMBIN:

<7.5 ng/mL

 

GAL1:

Not applicable

 

GAL2:

Not applicable

Interpretation

Alpha-fetoprotein (AFP)-L3 results of 10% or more are associated with a 7-fold increased risk of developing hepatocellular carcinoma (HCC). Patients with AFP-L3 levels of 10% or more should be monitored more intensely for evidence of hepatocellular carcinoma according to current practice guidelines.

 

Total serum AFP results above 200 ng/mL are highly suggestive of a diagnosis of HCC. In patients with liver disease, a total serum AFP level above200 ng/mL is near 100% predictive of HCC. With decreasing total AFP levels, there is an increased likelihood that chronic liver disease, rather than HCC, is responsible for the AFP elevation.

 

Based on a retrospective study at Mayo Clinic, for patients with total AFP levels 200 ng/mL or less, AFP-L3 specificity approaches 100% for HCC when its percentage exceeds 35% of the total AFP.(4)

 

AFP concentrations over 100,000 ng/mL have been reported in normal newborns, and the values rapidly decline in the first 6 years of life.

 

Des-gamma-carboxy prothrombin (DCP):

In patients with an elevated DCP result (≥7.5 ng/mL), the risk of developing HCC is 36.5% (95% CI 23.5%-49.6%). The risk of developing HCC with a negative DCP result (<7.5 ng/mL) is 7.6% (95% CI 4.4%-10.8%).

 

Gender, Age, AFP-L3, AFP, DCP (GALAD) Score and Probability of HCC:

The probability of the presence of HCC is estimated from the GALAD model score. Higher GALAD model scores correlate with increased risk of HCC. The area under the curve (AUC) of a receiver operating characteristic (ROC) curve of the GALAD score was 0.95 for all HCC detection, and 0.92 for the detection of early stage HCC. Additionally, the AUC of the GALAD score (0.95) was higher than that of ultrasound alone for all HCC detection (AUC of 0.82, P <0.01).

 

The sensitivity and specificity performance characteristics of the GALAD score for HCC will be influenced by the selected GALAD score cut-off. For example at an optimal AUC cutoff of -0.76, the GALAD score had 91% sensitivity and 85% specificity for HCC detection. At a more specific GALAD score cutoff of 0.88, the observed sensitivity was 80% for HCC detection with an observed specificity of 97%.

 

The GALAD model was developed and validated in patient cohorts with a prevalence of HCC ranging from 35% to 49%. The performance of the model may be altered in populations with different HCC prevalence. In addition, the clinical performance of the GALAD score varies by etiology of HCC and therefore may be different in different regions of the world.

Clinical Reference

1. Okuda K: Hepatocellular carcinoma. J Hepatol 2000;32(Suppl 1):225-237

2. Kawai K, Kojima T, Miyanaga N, et al: Lectin-reactive alpha-fetoprotein as a marker for testicular tumor activity. Int J Urol 2005;12:284-289

3. Noda K, Miyoshi E, Kitada T, et al: The enzymatic basis for the conversion of nonfucosylated to fucosylated alpha-fetoprotein by acyclic retinoid treatment in human hepatoma cells: Activation of alpha 1-6 fucosyltransferase. Tumor Biol 2002;23:202-211

4. Leerapun A, Suravarapu S, Bida JP, et al: The utility of serum AFP-L3 in the diagnosis of hepatocellular carcinoma: Evaluation in a U.S. referral population. Clin Gastroenterol Hepatol 2007;5(3):394-402

5. Carr B, Kanke F, Wise M, Satomura S: Clinical evaluation of Lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci 2007;52:776-782

6. Durazo FA, Blatt LM, Corey WG, et al: Des-gamma-carboxy prothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol 2008;23:1541-1548

7. Marrero JA, Feng Z, Wang Y, et al: Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137:110-118

8. Bertino G, Ardiri AM, Calvagno GS, et al: Prognostic and diagnostic value of des-gamma-carboxy prothrombin in liver cancer. Drug News Perspect 2010 Oct;23(8):498-508

9. Johnson P, Pirrie S, Cox T, et al: The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiol Biomarkers Prev 2014 Jan;23(1):144-153

10. Berhane S, Toyota H, Tada T, et al: Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatic 2016 Jun;14(6):875-886

11. Yang JD, Addissie BD, Mara KC, et al: GALAD Score for Hepatocellular Carcinoma Detection in Comparison with Liver Ultrasound and Proposal of GALADUS Score. Cancer Epidemiol Biomarkers Prev 2019 Mar;28(3):531-538 doi: 10.1158/1055-9965

12. Chaiteerakij R, Addissie BD, Roberts LR: Update on biomarkers of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2015 Feb;13(2):237-245 doi: 10.1016/j.cgh.2013.10.038

Day(s) and Time(s) Performed

Monday, Wednesday, Friday; 10 a.m.

Analytic Time

Same day/1 day

Test Classification

This test has been cleared, approved or is exempt by the U.S. Food and Drug Administration and is used per manufacturer's instructions. Performance characteristics were verified by Mayo Clinic in a manner consistent with CLIA requirements.

CPT Code Information

82107

83951

LOINC Code Information

Test ID Test Order Name Order LOINC Value
HCCGS HCC Risk Panel with GALAD Score, S 96452-8

 

Result ID Test Result Name Result LOINC Value
TAFP Total AFP, S 1834-1
DCP Des-Gamma-Carboxy Prothrombin, S 34444-0
GAL1 GALAD Model Score 96450-2
GAL2 Probability of HCC 96709-1
L3 %L3 42332-7
INT67 Interpretation 69048-7
Mayo Clinic Laboratories | Gastroenterology Catalog Additional Information:

mml-gi-liver-hcc