EL-MINIA MED., BULL., VOL. 18, NO. 1, JAN., 2007
El-Dahrouty et al
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SIGNIFICANCE OF HEPATOCYTE GROWTH FACTOR SERUM
LEVELS IN HCV CHRONIC INFECTION
By
El-Dahrouty* A.H., Madeha* M.A.M.,
Tahia**, H.S. and Zienab* M.S.
Departments of *Tropical Medicine, El-Minia Faculty of Medicine
and **Biochemistry, Assuit Faculty of Medicine
ABSTRACT:
Background and aim: Hepatocyte growth factor (HGF) is a potent stimulator of
hepatocyte growth and an important regulator of liver regeneration in response to
injury. This study aims to evaluate the significance of serum HGF levels in C-viral
chronic liver disease, and to study the possible correlation between these levels and
disease severity.
Material and Methods: Seventy patients (55 males, 15 females), seropositive for
HCV-Ab, seronegative for HBsAg and ten healthy controls (8 males, 2 females),
seronegative for HCV-Ab and HBsAg, were enrolled and divided into: (G1), 21
patients with chronic hepatitis, (G2), 26 patients with liver cirrhosis, (G3), 33 patients
with HCC, (G4), 10 healthy controls. Full history, clinical and sonographic
examinations, laboratory investigations included; liver function tests (ALT, AST,
serum; albumin, bilirubin, alkaline phosphatase and prothrombin concentration), alpha
fetoprotein (AFP) and serological assay for serum HGF (by ELISA), were performed
for all subjects.
Results: HGF serum levels were significantly higher in HCC group than in liver
cirrhosis group (P < 0.001), than in chronic hepatitis group (P < 0.01) than in control
group (P < 0.05). HGF serum levels were significantly higher in severe grades than in
mild grade (P < 0.05) of chronic hepatitis, and were significantly higher in child’s C
patients than that in child’s A (P < 0.05). HGF serum levels were positively correlated
with ALT, AST serum levels and negatively correlated with albumin serum levels and
prothrombin concentration.
Conclusion: hepatocyte growth factor serum level is a useful indicator for activity
and progression of C. viral chronic liver disease and predicts the development of
HCC. Hepatocyte growth factor serum concentrations may be useful tumor marker for
HCC, detection and therapy follow up. Hepatocyte growth factor therapy is a future
hop for treating chronic hepatitis, liver cirrhosis and HCC.
KEY WORDS:
Hepatocyte growth factor
Chronic hepatitis
Hepatocellular Carcinoma
Liver cirrhosis
hepatocytes and was described as a
potent stimulator of hepatocyte
growth, and an important regulator of
liver regeneration in response to
injury (Yanagita et al., 1992). HGF, is
produced by various cells including
INTRODUCTION:
Hepatocyte growth factor
(HGF) is a hepatotrophic factor which
stimulates liver regeneration. It was
originally identified and cloned as a
mitogenic
protein
for
mature
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EL-MINIA MED., BULL., VOL. 18, NO. 1, JAN., 2007
El-Dahrouty et al
_______________________________________________________________________________
fibroblasts, epithelial, endothelial,
kupffer and fat storing cells in the
liver and malignant cells such as lung
and pancreatic carcinoma and
leukemic cell lines (Selden et al.,
1999). HGF exerts its effect on
hepatocytes through, a transmembrane protein encoded by a C-Met
receptors (Hiroshi & Nakamura,
2003). The binding of HGF to the cMet
receptor
exerts
multiple
biological actions involved in cell
proliferation, migration, morphogenesis, apoptosis, and breakdown of
extracellular matrix (Jiang et al.,
2005). Many approaches indicated
that HGF is the most potent hepatotrophic factor in liver regeneration.
Expression of HGF increases in
response to liver injury, while
neutralization of HGF results in
impairment/retardation of liver regeneration (Hirohito & Nakamura,
2006). The liver is normally
responsible for clearance of HGF, if
this function is markedly compromised by liver damage (viral, toxic,
anoxic, resection) the circulating HGF
level rapidly increases and reaches a
high level to produce potent
mitogenic effect on liver cell
(Sakaguchi et al., 1994). HGF is a
multifunctional cytokine and has been
implicated in the pathogenesis of
several tumors, through increasing
motility and invasiveness of cancer
cells both under in vivo and in vitro
conditions (Matsumoto et al., 1994).
The aim of this study was to evaluate
the significance of serum HGF levels
in patients with HCV chronic liver
disease namely, chronic hepatitis,
liver cirrhosis and HCC, and to find
out the possible correlation between
these levels and severity of liver
disease.
and a mean of 48.02 ± 11.07 years,
seropositive for HCV-Ab, seronegative for HBSAg (by ELISA 3rd
generation), with history, clinical
examination, and abdominal ultrasonography and laboratory investigations suggestive of chronic liver
diseases, were included in this study.
They were randomly selected from
those admitted to Tropical Medicine
Department
El-Minia
University
Hospital and EL-Minia Oncology
Center. Ten healthy individuals,
seronegative for HCV-Ab and HBsAg,
matched for age, sex and social
background, were taken as a control
group. Patients with symptoms and
signs suggestive of acute viral
hepatitis, patients under immunotherapy, Diabetes mellitus, and
neoplasia
(rather
than
hepatic
malignancy), renal insufficiency and
pregnant women, were excluded from
the study. According to clinical &
ultrasonographic examination; laboratory investigations, and histopathological examination, the patients
were classified into three groups:
Group (1) included 21 patients with
chronic hepatitis. Group (2) included
26 patients with liver cirrhosis. Group
(3) included 23 patients with HCC on
top of liver cirrhosis. The diagnosis of
HCC was suggested by presence of
hepatic focal lesions on ultrasonographic
examination
(U/S),
confirmed by, serum level of alpha
fetoprotein and/or histopathology of
(U/S) guided needle liver biopsy.
Group
(4) included 10 healthy
controls. The patients and controls,
were subjected to; full history, clinical
examination,
abdominal
ultrasonography, laboratory investigations
included; serum level of; bilirubin,
ALT, AST, alkaline phosphatase,
albumin, prothrombin concentration
and
alpha
fetoprotein
(AFP).
Serological assay including; serum
markers of virus hepatitis (HCV-Ab,
PATIENTS AND METHODS:
Seventy patients (55 males, 15
females), with age range 25-70 years
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EL-MINIA MED., BULL., VOL. 18, NO. 1, JAN., 2007
El-Dahrouty et al
_______________________________________________________________________________
HBSAg by ELISA 3rd generation and
human hepatocyte growth factor (by
ELISA, BIOTECX Company) (Gohda,
1998). Patients of GII, III were
clinically classified according to childpugh scoring system (Pugh et al.,
1973) into class A, B and C. Needle
liver biopsy could be done for 31
patients.
Assessment
of
histopathological activity was performed according to Scheuer scoring
system (Scheuer, 1991).
namely (SPSS) for windows student
version 7.5 was used to analyze these
data. The data were expressed as mean
± SD. Sample t-test was used to
evaluate the difference between
studied groups. The difference was
considered significant if P value <
0.05. Correlation was tried in between
the essential studied parameters by
Pearson correlation tests, expressed as;
weak correlation 0-0.24, fair 0.250.49, moderate 0.50-0.74 and strong
> 0.75.
STATISTICAL ANALYSIS:
The data of all patients were
fed into an IBM-compatible computer
and statistical soft ware packages
RESULTS:
The results of this study are
summarized in the following tables
Table (1): Demographic data of the patients and controls
Variable
Patients
N=70
Controls
N=10
Age
Mean ± SD
range
48.02 ± 11.07
25 – 70 years
37.6 ± 5.98
23 – 70 years
55 (78.57 %)
15(21.43 %)
8 (80%)
2 (20%)
54 (77.15 %)
16 (22.85 %)
7 (70%)
3 (30%)
Sex
Males
Females
Residence
Rural
Urban
Table (2): Child’s classification of the patients with liver cirrhosis and HCC.
Child’s classification
Liver cirrhosis
HCC
Child’s A
6 (23%)
-
Child’s B
12 (46.17 %)
6 (26.1 %)
Child’s C
8 (30.8%)
17 (73.9 %)
Total
26 (100%)
23 (100 %)
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EL-MINIA MED., BULL., VOL. 18, NO. 1, JAN., 2007
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Table (3): The results of histopathological examination.
Biopsy Findings
Frequency
Percentage
- Mild
3
9.7%
- Moderate
- Severe
8
3
25.8%
9.7%
Liver cirrhosis
4
12.9%
HCC on top of liver cirrhosis
13
41.9%
Total
31
100%
Chronic hepatitis
Table (4): The mean serum levels of liver functions and AFP in the studied groups
Controls
Chronic
hepatitis
Liver
cirrhosis
HCC
0.603 ±.0.37
1.04 ± .28
2.29 ± 2.27
2.88 ± 2.3
22.7 ± 5.36
172 ± 105
78.54 ± 49.8
51 ± 26
Liver function
T bilirubin
(0.00-1mg/dl)
AST
(0-37 u/L)
ALT
(0-65 u/L)
Alk. Phosph.
(50-136 u/L)
S. albumin
(3.5-5.2 g/dl)
Proth. Con.
(70-100%)
AFP
(10 – 20 g/ml)
34.20 ± 3.5
98.30 ± 106.37
67.96 ± 37.58
60.90 ± 42.39
58.50 ± 6.72
90.52 ± 31.48
110.38 ± 48.2
383.56 ± 335
3.75 ± 0.27
3.9 ± 0.54
98.20 ± 1.98
86.95 ± 9.70
64.21 ± 11.68
64.03 ± 14.74
19.4 ± 4.6
52.4 ± 6.3
68.24 ± 11.6
480.8 ± 96.4
2.65 ± 0.64
2.35 ± 0.80
Table (5): The mean serum levels of HGF in the studied groups.
HGF (ng/ml)
Mean ± SD
Groups
Chronic hepatitis
(group 1)
0.547 ± 0.137
Liver cirrhosis
(group 2)
0.863 ± 0.200
HCC
(group 3)
1.61 ± 1.17
Control
(group 4)
0.344 ± 0.08
45
P value
0.001
1#2
0.002
2#3
0.0001
1#3
0.001
1#4
EL-MINIA MED., BULL., VOL. 18, NO. 1, JAN., 2007
El-Dahrouty et al
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Table (6): HGF serum levels in relation to the grades of chronic hepatitis.
HGF
X ± SD
HAI grade
P Value
Mild
0.42 ± 6.55
Moderate
0.58 ± 6.37
Severe
0.72 ± 2.64
0.06
1#2
0.09
2#3
0.002
1#3
HAI = histopathological activity index
Table (7): HGF serum levels in relation to the stages of liver cirrhosis
HGF
Mean ± SD
Child’s grading
Child’s A
0.46 ± 0.383
Child’s B
0.90 ± 0.986
Child’s C
1.30 ± 0.806
P value
0.01
Table (8): Correlation between the mean serum levels of HGF and liver function
tests in all patients.
TEST
HGF
R
P
T bilirubin
-0.042
.709
AST
0.336
0.002
ALT
0.303
0.006
Alk. Phosph.
0.102
0.366
S. albumin
-0.404
0.001
Proth. Conc. %
-0.413
0.001
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EL-MINIA MED., BULL., VOL. 18, NO. 1, JAN., 2007
El-Dahrouty et al
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eliminated from the circulation, and
that, the serum levels of HGF reflect
the degree of liver damage. Hotary et
al., (2000) reported that, HGF
increases production of metalloproteinases with subsequent destruction of
the basement membrane and increase
of the tumor growth and invasion.
Jiang et al., (2005) reported that, the
angiogenic and scattering effects of
HGF, contribute in the growth and
spread of primary and secondary
tumors. Jumbo et al., (1999) showed
that, high serum HGF levels in HCC
patients are associated with tumor
metastasis. Yamagamim et al., (2002)
reported that, all patients with chronic
liver disease, with HGF level more
than 0.6 ng/ml, had HCC, irrespective
of the serum level of alpha fetoprotein,
and found that, HGF serum levels
concomitantly increased with the
increase of the area of HCC. They
concluded that, the high serum level of
HGF represents the degree of
carcinogenic state in the liver in
patients with C-viral chronic hepatitis
and cirrhosis, and that, serum HGF
may be useful as a tumor marker for
HCC detection and follow up of
therapy. Yamazaki et al., (1996)
demonstrated that, early high HGF
serum levels, after HCC chemoembolization, refer to poor prognosis. Wu
et al., (2006) indicated that, increase in
postoperative peripheral serum HGF
level was related to tumor recurrence.
Chau et al., (2007) reported that, in
HCC patients, high serum HGF level,
is adverse factor related to postoperative survival. In the current study,
the mean serum level of HGF was
significantly higher in the patients with
severe grade (0.72 ± 0.64) than that in
the patients with mild grade (0.42 ±
0.37, P < 0.01) of chronic hepatitis and
was significantly higher in child’s C
(1.3 ± 0.8) than that in child’s A
patients (0.9 ± 0.98, P < 0.01). We
found that, HGF serum levels were,
DISCUSSION:
Hepatocyte
growth
factor
(HGF) is a cytokine with numerous
biological functions in the liver and
many other cells and tissues. It has a
potent mitogenic , motogenic and
morphogenic effects in addition to its
antiapoptotic and antifibrotic effects
(Jiang et al., 2005). The main HGF
producing cell in the liver is the fat
storing cell (Ito cell) (Schirmacher et
al.,1992). HGF exerts its effects on
hepatocytes through a transmembrane
protein (a tyrosine kinase receptor)
encoded by a C-Met receptors (Hiroshi
& Nakamura, 2003). Expression of
HGF increases in response to liver
injury, while neutralization of HGF
results in impairment / retardation of
liver
regeneration
(Hirohito
&
Nakamura, 2006). In the present study,
the mean serum level of HGF was
significantly higher in the patients with
HCC (1.61 ± 1.17) than in the patients
with liver cirrhosis ( 0.86 ± 0.2, P <
0.01) than in the patients with chronic
hepatitis (0.547 ± 0.137, P < 0.05) than
controls (0.34 ± 0.08, P < 0.05). These
results agree with that of (Tsubouchi et
al., 1991 and Shiota et al., 1995). They
reported that, the serum levels of HGF
in the patients with liver cirrhosis and
patients with HCC were significantly
higher than that in the patients with
chronic hepatitis. The highest level was
observed in those with HCC,
(Yamagamim et al., 2001). The authors
investigated the serum level of HGF in
99 patients with chronic HCV infection
(chronic hepatitis, liver cirrhosis and
HCC). They found that, the serum
concentrations of HGF were signifycantly higher in the patients with HCC
than in the patients with chronic
hepatitis or liver cirrhosis. Shiota et al.,
(1995) reported that, the increased
serum level of HGF may be due to
enhanced
production,
decreased
hepatic clearance or both, as the liver is
the major organ through which HGF is
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EL-MINIA MED., BULL., VOL. 18, NO. 1, JAN., 2007
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positively correlated with aminotransferases (ALT, AST) serum levels
(R = 0.303, P=0.006) and inversely
correlated with albumin serum levels
(R = –0.404, P=0.001) and prothrombin concentration (R= –0.413, P =
0.001), indicating a positive correlation
between HGF serum level and severity
of liver disease. Parallel to our results,
(Sami et al., 2003) found a significant
correlation between HGF expression
and severity of necro-inflammation in
the liver, where more HGF expression
was found in grade III, and grade II
compared to grade I, (Shiota et al.,
1995) investigated serum HGF in HCV
chronic infection. They reported that,
HGF serum levels in patients with
chronic hepatitis were, positively
correlated with the histopathological
activity index and that, the increased
HGF serum level reflect liver necrosis
followed by active regeneration. They
found signi-ficant higher levels of
serum HGF in child’s class C patients
than in those with class A.
indicator for activity and progression
of C-viral chronic liver disease and
predicts the development of HCC.
Hepatocyte growth factor serum
concentrations may be useful tumor
marker for HCC, detection and
therapy follow up. Hepatocyte growth
factor therapy is a future hop for
treating chronic hepatitis, liver
cirrhosis and HCC.
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growth factor serum level is a useful
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‫_______________________________________________________________________________‬
‫‪25. Yamazaki,‬‬
‫;‪H.‬‬
‫‪Oi,‬‬
‫;‪H.‬‬
‫‪Matsumoto, K. et al., (1996):‬‬
‫‪Biophasic‬‬
‫‪changes‬‬
‫‪in‬‬
‫‪serum‬‬
‫‪hepatocyte growth factor after transar‬‬‫‪terial chemo-embolization therapy for‬‬
‫‪HCC. cytokine, 8: 178.‬‬
‫أهمية معامل النمو الكبدي في السيرم في المرضي المصابين بأمراض الكبد‬
‫المزمنة والناتجة عن الفيروس الكبدي (سي) ودراسة عالقته بشدة المرض‬
‫على حسين الدهروطى*‪ ،‬مديحة محمد أحمد مخلوف*‪،‬‬
‫تحية هاشم سليم**‪ ،‬زينب مصطفى سعد*‬
‫أقسام *األمراض المتوطنة – كلية طب المنيا‬
‫و **الكيمياء الحيوية – كلية طب أسيوط‬
‫مقدمة ‪ :‬معامل النمو الكبدي )‪ (HGF‬هدو حددي المدواي اليةوادف الةعالدف الادع ل دا ئدي و دا‬
‫داواف ‪ ،‬ف و من حقوى المنب ات لاجياي يالاا الكبي المصابف نااجف الةاروسات حو السموم‪ .‬هددف‬
‫البحد يراسددف حهماددف قاددال معامددل النمددو الكبدديى فددع الدديم فددع المروددع المصددابان بددالةارول‬
‫الكبي (سع) وبالادياي مروى االلا اب الكبي المزمن ‪ ،‬اةا الكبدي وسدرنان الكبدي ويراسدف‬
‫ئالقاه بشي المرض‪ .‬حجرى هذا البدث ئةى سبعان مدراض ااجداباان لديال ل الةادرول الكبديى‬
‫(سع) وسةباان ليال ل الةارول الكبديى (بدع) (‪ 55‬ذكدور ‪ 55 ،‬إنداث) ‪ ،‬اادراوأ حئمدارهم بدان‬
‫‪ 07 – 55‬سنف باإلوافف إلع ئشر مدن اصصدداك كمجموئدف ودابنف‪ .‬ادم امسدام م الدى حربعدف‬
‫مجموئات ‪ :‬مجموئف (‪ 51 :)1‬مراض مصاب بااللا اب الكبي المزمن)‪، (Ch hepatitis‬‬
‫مجموئددف (‪ 52 :)5‬مددراض مصدداب باةا د الكبددي ( ‪ ، )Liver cirrhosis‬مجموئددف (‪53 :)3‬‬
‫مراض مصاب بسرنان الكبي ‪ ،‬مجموئدف (‪ :)4‬واشدمل ‪ 17‬مدن اصصدداك كمجموئدف ودابنف‪.‬‬
‫باإلوافف إلى الااراخ المروع والةدص االكةاناكع حجرى ل م ‪ ،‬فددص الدبنن بالموجدات فدو‬
‫الصددوااف ‪ ،‬فدو صددات معمةاددف واشددمل ‪ :‬و ددا الكبددي ‪ ،‬يال ددل الةاروسددات (ل ‪ ،‬بددع) ‪ ،‬يال ددل‬
‫اصورام )‪ ، (AFP‬وقاال معامل النمو الكبيى )‪ (HGF‬فع السدارم بنرامدف )‪ ، (ELISA‬حيدذ‬
‫ئانف من نساج الكبي من المروى الادى اسدمح ددالا م بدذل وفددص اصنسدجف‪ .‬نتداج البحد‬
‫ازياي مساوى معامل النمدو الكبديى )‪ (HGF‬فدع السدارم زاداي ذو ياللدف إدصدا اف فدع مرودى‬
‫سرنان الكبي ئن ا فع مروى اةا الكبي ئن ا فع مروى االلا داب الكبديى المدزمن ئن دا فدع‬
‫المجموئف الوابنف مدن اصصدداك‪ .‬وادزياي مسداوى معامدل النمدو الكبديى فدع السدارم زاداي ذو‬
‫ياللف إدصا اف كةما زاي نشان المرض واميمت مرادةه‪ .‬وااناسب مساوى معامدل النمدو الكبديى‬
‫فع السارم مد بعدض و دا الكبدي‪ .‬فااناسدب نريادا مد انزامدى اصماندات المادولدف ‪(ALT,‬‬
‫)‪ AST‬وااناسدددب ئكسددداا مددد مسددداوى اصلبادددومان (الدددزالل) ونسدددبف اركادددز البرو دددرومبان‪.‬‬
‫مسدداوى معامددل النمددو الكبدديى )‪ (HGF‬فددع السددارم فددع المروددى‬
‫المسددتخلم مددن البحدد‬
‫المصدابان بددامراض الكبددي الةاروسداف المزمنددف ‪ ،‬اعابددر م شددرا لنشدان المددرض وامديم مرادةدده ‪،‬‬
‫وانبئ بديوث حورام الكبي وامكن حن اساييم كادي يال ل اصورام اةاي فدع اشدياص حورام الكبدي‬
‫وماابعددف ئالج ددا‪ .‬اسدداييام معامددل النمددو الكبدديى فددع العددال حمددل مسددامبةع قددي اةاددي فددع ئددال‬
‫حمراض الكبي المزمنف‪.‬‬
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