Mona Talaat Kamel et al. UJP 2015, 04 (03): Page 92-97
Universal Journal of Pharmacy
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Research Article
ISSN 2320-303X
Take Research to New Heights
DETECTION OF SOME TUMOR MARKERS IN PATIENTS WITH LIVER CIRRHOSIS AND
HEPATOCELLULAR CARCINOMA RELATED TO HEPATITIS C VIRUS
Ola Sayed Mohammed1, Omnia Azat Ali2, Mona Talaat Kamel1, Hassan Shalaby3, Khadega K. El Gohary4,
Seham Mahmoud5, Amal El Shimy6
1
Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
3
Department of Internal Medicine, Misr University for Science and technology, Egypt
4
Department of Biochemistry, El Sahel Teaching Hospital, Egypt
5
Department of Tropical, El Sahel Teaching Hospital, Egypt
6
Department of Microbiology and Immunology, Faculty of Medicine, Cairo University, Egypt
2
Received 30-04-2015; Revised 28-05-2015; Accepted 26-06-2015
ABSTRACT
Hepatocellular carcinoma is the fifth most common cancer worldwide and the most common form of liver cancer, being
responsible for 80% of the primary malignant liver tumors in adults. Early detection of the disease is thus an important
goal allowing the patient to be treated before the enlargement of the tumor or its metastasis to distant organs. The
first serologic assay for detection and clinical follow up of patients with hepatocellular carcinoma was alphafetoprotein (AFP) which has been the standard tumor biomarker for Hepatocellular Carcinoma for many years. Further
studies showed the relationship between highly concentration of some biochemical parameters and the presence of
Hepatocellulr Carcinoma as Cerulplasmin, Des -gamma –Carboxy Prothrombin, Ferritin and iron for early diagnosis of
HCC.
Aim: To detect the level of some tumor markers as Alpha-fetoprotein, Cerulplasmin, Des -gamma –Carboxy
Prothrombin, Ferritin and Iron in sera of patients suffering from cirrhosis & HCC and comparing which one is more
sensitive and specific for early diagnosis of HCC.
Methods: This study was conducted on a total number of 150 patients admitted at El Sahel Teaching Hospital and
Department of Internal Medicine, Misr University for Science and technology. The patients of this study were
subdivided as follows: 50 apparently healthy individuals control, 50 patients with chronic hepatitis C (genotype 4) and
developed to cirrhosis and the other 50 patients as HCC group related to Hepatitis C virus (HCV). Complete
examination was carried out for each individual to confirm diagnosis. Individuals, sera were subjected to quantitative
determination of alpha-fetoprotein (AFP), Ceruoplasmin, Des -gamma -Carboxyprothrombin (DCP), Ferritin, iron and
other biochemical parameters.
Results: Using the best cut-off value of Ferritin (258.5 ng/mL) showed sensitivity and specificity of 86% and 78%
respectively , Iron cut-off value (210.5 μg/dL)showed a sensitivity and specificity of 86% and 61% respectively,
Ceruloplasmin cut-off value (322.5 ng/ml) showed a sensitivity and specificity of 68 % and 71% respectively , DCP cutoff value (4.15 ng/ml) showed a sensitivity and specificity of 80% and 35% respectively , while cut-off value of AFP
(17 μg/L ) showed a sensitivity and specificity of 70 % and 61% respectively.
Conclusion: Ferritin was proved to be superior to Alpha-fetoprotein, Ceruloplasmin , Des -gamma -Carboxyprothrombin
and Iron for early detection of HCC patients being highly sensitive and specific.
Keywords: Alpha fetoprotein –Ceruoplasmin -DCP– Ferritin-Hepatocellular carcinoma-HCV.
INTRODUCTION
Hepatocellular carcinoma is the fifth most common
cancer worldwide and the most common form of liver
*Corresponding author:
Mona Talaat Kamel
Department of Biochemistry, Faculty of Pharmacy, Al-Azhar
University, Cairo, Egypt, Address: Faculty of Pharmacy (Girls),
Al-Azhar University, Nasr City, Cairo, Egypt.
Telephone: +226066606, Mobile: +201117832406
cancer, being responsible for 80% of the primary
malignant liver tumors in adults. The 5-year relative
survival rate is about 7% and causes more than 600000
deaths annually worldwide1. Hepatocellular carcinoma
rarely occurs before the age of 40 years and reaches a
peak at approximately 70 years of age. Rates of liver
cancer among men are two to four times as high as the
rates among women. Risk factors for hepatocellular
carcinoma include infection with HBV or HCV, alcoholic
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liver disease, and most probably nonalcoholic fatty
liver disease. Less common causes include hereditary
hemochromatosis,
alpha1-antitrypsin
deficiency,
autoimmune hepatitis, some porphyrias, and Wilson’s
disease. The distribution of these risk factors among
patients with hepatocellular carcinoma is highly
variable, depending on geographic region and race or
ethnic group. Most of these risk factors lead to the
formation and progression of cirrhosis, which is present
in 80 to 90% of patients with hepatocellular
carcinoma2. The estimated risk of hepatocellular
carcinoma is 15 to 20 times as high among persons
infected with HCV as it is among those who are not
infected, with most of the excess risk limited to those
with advanced hepatic fibrosis or cirrhosis 3. Egypt has
the highest prevalence of HCV worldwide and has rising
rates of hepatocellular carcinoma (HCC). Egypt's unique
nature of liver disease presents questions regarding the
distribution of HBV and HCV in the etiology of HCC 4.
Early detection of the disease is thus an important goal
allowing the patient to be treated before the
enlargement of the tumor or its metastasis to distant
organs. Serum tumor markers may be useful in
predicting the tumor at early stages 5.The first
serologic assay for detection and clinical follow up of
patients with hepatocellular carcinoma was alphafetoprotein (AFP) which has been the standard tumor
biomarker for HCC for many years 6.Although detection
of AFP level is easy and less expensive, but it shows
less sensitivity7. Serum ferritin concentration is a
marker of varied pathophysiological events and is
elevated with increased liver iron concentration,
hepatic necroinflammation, and systemic illness, all of
which may cause a deterioration in liver function and
clinical status8. A study suggested a potential
association of increased hepatic iron deposition with
more advanced hepatic fibrosis in patients with chronic
hepatitis C virus infection. The serum ferritin value, an
independent predictor of severe hepatic fibrosis in
patients with chronic hepatitis C virus infection, may
predict hepatic iron deposition and severity of fibrosis9.
The Cu/Zn ratio was found to be significantly higher in
patients with HCC compared with that in age and sexmatched controls, with a sensitivity of 87.5%, this ratio
might be useful in the evaluation of suspected
hepatocellular malignancy10. Liebman, et al11., first
reported that 67% of patients with HCC had abnormally
elevated levels of des- γ –Carboxy Prothrombin (DCP),
also known as the protein induced by vitamin K absence
or antagonist II (PIVKA-II). So in this study we try to
compare the sensitivity of different marker as AFP,
Ceruloplasmin, DCP, Ferritin and Iron in HCC early
detection.
PATIENTS AND METHODS
This case control study was conducted on total numbers
150, subdivided as follows: 50 apparently healthy
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individuals as control, 50 patients with chronic
hepatitis C (genotype 4) proven by Polymerase Chain
Reaction (PCR) and 50 patients as HCC group proven by
PCR for chronic hepatitis C and using Computed
Tomograghy (CT) for proven of Hepatocellular
Carcinoma cases. An informed consent was taken from
each patient before the beginning of the study. The
Ethical Committee of El Sahel Teaching Hospital
approved the study protocol, which was prepared in
accordance with the ethical guidelines of the 1975
Declaration of Helsinki and later revisions. On
admission to the hospital during the study period, every
patient fulfilling the inclusion criteria is allocated to
one intervention group and informed written consent
for the study was obtained from all patients. The
inclusion criteria of HCV- Cirrhotic cases were: adult
male or female (30–73 years old) with proven genotype
4 chronic hepatitis C, positive serum HCV RNA by
quantitative polymerase chain reaction (PCR) and
developed to cirrhosis. Those with HCC proved by liver
biopsy were allocated to GIII. Besides the necessary
investigations needed to fulfill the selection criteria all
individuals included in this study were subjected to the
following: Full history was taken with special reference
to risk factors for HCV infection: as previous exposure
to HCV in surgical wards, blood transfusions, dental
clinics, needle stick injury, history of HCV in the spouse
and i.v. injection.
2. Serum samples
Ten ml of venous blood were withdrawn from each
patient in dry sterile vacutainers. After centrifugation,
the serum was tested for: a- liver function tests: which
included serum aminotransferases (AST), (ALT) and
total bilirubin (Beckman Synchron systems; Galway,
Ireland).b- Quantitative determination of serum alpha
fetoprotein (AFP) level by using Monobind INC. kit USA.
c- Quantitation of HCV-RNA using Real Time polymerase
chain reaction (RT-PCR) (Strata gene) was done after
RNA Extraction (by Viral RNA Extraction Kit, QiagenGermany). d-ELISA for HBcAb and HBsAg was done for
all cases to exclude presence of hepatitis B viral
etiology of liver disease. e-Quantitative Colorimetric
Determination of Iron by Stanbio procedure (USA). fDetection of
Ferritin by DRG® Ferritin (EIA1872)ELISA(USA).h-Detection of Human Ceruloplasmin
and Des-γ-Carboxy Prothrombin by EIAab ELISA kit.
Statistical methods
Data management and statistical analysis were
performed using Statistical Package for Social Sciences
(SPSS) vs. 21.Numerical data were summarized using
means and standard deviations or medians and ranges.
Categorical data were summarized as percentages.
Comparisons between the 3 groups with respect to
normally distributed Univariate ANOVA and Bonferroni
post hoc test numeric. For categorical variables,
differences were analyzed with 2(chi square) tests.
Correlations among different study parameters were
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determined by using Pearson’s test. Receiver Operator
Curve (ROC curve) was done to determine the cut off
value of different markers in diagnosis of HCC. All pvalues are two-sided. P-values < 0.05 were considered
significant.
RESULTS
Baseline characteristics
The mean age of the studied control group was 32.8.
Patients in GII with a mean age of 52.6, while GIII with
a mean age 58.8. Sex distribution in GI was 12 (60%)
females and 8 (40%) males, in GII number of females
was 12 (48%) and number of males was 13(52%),while in
GIII, there were 7(28%) females and 18(72%) males.
There was no statistically significant difference
between the three groups as regards the distribution of
sex (Table 1).
Results of laboratory investigation
We found a significant difference of AST, ALT, T.Bil.,
D.Bil., Glucose, PT, Creatinine, Albumin, INR, WBCs
and GGT levels in HCC and cirrhotic patients groups
compared to healthy control ( P< 0.001). Also, There
was a significant difference between HCC group
compared to cirrhotic group AST, ALT, T.Bili., INR,
Glucose, Albumin, PT, WBCs and GGT( P< 0.001) .There
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was a higher mean level of AFP , Iron, Ferritin,
Ceruloplasmin and DCP
among cases with HCC
compared to cirrhosis and control groups with highly
statistically significant difference( P< 0.001) (Table 2).
No statistical difference between HCC and Cirrhosis
was found regarding weight loss, elevation of
Temperature, Abdominal pain and Jaundice, while
regarding to Encephalopathy and Bleeding showed
highly statistical significant difference between the
two groups. (Fig .1)
& Table (3): showed the
comparison between the five parameters regarding to
the ROC curve and the area under the curve. The
present study reveals that the Ferritin was the best
tumor with cut off (258.5 ng/mL) showed sensitivity
and specificity of 86% and 78% respectively , Iron cutoff value (210.5 μg/dL) showed a sensitivity and
specificity of 86% and 61% respectively , Ceruloplasmin
cut-off value (322.5 ng/ml) showed a sensitivity and
specificity of 68 % and 71% respectively , DCP cut-off
value (4.15 ng/ml) showed a sensitivity and specificity
of 80% and 35% respectively , while cut-off value of
AFP (17 μg/L ) showed a sensitivity and specificity of
70 % and 61% respectively.
Table 1: Comparison regarding clinical Characteristics between all studied groups
Control
Cirrhosis
HCC
Factors
n=50(%)
n=50(%)
n=50(%)
P value
Mean ±SD
Age (yrs.)
32.8±8.1
52.6±9.8
58.8±9.6
<0.001
Gender
Male
23(46.0)
24(48.0)
31(62.0)
0.218
Female
27(54.0)
26(52.0)
19(38.0)
Abdominal pain
3(6.0)
23(46.0)
25(50.0)
<0.001
Encephalopathy
0
10(20.0)
24(48.0)
<0.001
Bleeding
0
21(42.0)
23(46.0)
<0.001
Elevated BT
3(6.0)
15(30.0)
21(42.0)
<0.001
BT: Body Temperature., P-values < 0.05 were considered significant.
Table 2: Comparison regarding laboratory investigations of all studied groups
Control
Cirrhosis
HCC
n=50(%)
n=50(%)
n=50(%)
P value
PT
11.5±0.6
12.4±1.9
14.1±1.3
<0.001
INR
1.0±0.1
1.0±0.2
1.2±0.1
<0.001
ALT
29.6±5.8
57.3±16.5
64.3±18.9
<0.001
AST
32.2±8.9
61.2±36.3
149.7±66.2
<0.001
T.Bil
0.7±0.2
1.3±0.7
2.7±1.0
<0.001
D.Bil
0.1±0.1
0.3±0.2
0.8±0.4
<0.001
Glucose
101.2±13.0
167.9±35.8
217.7±166.1
<0.001
Creatinine
0.9±0.1
1.8±0.5
1.8±0.6
<0.001
Alb
3.9±0.2
3.5±0.5
2.7±0.6
<0.001
GGT
287.8±85.0
182.9±53.9
122.3±28.3
<0.001
Hb
11.9±1.7
11.1±1.1
11.0±1.1
0.003
WBCs
6900.0±2290.3
5204.6±1684.6
5204.6±1684.6
<0.001
Iron
175.3±38.3
221.4±54.0
259.7±55.4
<0.001
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Ferritin
Ceruloplasmin
DCP
AFP
175.8±98.0
186.4±99.3
12.1±20.9
14.9±24.7
240.2±68.5
299.8±95.2
26.8±14.5
35.9±30.1
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338.4±97.0
403.1±159.2
36.0±33.4
306.8±281.5
<0.001
<0.001
<0.001
<0.001
PT: Prothrombin Time, INR: International Normalized Ratio, AST: Aspartate transaminase, ALT: Alanine transaminase,
T.Bil: Total Bilirubin, D.Bil: Direct Bilirubin , GGT :gamma-glutamyltransferase, Hb :Hemoglobin ,WBCs: White Blood Cells,
DCP: Des -gamma -carboxyprothrombin , AFP :alpha-fetoprotein,P-values < 0.05 were considered significant..
Table 3: Comparison between the different biochemical markers regarding Area under
curve, Sensitivity and Specificity
Area under curve
P- value
Cut off
Sensitivity %
Specificity %
AFP
0.778
<0.001
17
70%
61%
Iron
0.804
<0.001
210.5
86%
61%
Ferritin
0.855
<0.001
258.5
86%
78%
Ceruloplasmin
0.771
<0.001
322.5
68%
71%
DCP
0.66
0.001
4.15
80%
35%
AFP: alpha-fetoprotein, DCP: Des -gamma –carboxyprothrombin,P-values < 0.05 were considered significant.
Figure1: ROC curve of AFP, Ceruloplasmin, DCP, Ferritin and Iron
DISCUSSION
Primary liver cancer is one of the most common and
deadly malignant neoplasms worldwide. The incidence
and mortality rates for hepatocellular carcinoma (HCC)
are virtually identical, reflecting the poor overall
survival of patients with this kind of tumor12. The
management of patients at risk for developing HCC
remains challenging. Increased understanding of cancer
biology and technological advances have enabled
identification of a multitude of pathological, genetic,
and molecular events that drive hepatocarcinogenesis
leading to discovery of numerous potential biomarkers
in this disease. They are currently being aggressively
evaluated to establish their value in early diagnosis,
optimization of therapy, reducing the emergence of
new tumors, and preventing the recurrence after
surgical resection or liver transplantation. These
markers not only help in prediction of prognosis or
recurrence but may also assist in deciding appropriate
modality of therapy and may represent novel potential
targets for therapeutic interventions13. Detection of
HCC at early stages is critical for good clinical outcome
as the prognosis of HCC patients is very poor when
diagnosed at late stages14. Although serum AFP is the
most established tumor marker in HCC and considered
as the golden standard to which other markers are
compared, it was found to be normal in about 30% of
the patients, especially in early stages14. In this study
AFP showed sensitivity and specificity of 70 % and 61%
respectively at Cut off (17 μg/L). Iron excess was
mainly located within reticuloendothelial cells, and this
is the main argument in favour of the role of iron
deposits in hepatic carcinogenesis. Iron plays a role in
HCC development in chronic liver diseases associated
with minor iron overload/siderosis15.Regading to this
study Iron showed high Area under curve of (0.804),
sensitivity reach to 86 % and specificity of 61 % at
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Cut off (210.5 μg/dL). Other studies reported that
liver iron deposition was more frequent and more
important in viral C cirrhotic patients with HCC than in
HCC free controls. Liver iron overload seems to
contribute to the development of HCC in patients with
viral C cirrhosis. Patients with viral C cirrhosis that
histological liver iron deposits were more frequent and
more important in patients who had developed HCC
compared with controls without HCC15. So further
prospective studies are needed to confirm the
hypothesis that iron deficiency protects against HCC in
chronic liver disease CLD. Serum Ferritin concentration
is a marker of varied pathophysiological events and is
elevated with increased liver iron concentration,
hepatic necroinflammation, and systemic illness, all of
which may cause a deterioration in liver function and
clinical status. Serum Ferritin concentration (SF) is a
widely available and easily measured biochemical
parameter. SF is increased in patients with elevated
body iron stores, hepatic necroinflammatory activity,
and systemic inflammatory states. These causes of
increased SF may be associated with an increased risk
of clinical deterioration and progressive liver
dysfunction8.Our results showed Ferritin had increased
levels in both cirrhotic and HCC groups at Cut off
(258.5ng/mL) with high sensitivity (86%) and high
specificity (78%).Our results agree with Dibiscegli and
his colleagues (1992) who reported considerable
increase in the levels of Ferritin in 30% of 80 patients
with viral chronic hepatitis and its increase in males
was higher than females16. Also, Albert and his
colleagues (1994) reported increase in serum Ferritin in
about 31% of HCV positive patients 17. Patil, et al18.,
found an independent association between serum
ferritin levels and HCC in patients with CLD of viral
etiology. Combination of AFP and ferritin is useful for
early detection of HCC. Correct diagnosis were made in
65.9% of cases by measurement of serum AFP only ,in
56.8% of the cases by measurement of ferritin ,and in
88.6% of the cases by combination of these two tests,
and combination of tests for HCC did not decrease the
specificity appreciably19.While our results disagreed
with Lin, et al20., who considered that several proteins
markers in serum have been studied for possible use in
the detection of HCC but have not proven to be useful
because of poor sensitivity and/or specificity. These
include C-reactive protein, matrix metalloproteinase-2
and -9, tissue polypeptide specific antigen, beta2microglobulin, CA 19-9, carcinoembryonic antigen, CA
72-4 and Ferritin. Liebman, et al11., first reported that
67% of patients with HCC had abnormally elevated
levels of des- γ -carboxyprothrombin (DCP), also known
as the protein induced by vitamin K absence or
antagonist II (PIVKA-II). A significant elevation of
PIVKA-II and AFP levels in HCC group compared to
control and HCV groups. PIVKA-II showed more increase
than AFP level in malignant compared to benign liver
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diseases 11. There is excessive synthesis of prothrombin
precursors by human HCC tissues, which might
contribute to production of PIVKA-II, rendering the
latter a useful marker for HCC with a very high
specificity21. Durazo, et al., reported that PIVKA-II
levels significantly correlate with histopathological
grade of HCC and size of solitary tumors, being 25
times higher in tumors more than 2 cm, compared to
those less than 2 cm. AFP showed no significant
correlations with the stage of HCC. In contrary PIVKA-II
showed gradual increase in its level with increase of
disease stage22. PIVKA-II was positive in 96%, 93% and
74% in patients with tumor size larger than 5, 3–5, and
less than 3 cm while AFP was positive in 65%, 57% and
48% respectively. PIVKA-II levels showed significant
elevation in HCC patients with portal vein thrombosis,
while AFP level was not affected 21. Recent studies
have revealed that DCP functions as a growth factor
and might play significant roles in cancer progression.
Thus, DCP represents a potential target of drug
discovery to establish new chemotherapeutic strategy
for HCC. So, DCP have revealed not only the usefulness
of this molecule as a diagnostic marker but also its
significant role in cancer progression23. Regarding to
this study, PIVKA-II showed sensitivity and specificity of
80% and 35% respectively at cut-off value (4.15
ng/ml).In a study Ryaidh, et al., reported that high
increasing ceruloplasmin levels, copper and decreased
in concentrations of zinc and the increased
concentrations of copper in serum do not seem to
result from a shift of zinc into or release of copper out
of the malignant tumor tissue. Cp accumulates to
extremely high levels in the serum of the transgenic
mice developing HCC24. About one-half of the Cp from
tumor bearing mice is complexed with copper; this is
shown by its characteristic absorption at 600 nm as
well as by the high specific phenol oxidase and
ferroxidase activities and by the immunological
quantification of holo-Cp in the serum of the transgenic
mice25.Our results showed that Ceruloplasmin with Cutoff value (322.5 ng/ml) showed a sensitivity of (68 %)
and specificity of (71%).
CONCLUSION
Further investigations on a larger scale using wellstandardized techniques are recommended to validate
the cut off value or define appropriate one.
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Source of support: Nil, Conflict of interest: None Declared
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