|
Chung-Pin
Li, Fa-Yauh Lee, Shinn-Jang Hwang, Rei-Hwa Lu, Wei-Ping Lee,
Sung-Sang Wang, Full-Young Chang, Shou-Dong Lee, Division of
Gastroenterology, Department of Medicine, Taipei Veterans General
Hospital and Institute of Clinical Medicine, National Yang-Ming
University School of Medicine, Taipei, Taiwan, China
Yee Chao, Cancer Center, Taipei Veterans General Hospital and
National Yang-Ming University School of Medicine, Taipei, Taiwan,
China
Jacqueline Whang-Peng, Cancer Research Division, National
Health Research Institutes and Institute of Clinical Medicine,
National Yang-Ming University School of Medicine, Taipei, Taiwan,
China
Correspondence to: Chung-Pin Li, Division of Gastroenterology,
Department of Medicine, Taipei Veterans General Hospital, No. 201,
Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan, China.
cpli@vghtpe.gov.tw
Telephone: +886-2-28757308
Fax: +886-2-28739318
Received: 2003-08-23
Accepted: 2003-10-12
Abstract
AIM: To investigate whether vascular endothelial growth factor (VEGF)
and basic fibroblastic growth factor (bFGF) are associated with
spider angiomas in patients with liver cirrhosis.
METHODS:
Eighty-six patients with liver cirrhosis were enrolled and the
number and size of the spider angiomas were recorded. Fifty-three
healthy subjects were selected as controls. Plasma levels of VEGF
and bFGF were measured in both the cirrhotics and the controls.
RESULTS:
Plasma VEGF and bFGF were increased in cirrhotics compared with
controls (122±13
vs. 71±11
pg/mL, P=0.003 for VEGF; 5.1±0.5
vs. 3.4±0.5
pg/mL, P=0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF
were also higher in patients with spider angiomas compared with
patients without spider angiomas (185±28
vs. 90±10
pg/mL, P=0.003 for VEGF; 6.8±1.0
vs. 4.1±0.5
pg/mL, P=0.017 for bFGF). Multivariate logistic regression
showed that young age and increased plasma levels of VEGF and bFGF
were the most significant predictors for the presence of spider
angiomas in cirrhotic patients (odds ratio [OR]=6.64, 95 %
confidence interval [CI]=2.02-21.79, P=0.002; OR=4.35,
95 % CI=1.35-14.01, P=0.014; OR=5.66, 95 %
CI=1.72-18.63, P=0.004, respectively).
CONCLUSION:
Plasma VEGF and bFGF are elevated in patients with liver cirrhosis.
Age as well as plasma levels of VEGF and bFGF are significant
predictors for spider angiomas in cirrhotic patients.
Li
CP, Lee FY, Hwang SJ, Lu RH, Lee WP, Chao Y, Wang SS, Chang FY,
Whang-Peng J, Lee SD. Spider angiomas in patients with liver
cirrhosis: Role of vascular endothelial growth factor and basic
fibroblast growth factor. World J Gastroenterol
2003; 9(12): 2832-2835
http://www.wjgnet.com/1007-9327/9/2832.asp
INTRODUCTION
Liver cirrhosis is a major disease in Asian countries and causes
marked morbidity and mortality. Spider angioma is a common
presentation of liver cirrhosis[1,2]. It appears
frequently in alcoholic cirrhotics or when liver function
deteriorates[2-4] and may be associated with esophageal
variceal bleeding[5]. However, the exact pathogenesis has
been unclear.
Angiogenesis is a possible mechanism in the pathogenesis of
spider angiomas and has not been well investigated. Serum vascular
growth factors, such as vascular endothelial growth factor (VEGF)
and basic fibroblast growth factor (bFGF), have been found to be
elevated in cirrhotic patients[6-9]. These vascular
growth factors may play a role in the neovascularization and
formation of spider angiomas in patients with liver cirrhosis.
The aim of this study was to evaluate the predictive value of
plasma VEGF and bFGF for the presence of spider angiomas in patients
with liver cirrhosis.
MATERIALS
AND METHODS
Study patients
Eighty-six consecutive liver cirrhotic patients from Taipei
Veterans General Hospital were enrolled into this study. Fifty-three
age- and sex-matched subjects from apparently healthy adults who
were admitted to our hospital for routine physical checkups were
randomly selected as healthy controls. The etiologies of liver
cirrhosis included hepatitis B in 37 patients (43 %), hepatitis C in
18 patients (21 %), alcoholism in 12 patients (14 %), primary
biliary cirrhosis in 2 patients (2 %), hepatitis B and alcoholism in
7 patients (8 %), hepatitis C and alcoholism in 6 patients (7 %),
and being cryptogenic in 4 patients (5 %). The diagnosis of
cirrhosis was confirmed by liver biopsy or peritoneoscopy in 8
patients, and based on typical clinical findings (splenomegaly,
ascites, and/or esophageal varices), imaging studies (abdominal
sonography[10], computerized tomography, and/or
angiography), and characteristic laboratory findings in the
remaining 78 patients. The severity of cirrhosis was categorized
according to the Child-Pugh classification[11]. Patients
with hypertension, diabetes mellitus, atherosclerosis, uremia, and
peripheral vascular occlusive diseases were excluded. None of these
patients had received antibiotics or vasoactive drugs in the
previous week before blood sampling. All the subjects gave informed
consent to participate in this study, which was approved by the
Hospital Ethics Committee. This study also conformed to the
provisions of the World Medical Association Declarations of
Helsinki.
All the patients received a complete physical examination to
reveal the number and size of the spider angiomas. Serum albumin
(reference range 3.7-5.3 g/dL), bilirubin (0.2-1.6 mg/dL), aspartate
transaminase (AST, 5-45 U/L), alanine transaminase (ALT, 0-40 U/L),
creatinine (0.7-1.5 mg/dL), and blood urea nitrogen (7-20 mg/dL)
concentrations were measured in each patient using standard
laboratory methods (Hitachi Model 736 automatic analyzer, Tokyo,
Japan) on the same day the blood was sampled for assays of plasma
vascular growth factors. Each cirrhotic patient underwent an upper
GI endoscopy (Olympus GIF-XQ240; Olympus Corp., Taipei, Taiwan) to
document the presence of esophageal varices. The severity of varices
was graded F1: small straight varices, F2: enlarged tortuous varices,
and F3: largest-sized coil-shaped varices, as suggested by Beppu et
al[12].
Determination
of plasma levels of VEGF and bFGF
All the plasma samples were centrifuged at 3 000 rpm for 10
minutes at 4 °C and stored at -80 °C until tested. Samples from all the patients and controls were
coded so that the technicians running the assays were blind to the
sources of the samples. Plasma levels of VEGF and bFGF were measured
by using commercially available enzyme-linked immunoabsorbent assay
kits (R&D Systems Inc., Minneapolis, MN) according to the
manufacturer’s instructions. Standard curves were constructed
using serial dilutions of recombinant VEGF and bFGF. Optical
densities were determined using a micro-titer plate reader
(Bio-Kinetics Reader, Bio-Tek Instruments, VT). Tests were performed
in duplicate. The intra- and inter-assay variations of these assays
were less than 10 %.
Statistical
analysis
Results
were expressed as mean ± SEM. Unpaired Student t-test was used to analyze continuous variables
between groups. Chi-square test or Fisher’s exact test was used
for comparison of categorical variables. Pearson correlation
coefficient was used to determine the relationship between numerical
variables, such as plasma levels of VEGF and the size of spider
angiomas. Cut-off values were determined for each serum angiogenic
factor according to the best discrimination between patients with or
without spider angiomas regarding optimal values of sensitivity and
specificity using the receiver operating characteristics (ROC) curve
analysis. Logistic regression was used to assess the relationship of
independent variables with the presence of spider angiomas in
cirrhotic patients. Statistical analyses were performed using the
SPSS software (SPSS 10.0, SPSS Inc., Chicago, IL, USA). Results were
considered statistically significant at P<0.05.
RESULTS
Plasma angiogenic factors in patients with liver cirrhosis
Plasma VEGF and bFGF levels in patients with liver cirrhosis
are listed in Table 1. Plasma levels of VEGF and bFGF were increased
in patients with liver cirrhosis compared with healthy controls (P<0.05).
There was no difference in age, sex, and serum levels of creatinine
between the two groups (data not shown).
Table
1 Plasma
levels of VEGF and bFGF
| Parameters |
Healthy
controls(n=53) |
Cirrhotics(n=86) |
P
Value |
| VEGF
(pg/mL) |
71±11 |
122±13 |
0.003 |
| bFGF
(pg/mL) |
3.4±0.5 |
5.1±0.5 |
0.022 |
VEGF=vascular
endothelial growth factor, bFGF=basic fibroblast growth factor.
Patient
characteristics
Characteristics of the 86 patients with liver cirrhosis are
listed in Table 2. Plasma VEGF and bFGF were increased in the 31
cirrhotic patients with spider angiomas compared with the 55
patients without spider angiomas (185±28
pg/mL vs. 90±10
pg/mL, P=0.003 for VEGF; 6.8±1.0
pg/mL vs. 4.1±0.5
pg/mL, P=0.017 for bFGF). Plasma VEGF was also higher in the
26 patients with alcohol-related liver cirrhosis compared with the
60 patients with non-alcoholic liver cirrhosis (167±29
pg/mL vs. 103±13
pg/mL, P=0.04).
Table
2 Characteristics
of patients
|
No.
of
patients |
VEGF(pg/ml) |
bFGF(pg/ml) |
| Sex |
|
|
|
| Male |
67 |
121±14 |
4.8±0.5 |
| Female |
19 |
123±27 |
6.1±1.5 |
| Age |
|
|
|
| ≤60
years |
36 |
149±24 |
5.2±0.8 |
| >60
years |
50 |
103±13 |
5.1±0.6 |
| Etiology |
|
|
|
| Alcohol-related |
26 |
167±29* |
4.6±0.7 |
| Non-alcoholic |
60 |
103±13 |
5.4±0.6 |
| Albumin
(g/dL) |
|
|
|
| ≤3.6 |
48 |
132±15 |
5.1±0.7 |
| >3.6 |
38 |
109±21 |
5.2±0.7 |
| Creatinine
(mg/dL) |
|
|
|
| ≤1.5 |
83 |
122±13 |
5.2±0.5 |
| >1.5 |
3 |
125±73 |
4.5±2.6 |
| ALT
(U/L) |
|
|
|
| ≤40 |
37 |
136±22 |
4.1±0.6 |
| >40 |
49 |
111±15 |
5.9±0.7 |
| Total
bilirubin (mg/dL) |
|
|
|
| ≤1.6 |
54 |
115±16 |
5.2±0.6 |
| >
1.6 |
32 |
133±20 |
5.0±0.9 |
| Child-Pugh
score |
|
|
|
| A |
47 |
98±19 |
5.5±0.7 |
| B,
C |
39 |
141±16 |
4.8±0.7 |
| Prothrombin
time prolongation >4 s |
|
|
|
| Yes |
27 |
145±23 |
5.0±1.0 |
| No |
59 |
112±15 |
5.3±0.6 |
| Platelet
count (/mL) |
|
|
|
| ≤150
000 |
71 |
109±12+ |
6.8±1.5 |
| >
150 000 |
15 |
204±41 |
4.7±0.5 |
| Esophageal
varices |
|
|
|
| Yes |
59 |
122±14 |
5.0±0.6 |
| No |
27 |
119±28 |
5.8±1.0 |
| Spider
angioma |
|
|
|
| Yes |
31 |
185±28b |
6.8±1.0a |
| No |
55 |
90±10 |
4.1±0.5 |
aP<0.05,
bP<0.005. VEGF=vascular endothelial growth
factor, bFGF=basic fibroblast growth factor.
Plasma
angiogenic factors and clinical features
Table
3 summarizes the clinical features of cirrhotic patients with spider
angiomas and those without. Cirrhotic patients with spider angiomas
were younger (54±2
years vs. 66±1
years, P<0.001) and had higher serum bilirubin (3.1±0.5 mg/dL vs. 1.7±0.2 mg/dL, P=0.03), longer prothrombin time (16.6±0.7
sec vs. 14.8±0.4
sec, P=0.015), and higher proportion of alcoholism (45 % vs.
20 %, P=0.014) than those without. Sex, serum albumin,
creatinine, AST, ALT, platelet count, size of esophageal varices,
and Child-Pugh score did not differ between the two groups.
In the cirrhotics, plasma VEGF was significantly correlated
with the size of spider angiomas (r=0.38, P<0.001).
Plasma VEGF level also showed correlation with serum bilirubin level
(r=0.3, P=0.006) and platelet count (r=0.5, P<0.001).
Univariate
analysis of predictive factors for spider angiomas
Univariate
analysis of factors predicting the presence of spider angiomas in
patients with liver cirrhosis by using logistic regression is shown
in Table 4. The cut-off values of 134 pg/mL for VEGF and 4.8 pg/mL
for bFGF obtained by the ROC analysis were used in the univariate
analysis. Young age, elevated serum AST and bilirubin, prolonged
prothrombin time, elevated plasma VEGF and bFGF, and alcoholism were
associated with the presence of spider angiomas in cirrhotic
patients.
Table
3 Clinical features
of cirrhotic patients with and without spider angiomas
| Parameters |
Spider
(+)(n=31) |
Spider
(-)(n=55) |
P
Value |
| Age
(years) |
54±2 |
66±1 |
<0.001 |
| Sex
(male/female) |
27/4 |
41/14 |
0.17 |
| Albumin
(g/dL) |
3.4±0.1 |
3.5±0.1 |
0.69 |
| Creatinine
(mg/dL) |
1.0±0.1 |
1.1±0.1 |
0.24 |
| AST
(U/L) |
91±9 |
89±13 |
0.93 |
| ALT
(U/L) |
59±9 |
72±11 |
0.36 |
| Platelet
count (/uL) |
108
097±12
379 |
94
762±7
541 |
0.33 |
| Esophageal
varices(nil/F1/F2/F3) |
7/6/12/6 |
18/12/14/11 |
0.88 |
| Child-Pugh
score |
8.2±0.5 |
7.3±0.3 |
0.99 |
| Bilirubin
(mg/dL) |
3.1±0.5 |
1.7±0.2 |
0.03 |
| Prothrombin
time (s) |
16.6±0.7 |
14.8±0.4 |
0.015 |
| Alcoholism |
14
(45 %) |
11
(20 %) |
0.014 |
AST=aspartate
transaminase, ALT=alanine transaminase.
Table 4 Univariate
analysis of predictive factors for spider angiomas
| Parameters |
Odds
ratio |
95 % Confidence interval |
P
Value |
| Age
(≤60 years) |
5.12 |
1.97-13.28 |
0.001 |
| Albumin
(≥3.7 g/dL) |
0.66 |
0.27-1.64 |
0.369 |
| Creatinine
(>1.5 mg/dL) |
0.58 |
0.06-5.81 |
0.642 |
| AST
(>45 U/L) |
5.76 |
1.56-21.3 |
0.009 |
| ALT
(>40 U/L) |
1.24 |
0.51-3.02 |
0.634 |
| Bilirubin
(>1.6 mg/dL) |
2.71 |
1.09-6.74 |
0.031 |
| Platelet
count (>150 000/uL) |
1.41 |
0.44-4.52 |
0.563 |
| Prothrombin
time prolongation (>4 s) |
2.96 |
1.15-7.58 |
0.024 |
| Child-Pugh
score C |
1.64 |
0.59-4.53 |
0.344 |
| VEGF
(≥134 pg/mL) |
5.33 |
1.93-14.74 |
0.001 |
| bFGF
(≥4.8 pg/mL) |
4.38 |
1.67-11.5 |
0.003 |
| Alcoholism |
3.29 |
1.25-8.67 |
0.016 |
AST=aspartate
transaminase, ALT=alanine transaminase, VEGF=vascular endothelial
growth factor, bFGF=basic fibroblast growth factor.
Table
5 Multivariate analysis of predictive values of VEGF, bFGF,
and age for spider angiomas
| Parameters |
Odds
ratio |
95% confidence interval |
P
Value |
| Age
(≤60 years) |
6.64 |
2.02-21.79 |
0.002 |
| VEGF
(≥134 pg/mL) |
4.35 |
1.35-14.01 |
0.014 |
| bFGF
(≥4.8 pg/mL) |
5.66 |
1.72-18.63 |
0.004 |
VEGF=vascular
endothelial growth factor, bFGF=basic fibroblast growth factor.
Multivariate
analysis of plasma VEGF and bFGF, age and their predictive values
for spider angiomas
Multivariate analysis with logistic regression showed that
young age and elevated plasma levels of VEGF and bFGF were the most
independent predictive factors for spider angiomas in cirrhotic
patients, as shown in Table 5. The predictive values of plasma VEGF
for spider angiomas were the following: sensitivity, 53 %;
specificity, 82 %; positive predictive value, 64 %; and negative
predictive value, 75 %. The predictive values of plasma bFGF for
spider angiomas were: sensitivity, 60 %; specificity, 75 %; positive
predictive value, 58 %; and negative predictive value, 76 %.
DISCUSSION
Spider angioma has been commonly seen in patients with liver
cirrhosis[1,2]. The pathogenesis is still unknown.
Neovascularization is a likely mechanism, but has not been proved.
In the current study, we found significantly elevated plasma levels
of VEGF and bFGF in cirrhotic patients compared with healthy
controls. Elevated plasma VEGF was correlated with the size of
spider angiomas. To our knowledge, this is the first study to
demonstrate that age and plasma VEGF and bFGF are the most
significant independent predictors of spider angiomas in cirrhotic
patients.
VEGF has been found to be a glycoprotein that selectively
induces endothelial proliferation, angiogenesis, and capillary
hyperpermeability[13-15]. VEGF gene was expressed in a
wide variety of normal human tissues, including the liver[16,17].
Blood levels of VEGF in patients with cirrhosis remain controversial[6,18].
Our results showed that plasma VEGF was elevated in patients with
liver cirrhosis. In addition, plasma VEGF levels were negatively
correlated with liver function reserve in patients with liver
cirrhosis. The elevated VEGF might be due to ischemic or damaged
liver cells, which released cellular VEGF to facilitate damage
repair by stimulating angiogenesis[19]. Increased
production of VEGF by the cirrhotic liver has also been reported[20],
and may subsequently lead to the formation of spider angiomas.
bFGF has also been found to be a potent stimulator of
endothelial cell proliferation, migration, and angiogenesis[21].
Our results showed that plasma bFGF was elevated in patients with
liver cirrhosis which was consistent with previous reports[7-9].
The elevated bFGF might be due to a release from damaged liver cells[22]
or increased production by the cirrhotic liver[9]. bFGF
could also stimulate the production of VEGF and enhance angiogenesis[23].
The presence of spider angiomas has been reported to be
associated with esophageal variceal bleeding[5]. The
pathophysiological mechanism has been unclarified. Spider angiomas
originate from arterioles, while esophageal varices are one kind of
veins. They are different in nature. In this study, there was no
relationship between the presence of spider angiomas and the degree
of esophageal varices. In addition, there was no association between
esophageal varices and these angiogenic factors.
A positive correlation was also found between serum VEGF
level and the platelet count. This result was in accordance with the
findings reported by others[24]. Platelets release a
variety of vasoactive substances, including VEGF, and promote
angiogenesis, endothelial permeability, and endothelial growth[25].
Although there was a positive correlation between the serum VEGF
level and platelet count, there was no significant association
between platelet count and spider angioma in the present study.
Serum VEGF level was an independent predictor of spider angioma.
Plasma VEGF was increased in alcoholic cirrhotics compared
with non-alcoholic cirrhotics in our study. Ethanol could induce
expression of vascular endothelial growth factor and stimulate
angiogenesis[26]. This may lead to the high prevalence of
spider angiomas in alcoholic cirrhotic patients.
Young age was a significant predictor for the presence of
spider angiomas in cirrhotics in our study. This was in conformity
with previous reports[1]. The underlying mechanism is
unknown. A decline in angiogenic capacity in the aged[27,28]
may cause impaired neovascularization and formation of spider
angiomas in cirrhotic patients.
In summary, plasma VEGF and bFGF are elevated in patients
with liver cirrhosis, especially in those with spider angiomas.
Age-related angiogenic capacity as well as VEGF and bFGF may play
important roles in the formation of spider angiomas in cirrhotic
patients.
ACKNOWLEDGMENT
This work was supported by grant NSC 89-2315-B-075-004 from the
National Science Council, and grant VGH 90-070 from Taipei Veterans
General Hospital, Taiwan.
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Edited
by Zhu
LH
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PubMed