949

Serum IGF-1, IGF-2 and IGFBP-3 as Param-

eters in the Assessment of Liver Dysfunction in
Patients with Hepatic Cirrhosis and in the Diag-
nosis of Hepatocellular Carcinoma
Rania Naguib Abdel Mouteleb Abdel Rehem1 and Wafaa Mohamed Hussein Mekky El-Shikh2
1
Endocrinology and 2Gastroenterology Units Internal Medicine Department, Faculty of Medicine,
Alexandria University, Alexandria, Egypt
Corresponding author: Rania Naguib Abdel Mouteleb Abdel Rehem, Internal Medicine Department,
Endocrinology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt
Tel: +966540703704, E-mail: ranianaguid2000@yahoo.com

ABSTRACT

Background/Aims: Insulin like growth factor
system becomes impaired in liver cirrhosis. Hepa-
tocellular carcinoma (HCC) is associated with
altered synthesis and secretion of several growth
factors.
Methodology: Studying the relation between
serum levels of IGF-I, IGF-II and IGFBP-3 and
clinical grades of liver disease according to Child-
Pugh (C-P) score. Also, evaluation of their role in
the diagnosis of HCC. IGF-I, IGF-II and IGFBP-
3 were measured in 20 healthy subjects, 60 liver
cirrhosis patients and 20 HCC patients included
in the study.
Results: IGF-I, IGF-II and IGFBP-3 levels were
significantly lower in cirrhotic patients compared
to the healthy subjects and were correlated with
the degree of liver dysfunction. IGF-I and IGFBP-
3 levels in patients with HCC were significantly
lower than in both healthy subjects and in patients
with liver cirrhosis. Both IGF-II and AFP levels
in HCC were significantly higher than in healthy
subjects and in patients with liver cirrhosis.
Conclusions: Estimation of serum IGF-I, IGF-II
and IGFBP-3 together with C-P score is more ef-
fective in predicting hepatic dysfunction and its
severity than C-P score alone. Serum IGF-II level
can be used as a serological marker to discrimi-
nate HCC from cirrhosis

INTRODUCTION indirectly combining with its receptor in neighbor-

Growth hormone (GH) is released from the an-
terior pituitary gland and binds to its receptors on
the liver. The liver in turn synthesizes insulin-like
growth factors (IGF) (1). The IGF system operates
in anabolism and cell proliferation (2, 3). The liver is
the predominant site of IGF production so the GH-
IGF system is adversely affected in liver cirrhosis.
Insulin-like growth factor-I and II (IGF-I, IGF-
II) are the two major forms of insulin-like growth
factor family. They are single-chain molecules
with three intrachain disulfide bridges (4,5). Both
of them may be considered as important anabolic
hormones which are active throughout ones life,
inducing anabolic metabolism, stimulation of DNA
synthesis, cell proliferation and meiotic division (2,
3). IGF-I is considered the most important member
of this system. It is generally believed that IGF-I
bioactivity is maintained primarily through free,
unbound IGF-I (6, 7).
Compared with IGF-I, IGF-II is more well-known
as a tumor genesis marker. As serum IGF-II may
be produced and secreted by hepatoma cells, the
hormone could accelerate or magnify its function of
continuously stimulating cell growth by directly or
Hepato-Gastroenterology 2011; 58:949-954
H.G.E. Update Medical Publishing S.A., Athens-Stuttgart
ing cells or hepatoma cells themselves (8, 9).
Insulin-like growth factor- II (IGF-II) is a fe-
tal growth peptide produced by the liver which is
structurally and functionally closely related to in-
sulin (10). It is over expressed in a wide variety of
neoplasms (11, 12) and is involved in experimental
liver carcinogenesis. In vitro, a pathophysiological
link between IGF-II over-expression and hepato-
cyte proliferation was demonstrated by Lin et al.
(13), who found high concentrations of IGF-II in hu-
man hepatoma cell lines. In vivo, Rogler et al. (14)
reported an increased frequency of hepatocellular
carcinoma (HCC) in IGF-II transgenic mice and se-
rum IGF-II has been recently proposed as a marker
for human HCC to improve the diagnostic accuracy
and sensitivity in patients with low serum alpha-
fetoprotein (AFP) levels (15).
IGF-II is speculated to serve as an autocrine
growth factor in various cancers because they often
co-express IGF-II and IGF-II receptors. It is highly
expressed during hepatocarcinogenesis, and re-ex-
pression of the IGF-II gene has recently been de-
scribed in HCC. HCC is generally considered to be
a hypervascular tumor (16) and IGF-II may play an
important role in the development of neovasculariza-
950 Hepato-Gastroenterology 58 (2011)
tion of HCC. Park et al. reported that most of the cir-
rhotic and HCC tissues express IGF-II (17). HCC is
one of the most common malignancies, and the death
rate due to this tumor has been increasing over the
past 20-30 years. Chronic infection with hepatitis C
virus (HCV) has been associated causally with HCC
worldwide, because approximately 20% of HCV-in-
fected individuals have disease that progresses to fi-
brosis and cirrhosis, and about 40% of these patients
develop HCC after a mean of 10-15 years (18, 19).
Consequently, surveillance programs based on peri-
odic ultrasound examination and AFP determination
are recommended for patients with cirrhosis (20).
However, the effectiveness of these programs has not
been fully assessed, and the need for new predictors
for individual patients remains very high.
More than 70% of Insulin-like growth factor
binding protein (IGFBP) is insulin-like growth factor
binding protein-3 (IGFBP-3). IGFBP-3 is considered
the most important component of circulating binding
proteins (21). It consists of 264 amino acid residues
and binds nearly 95% of circulating IGFs in the hu-
man body, forming a stable complex with the acid-
labile subunit. The complex is believed to serve as a
reservoir in circulation to prolong half-lives of both
IGF-I and IGF-II (22, 23). Since most circulating
IGF-I, IGF-II and IGFBP-3 are synthesized by hepa-
tocytes, lower levels of the above three parameters
should be found in patients with liver diseases due to
decreased hepatic synthesis (24, 25). These changes
may also result from hormonal alterations and nu-
tritional deficiencies known to exist in patients with
severe liver dysfunction (26).
This study was designed to clarify the influences
of associated liver cirrhosis as assessed by Child-Pugh
score (C-P score) on the IGF system parameters, to
determine whether measurement of these three pa-
rameters could reflect the severities of cirrhosis and
liver dysfunction, to reveal whether the combination
of these three parameters with C-P score could be a
more reasonable clinical option for evaluating liver
function. The interrelationship between these three
parameters and the conventional hepatic function
tests was examined. Also to clarify the role of IGF-
II as a predictor for the development of HCC in pa-
tients with HCV-related cirrhosis and as a screening
method beside the conventional AFP and imaging
techniques for the detection of HCC.
METHODOLOGY
Patients
The present study was done in The Department
of Internal Medicine, Faculty of Medicine, Alexan-
dria University. The period of study was six months.
The study protocol was approved by the local ethics
committee. Written informed consent according to
the hospital policy guidelines was obtained from all
patients and controls before initiating any study-
related activity.
A total of 100 subjects were enrolled in this
study. Sixty patients with hepatitis C-induced liver
RNAMA Rehem, WMHM El-Shikh
cirrhosis (40 males and 20 females with a mean age
of (509) years, ranging from (29-69) years were
selected. Patients with liver cirrhosis were diag-
nosed by clinical and biochemical examinations,
ultrasonography and computerized tomography.
Patients were divided into 3 groups by C-P score
(27), 20 people were C-P A (scored 5-6), 20 were C-P
B (scored 7-10) and 20 were C-P C (scored 11-15).
A total of 20 healthy subjects were served as con-
trols (15 males and 5 females, mean age of (346)
years, ranging from (24-47). Twenty patients with
liver cirrhosis with HCC were enrolled in the study
(15 males and 5 females, mean age of 5810 years,
ranging from 39-69 years.
Any patient with cardiac, respiratory or renal
dysfunction was excluded. Diabetic patients, pa-
tients with evidence of recent systemic infection or
active variceal bleeding, hepatic encephalopathy or
spontaneous bacterial peritonitis were also exclud-
ed. None of the control group was suffering from
any other medical conditions.
All patients were subjected to complete physi-
cal examination, standard biochemical tests, serum
alfa-fetoprotien (AFP) determination and abdomi-
nal ultrasonography. Patients with HCC were di-
agnosed by triphasic CT with or without elevated
AFP levels.
Blood samples were collected for assessment
of aspartate aminotransferase (AST), alkaline
phosphatase (ALP), bilirubin (Bb), albumin, pro-
thrombin time (PT), creatinine (Cr), sodium (Na),
AFP, IGF-I, IGF-II and IGFBP-3. Samples were
collected in the fasting state in the morning. Sam-
ple collection, processing and storage were done ac-
cording to the instructions of the reference labora-
tory and the kits.
Assays
Plasma levels of IGF-I and IGF-II were quan-
tified by RIA (RIA-CT) kit following acid-acetone
extraction. Intra- and inter-assay coefficients of
variations were 3.5% and 6.2% for IGF-I and 5.5%
and 12.9% for IGF-II, respectively. The results were
defined in ng/mL. IGFBP-3 was measured by a two-
site immunoradiometric assay (IRMA) using DSL-
6600 IGFBP-3 coated-tube IRMA kit (Diagnostic
System Laboratories, Webster, TX, USA) Intra- and
inter assay coefficients of variations were 4.6% and
15.5% respectively.
Statistical analysis
Data were collected, tabulated and analyzed us-
ing SPSS Ver.17. Qualitative data were presented
as numbers and percent. Quantitative data were ex-
pressed as means and standard deviation. ANOVA
test was used for comparison between the means
of quantitative variables, with post-HOC tests for
paired comparisons. Spearmans correlation coeffi-
cient by rank was used to analyze correlations be-
tween different parameters. A 5% level was chosen
as a level of significance in all statistical tests used
in the study. ROC curve was used to calculate the
Insulin-like Growth Factors and Cirrhosis
cut off value and the area under the curve to calcu-
late the sensitivity, specificity and accuracy of both
IGF-II and AFP.
RESULTS
Serum IGF-I in cirrhotic patients, HCC and
matched controls
The mean value for IGF-I in 60 cirrhotic pa-
tients was (6250ng/mL). It was significantly lower
than in the 20 healthy subjects (27252ng/mL). The
mean value for IGF-I in 20 patients with HCC was
(287ng/mL). It was significantly lower than in the
20 healthy subjects and patients with liver cirrho-
sis (p<0.001).
Serum IGF-II in cirrhotic patients, HCC and
matched controls
The mean value for IGF-II in 60 cirrhotic pa-
tients was (432204ng/mL) .It was significantly
lower than in the 20 healthy subjects (1122103ng/
mL). The mean value for IGF-II in the 20 patients
with HCC was (888623ng/mL). It was significantly
higher than liver cirrhosis and lower than healthy
subjects (p<0.001).
Serum IGFBP-3 in cirrhotic patients, HCC
and matched controls
The mean value for IGFBP-3 in 60 cirrhotic pa-
tients was (128ng/mL). It was significantly lower
than those in 20 healthy subjects (404ng/mL). The
mean value for IGFBP-3 in the 20 patients with
HCC was (72ng/mL). It was significantly lower
than those in 20 healthy subjects and those pa-
tients with liver cirrhosis (p<0.001).
Since mean values of the three parameters were
negatively correlated to age according to our statis-
tical show (r=-0.692, -0.249, -0.670), data were re-
vised with covariance analysis to remove the effect
of age on the three parameters and a similar result
was obtained (p<0.001).
Serum IGF-I, IGF-II and IGFBP-3 levels in
patients with different C-P scores
The mean values for IGF-I, IGF-II and IGFBP-3
were 12045, 594144 and 217ng/mL, respectively,
in C-P A; 4219, 365104 and 104ng/mL, respec-
tively, in C-P B. The mean values for IGF-I, IGF-II
and IGFBP-3 in patients classed as C-P C stage, the
worst stage of liver dysfunction, were 258, 339239
and 62ng/mL, respectively. A significant difference
of the three parameters was found between the con-
trol group and any stage of cirrhosis. These three
parameters gradually diminished, along with dis-
ease progression (p<0.001).
Circulating Levels of serum AFP, IGF-II in
healthy subjects, patients with chronic liver
diseases and in patients with HCC
The mean value of serum AFP in HCC patients
was (599800ng/mL). It was significantly higher
than those patients with liver cirrhosis (3039ng/
Hepato-Gastroenterology 58 (2011) 951
mL) and higher than healthy subjects (114ng/mL)
(p<0.001).
Regarding the mean values of different liver
biochemical tests, these showed no significant dif-
ference in the AST level between the three stud-
ied groups. Serum bilirubin, ALP, creatinine and
splenic size were significantly higher in the HCC
group than in the liver cirrhosis and control sub-
jects. These parameters were significantly higher
in the cirrhotic group than in the healthy control
group. The mean values of serum bilirubin, ALP,
creatinine and splenic size showed significant in-
crease with worsening of the degree of liver cirrho-
sis. The mean values of serum albumin and PT%
were significantly lower in the HCC group than in
the liver cirrhosis and control groups. They were
significantly lower for the cirrhotic group than for
the healthy control subjects. They showed signifi-
cant decrease with worsening of the degree of liver
cirrhosis.
In the three studied groups, mean IGF-I lev-
el was negatively correlated with age (r=-0.692,
p=0.001), mean serum bilirubin level (r=-0.523,
p=0.001), ALP (r=-0.923, p=0.001), creatinine
(r=0.508, p=0.001) and splenic size (r=-0.819,
p=0.001). It was positively correlated with mean
serum albumin level (r=0.762, p=0.001) and with
PT% (r=0.734, p=0.001). There was no significant
correlation between serum IGF-I and both mean
serum AST (r=0.016, p=0.873) and sodium levels
(r=0.194, p=0.053).
In the cirrhosis group of patients, the mean
IGF-II level was negatively correlated with age
(r=-0.664, p=0.001), mean serum bilirubin level
(r=-0.505, p=0.001), ALP (r=-0.927, p=0.001), creati-
nine (r=-0.471, p=0.001) and splenic size (r=-0.837,
p=0.001). It was positively correlated with mean se-
rum albumin level (r=0.702, p=0.001) and with PT%
(r=0.715, p=0.001).
While in the HCC group, the mean IGF-II level
was positively correlated with age (r=0.564, p=0.001),
mean serum bilirubin level (r=0.476, p=0.001), ALP
(r=0.836, p=0.001), creatinine (r=0.739, p=0.001) and
splenic size (r=0.654, p=0.001). It was negatively cor-
related with mean serum albumin level (r=-0.787,
p=0.001) and with PT% (r=-0.682, p=0.001).
There was no significant correlation between
serum IGF-II and both mean serum AST (r=0.002,
p=0.988) and sodium levels in both liver cirrhosis
and HCC groups (r=0.163, p=0.106). There was a
significant positive correlation between mean se-
rum IGF-II and serum IGF-I (r=0.893, p=0.001) in
the control and liver cirrhosis group groups. But a
significant negative correlation between them in
HCC group (r=-0.732, p=0.001).
The mean IGFBP-3 level was negatively cor-
related with age (r=-0.670, p=0.001), mean serum
bilirubin level (r=-0.562, p=0.001), ALP (r=-0.926,
p=0.001), creatinine (r=0.544, p=0.001) and splenic
size (r=-0.842, p=0.001). On the other hand, it was
positively correlated with mean serum albumin
level (r=0.766, p=0.001) and with PT% (r=0.779,
952 Hepato-Gastroenterology 58 (2011)
p=0.001). There was no significant correlation be-
tween serum IGFBP-3 and both mean serum AST
(r=0.011, p=0.917) and sodium levels (r=0.194,
p=0.053). There was a significant positive correla-
tion between mean serum IGFBP-3 and both se-
rum IGF-I (r=0.905, p=0.001) and serum IGF-II
(r=0.918, p=0.001) in the control and liver cirrhosis
group but IGFBP-3 was negatively correlated with
IGF-II in the HCC group (r=-0.562, p=0.001).
The mean level of AFP level was positively cor-
related with age (r=0.259, p=0.008), mean serum
bilirubin level (r=0.395, p=0.001), ALP (r=0.327,
p=0.003), creatinine (r=283, p=0.011) and splenic
size (r=0.375, p=0.001). On the other hand, it was
negatively correlated with mean serum sodium level
(r=-0.268, p=0.016), mean albumin level (r=-0.420,
p=0.001), and with PT% (r=-0.485, p=0.001). There
was no significant correlation between serum AFP
and mean serum AST (r=-0.006, p=0.961). There was
a significant negative correlation between mean se-
rum AFP and both serum IGF-I (r=-0.281, p=0.012)
and serum IGFBP-3 (r=-0.283, p=0.011) while there
was no significant correlation between AFP and se-
rum level of IGF-II in the three studied groups.
The optimal cut-off values of IGF-II (99ng/mL)
and AFP (20ng/mL) were determined with ROC
curves. The sensitivity, specificity and diagnostic
accuracy values for IGF-II were 73%, 64% and 65%,
respectively. Those for AFP were 45%, 50% and
46%, respectively. Determination of both markers
in parallel significantly increases the diagnostic
accuracy (69%) and sensitivity (78%), with a high
specificity (70%). In conclusion, IGF-II and AFP
may be used as complementary tumor markers to
discriminate HCC from cirrhosis.
DISCUSSION
The liver is the main source of most serum pro-
teins (28). Therefore, in patients with hepatic cir-
rhosis, it is expected to find a reduction of serum
albumin and other plasma proteins as well as dis-
turbed endocrine functions (29). In the liver, syn-
thesis of IGFs takes place under the control of GH
(30). It has been found that more than 98% of IGF
in serum circulate bound to IGFBP-3 (31).
Since the liver is the abundant site of IGF-I,
IGF-II and IGFBP-3 production, several studies
have been performed to show if they can be used as
markers of the severity of hepatocyte dysfunction.
To confirm this assumption we compared changes
in serum IGF-1, IGF-II and IGFBP-3 levels in the
different stages of cirrhosis with other commonly
used hepatic function tests. The mean IGF-I, IGF-
II and IGFBP- 3 levels were negatively correlated
with mean serum bilirubin level, ALP, creatinine
and splenic size. On the other hand, it was posi-
tively correlated with mean serum albumin level
and with PT%. These results were compatible with
those of the other reports in the literature (6,25,32).
Low levels of IGF-I, IGF-II, IGFBP-3, and albumin
may be attributable also to poor nutritional status
(33). Another explanation for the markedly dropped
RNAMA Rehem, WMHM El-Shikh
levels of IGF-I, IGF-II and IGFBP-3 in liver cirrho-
sis is the presence of severe GH resistance caused
by the feedback maladjustment of the GH-IGF-I-
IGFBP-3 axis which reflects the effect of injury to
the liver. In addition, the production/secretion of
GH receptor is markedly reduced due to severely
damaged hepatocytes, thus leading to the distur-
bance of feedback maladjustment and GH resist-
ance (33, 34).
Our data reported a progressive decrease in
IGF-I, IGF-II and IGFBP-3, which was statisti-
cally significant, with the degree of liver dysfunc-
tion with a progressive decrease from C-P A to C-P
C. This was consistent with previous studies (35,
36). Donaghy et al. (37) also reported that serum
IGFBP-3 levels effectively predicted functional liv-
er reserve and prognostic and clinical states of the
patients. In agreement with our result, Assy et al.
(38) also speculated that C-P score alone could not
be regarded as an ideal predictive method for pa-
tients with liver cirrhosis.
The IGF system also has a role in cellular
growth and differentiation. Thus, it may play an
important role in hepatocarcinogenesis as well
as in other types of carcinomas. Transformation
of hepatocytes to neoplastic cells demands these
growth factors. Many products of oncogenes are
similar to IGF receptors in terms of transmembra-
nous tyrosine kinase activity. IGFs also promote
transcription of proto-oncogenes that modulates
transcription of other genes stimulating cellular
growth (39).
Recent studies have discovered changes in the
IGF axis that affect the molecular pathogenesis of
HCC, including the autocrine production of IGFs,
IGF binding proteins (IGFBPs). Characteristic al-
terations detected in HCC and hepatoma cell lines
comprise the over expression of IGF-II (12).
Hepatocellular carcinoma is one of the most com-
mon forms of malignant cancer with the 4th highest
mortality rate worldwide (40). Serum AFP was con-
sidered as the gold standard marker of HCC, but its
significance in the early diagnosis of HCC is unclear
and the positive rate is not high (41, 42). Its sensi-
tivity varies around a value of approximately 65%
(43-45). This means that 35% of examined HCC pa-
tients may be considered false negatives. Thus there
is a need for the enhancement of the detection of
HCC using AFP. Our study investigated the concept
of combined detection using IGF-II in order to sup-
port the detection of HCC using AFP. The choice of
markers in our study was AFP, which is the main
tumor marker of HCC and IGF-II, and is mainly
produced by liver cells and transcribed in many pri-
mary HCC cell lines (46, 47). IGF-II was found to be
significantly higher in HCC than liver cirrhosis and
healthy subjects. The sensitivity, specificity and di-
agnostic accuracy values for IGF-II were 62%, 57%
and 58%, respectively. Those for AFP were 45%,
50%,and 46%, respectively. Determination of both
markers in parallel significantly increases the diag-
nostic accuracy (60%) and sensitivity (72%), with a
Insulin-like Growth Factors and Cirrhosis
high specificity (65%).
In conclusion, data of previous studies as well
as our own proved that the IGF system is an impor-
tant indicator of liver function. IGF-I, IGF-II and
IGFBP-3 may serve as markers of hepatocellular
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