Patients affected by liver cirrhosis are at high risk for developing hepatocellular carcinoma. The aim of this study was to evaluate the feasibility of PIVKA-II (protein induced by vitamin K absence or antagonist-II) alone or in combination with α-1 fetoprotein, as a screening marker for development of hepatocellular carcinoma. Subjects and methods: A case-control study was conducted on 103 Military Hospital. 53 patients affected by hepatocellular carcinoma were considered as cases, while 31 patients affected by liver cirrhosis were considered as control. Results: At the set cut-off value of 40 mAU/mL, PIVKA-II was more sensitive (92.45% vs. 81.13%), but less specific than α-1 fetoprotein at the set cut-off value of 10 ng/mL (61.29% vs. 83.87%). The negative predictive value of PIVKA in combination with α-1 fetoprotein was 88.23% and the sensitive was 96.2%. Conclusion: PIVKA- II was more sensitive but less specific than α-1 fetoprotein in diagnosis of hepatocellular carcinoma and PIVKA-II, when combined with α-1 fetoprotein, may be considered as a screening test for hepatocellular carcinoma due to its high sensitive and negative predictive value.
Trang 1DIAGNOSTIC ACCURACY OF PIVKA-II, ALPHA-FETOPROTEIN
AND A COMBINATION OF BOTH IN DIAGNOSIS OF
HEPATOCELLULAR CARCINOMA
Pham Van Tran 1 ; Hoang Thi Minh 1
SUMMARY
Background/aim: Patients affected by liver cirrhosis are at high risk for developing hepatocellular carcinoma The aim of this study was to evaluate the feasibility of PIVKA-II (protein induced by vitamin K absence or antagonist-II) alone or in combination with α-1 fetoprotein, as a screening marker for development of hepatocellular carcinoma Subjects and methods: A case-control study was conducted on 103 Military Hospital 53 patients affected by hepatocellular carcinoma were considered as cases, while 31 patients affected by liver cirrhosis were considered as control Results: At the set cut-off value of 40 mAU/mL, PIVKA-II was more sensitive (92.45%
vs 81.13%), but less specific than α-1 fetoprotein at the set cut-off value of 10 ng/mL (61.29%
vs 83.87%) The negative predictive value of PIVKA in combination with α-1 fetoprotein was 88.23% and the sensitive was 96.2% Conclusion: PIVKA- II was more sensitive but less specific than α-1 fetoprotein in diagnosis of hepatocellular carcinoma and PIVKA-II, when combined with α-1 fetoprotein, may be considered as a screening test for hepatocellular carcinoma due to its high sensitive and negative predictive value
* Keywords: Cirrhosis; Hepatocellular carcinoma; PIVKA-II; α-1 fetoprotein
INTRODUCTION
Chronic hepatitis, cirrhosis, hepatocellular
carcinoma (HCC) are common and
dangerous diseases of the liver Currently,
there are many supportive methods for
the diagnosis, treatment monitoring and
prognosis of these diseases Non-invasive
diagnostic methods have been developed
One of these methods is the quantification
of biomarkers circulating in the blood
This method is easy to use and can be
carried out regularly
The most commonly utilized biomarker
in clinical practice for HCC is α-1 fetoprotein
(AFP) AFP may be used as a diagnostic
and prognostic marker Serum AFP levels also correlate with tumor size, tumor doubling time and post-treatment relapse [1, 2] However, it is not recommended for routine screening because it lacks specificity AFP may be elevated in other malignancies
(e.g gastric, embryonic cancer, intrahepatic
cholangiocarcinoma), as well as in many
benign conditions, both hepatic (e.g cirrhosis,
necrosis, acute hepatitis), and extrahepatic
(e.g pneumonia) Finally, AFP lacks sensitivity;
serum AFP levels are high in only 40 - 60%
of HCC cases and only 10 - 20% of early HCC [2] For these reasons, more sensitive and specific HCC markers are required
1.103 Military Hospital
Corresponding author: Pham Van Tran (phamvantran@yahoo.fr)
Date received: 20/12/2018
Date accepted: 21/01/2019
Trang 2PIVKA-II (protein induced by vitamin K
absence or antagonist II) also known as
des-gamma-carboxyprothrombin - DCP),
is an immature form of prothrombine without
any coagulative function It is synthesized
in the presence of acquired defects of
precursor carboxylation found in patients
with HCC [5] PIVKA-II may have a role in
HCC progression by acting as an autologous
growth factor [6] Moreover, high serum
levels of PIVKA-II are associated with
HCC size, microvascular invasion, metastatic
dissemination and HCC relapse after liver
transplantation and/or HCC nodule ablation
PIVKA-II is a specific marker for HCC, it is
poorly related to AFP and exhibits higher
sensitivity and specificity than AFP in
diagnosing HCC PIVKA-II is not elevated
in benign hepatic diseases (e.g cirrhosis,
necrosis), while it is elevated in HCC at
early stage as well as in HCC nodules of
all sizes For these reasons, some authors,
and especially Japanese guidelines on
HCC management proposed the use of
PIVKA-II for routine follow-up in patients
with high risk for developing HCC, as well
as a prognostic biomarker before surgery
to predict microvascular invasion, relapse
and overall poor prognosis [4, 8] In detail,
Japanese guidelines have suggested to
consider as a diagnostic marker of HCC with
high elevation of tumor markers, namely
AFP ≥ 200 ng/mL and PIVKA-II ≥ 40 mAU/mL
However, data on its performance as a
diagnostic marker are still incomplete
The aim of this study was: To evaluate
the feasibility of PIVKA-II (protein induced
by vitamin K absence or antagonist-II)
alone or in combination with AFP, as a
screening marker for development of HCC
SUBJECTS AND METHODS
A case-control study was performed in Gastroenterology Department, 103 Military
Hospital 53 patients affected by HCC were
considered as cases, while 31 patients affected by liver cirrhosis were considered
as control
All patients are diagnosed definitively and grouped based on underwent history-taking, physical examination, routine laboratory examinations and abdominal imaging either by abdominal ultrasonography, CT-scanning Cases: Cytological evidence of HCC as assessed in AASLD Hepatocellular Carcinoma Guidelines [2] Controls: Chronic hepatitis, cirrhosis and absence of nodular hepatic lesions under abdominal ultrasonography
In each patient: Take 2 mL of anticoagulant blood with heparin after fasting for at least 8 hours Centrifugal plasma separator AFP and PIVKA-II assay was performed using Architect ci16200 system of Abbott Company based on the principle of immunization with microcrystalline luminescence
Statistical analysis was performed using software package SPSS statistic 2.2
RESULTS
Table 1: Characteristics of patients (n = 84)
(n = 53)
Control
No differences were observed in gender and age between the two groups
Trang 3RESULTS
Table 1: Characteristics of patients (n = 84)
No differences were observed in gender and age between the two groups
Figure 1: The common clinical symptoms in two groups
In HCC, the common clinical symptoms were fatigue and right lower back pain
Other symptoms such as weight loss, gastrointestinal disorders were less frequent and
are comparable to patients with chronic liver disease
Table 2: Characteristics of tumor on abdominal ultrasonography and CT
Location
Number of tumor
Patients with primary tumors were on the right liver, followed by both lobes
Most patients had a tumor The results of abdominal ultrasonography and CT were not
uniform across all parameters
0 10
20
30
40
50
60
70
80
Cases Control
Trang 4Table 3: Concentration of AFP and PIVKA-II
Cases (n = 53) Median (min - max)
Controls (n = 31)
Both serum AFP (1286.28 vs 4.59 ng/mL, p < 0.001) and serum PIVKA-II concentrations (5.742 vs 27.10, p < 0.001) were higher in the case group
Figure 2: Linear correlation between AFP and PIVKA-II in HCC
Serum levels of AFP and PIVKA-II were correlated (ρ < 0.05)
Figure 3: Received operating characteristics curve (ROC) comparing specificity and
sensitivity of PIVKA-II and AFP in detecting HCC
Trang 5The performance of both PIVKA-II and AFP in the diagnosis of HCC were plotted on
a ROC curve (figure 2) showing similar areas under curve for both markers; specifically,
areas under curve (AUC) for PIVKA-II (cut-off: 40 mAU/mL) and AFP (cut-off: 10 ng/mL) were 0.864 (95%CI = 0.777 - 0.950) and 0.925 (95%CI = 0.870 - 0.981), respectively
Table 4: Sensitivity, specificity, positive predictive value (PPV) and negative predictive
value (NPV) of AFP, PIVKA-II and the combination of both in detecting HCC
> 40 mAU/mL
At the set cut-off value of 40 mAU/mL, PIVKA-II was more sensitive (92.45% vs 81.13%) but less specific than AFP at the set cut-off value of 10 ng/mL (61.29% vs
83.87%) The negative predictive value of PIVKA in combination with AFP was 88.23% and it was higher when compared both to AFP (72.22%) and PIVKA alone (82.6%)
(table 2)
DISCUSSION
HCC is the sixth most common cancer
in the world and the third most common
cause of cancer-related death In our
study, patients with HCC were older than
patients without HCC and men dominate
the two groups Male predominance may
be explained by greater exposure to
toxins, HCV prevalence and hepatocyte
androgenic stimulation [9] Imaging
methods play an important role in the
diagnosis and evaluation of treatment
outcome as well as relapse after
treatment In clinical practice today,
ultrasound and CT are the most widely
used method We conducted simultaneous
study of ultrasonographic and CT results
of patients who studied, the results were
quite similar between the two methods
with liver tumors mainly concentrated in the right liver, a few patients have tumor
in the left liver and most patients had a
tumor (table 2)
Patients with cirrhosis, especially if due
to HBV or HCV, are at high risk for developing HCC and, therefore, undergo active surveillance with six-monthly upper abdominal ultrasound However, researches for the identification of an effective serum marker for screening of HCC are currently ongoing AFP is widely used for this purpose, even though it is not recommended by neither EASL nor AASLD Guidelines because of its low sensitivity and specificity [9] AFP is elevated in only 40 - 60% of cases of HCC Sensitivity is even lower in early HCC cases, with serum elevation of AFP
in only 10 - 20% of cases Moreover,
Trang 6as a non-specific inflammation and
regeneration marker, it may also be
elevated in liver diseases (e.g liver
cirrhosis and hepatic necrosis), as well as
in some extra-hepatic conditions such as
pneumonia and embryonal tumors [3]
PIVKA-II is an abnormal prothrombine
due to carboxyl group deficiency at
gamma position in 10 glutamic acid
molecules located at the N-terminal side
of the prothrombine Carboxylation
(COOH binding) is dependent on the
presence of vitamin K The loss of
carboxyl group in 10 glutamic acid
molecules should reduce the ability of
Ca2+ to bind to prothrombine and may
cause reversibility normal blood clotting
The role of PIVKA-II in liver cancer was
first reported in 1984 by Liebman H.A et
al In the first time, the role of PIVKA-II in
the diagnosis, prognosis, evaluation of the
effectiveness of HCC treatment was
studied as well as the most clinical
application in Japan In recent times, role
of PIVKA-II has been paid more attention
to research by the United States, some
European countries, as well as in Asia In
chronic liver disease and HCC, the
biological processes of AFP and PIVKA
are independent of each other Most
studies in Japan and Asia have shown
that PIVKA-II plays a better role than
AFP, especially with respect to tumor
size, correlation with thrombosis or
invasion of blood vessels, assess the
possibility of relapse after treatment [5]
When conducting AFP and PIVKA-II levels
in patients with chronic liver disease and
HCC, performing a quantitative test on the
same principle and the same analytical system we found that both plasma PIVKA-II and AFP levels were statistically significantly different in patients with chronic hepatitis and cirrhosis This is also consistent with many other studies in the world as authored by Inagaki Y et al [5] Similarly to other authors, we observed correlation between PIVKA-II and AFP serum levels This allowed us to evaluate the combined performance of both markers in the diagnosis of HCC, as suggested by already available evidence [10] When cut-off values of 40 mAU/mL for PIVKA-II and 10 ng/mL for AFP were selected, we showed that PIVKA-II had a higher sensitivity but a lower specificity than AFP Combining both markers further increased overall sensitivity and negative predictive value at the expense
of specificity (88.23%) These results slightly differed from a recent French study in which the authors showed that PIVKA-II had a better performance than AFP for early HCC diagnosis with a
sensitivity of 77% (vs 61%), a specificity
of 82% (vs 50%), a positive predictive value of 76% (vs 51%) and a negative predictive value of 83% (vs 62%), at a
cut-off values of 42 mAU/mL for PIVKA-II and 5.5 ng/mL for AFP [7]
CONCLUSION
PIVKA-II was more sensitive but less specific than AFP in diagnosis of HCC and PIVKA-II, when combined with AFP, may be considered as a screening test for HCC due to its high sensitive and negative predictive value
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