Liver
and biliary tract
Jetra i bilijarni trakt
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GASTROENTEROHEPATOL 2002; 21 ( No 1 – 2 ):
Plasma
endothelin-1 level in children with cholestatic liver diseases
Nivo
endotelina-1 u plazmi dece sa holestatskim bolestima jetre
(
accepted May 17th, 2002 )
1Nafiye Urgancı, 1Fügen
Çullu, 2Bayram Kıran, 1Tülay Erkan, 1Tufan
Kutlu, 1Güngör Tümay, 3Gülºen
Özbay,
1Department of Pediatric
Gastroenterology, Cerrahpasa Faculty of Medicine, University of Istambul,
Istambul,
2DETAM Research Institute,
Istambul,
3Department of Pathology,
Cerrahpasa Faculty of Medicine, University of Istanbul, Istambul, Turkey.
Address
correspondence to: Professor Dr Nafiye Urgancı
Dereboyu caddesi, Cudi Efendi sok.
Pinyal apt. No: 3/6
80840
Ortaköy – Istanbul / Turkey
FAX:: +90 216 5222222
E-mail: aurganci@netas.com.tr
…………………………………………. ………………………………..
Endothelin-1
in cholestatic liver diseases Gastroenteroloska
sekcija SLD-
01727,
2002.
Cholestatic paeditric liver diseases are prevaling
during infancy and early childhood. They frequently lead to early biliary
cirrhosis and portal hypertension. This study was planned to determine the
relationship between the endothelin-1 level and the prognosis of cholestatic
liver disease in early childhood. Nine cases of Biliary Atresia (BA), 4 cases
of progressive intrahepatic cholestasis
(PFIC), and one case of Alagille syndrome (AS), who were followed in the
Pediatric Clinic of Cerrahpaºa Faculty of Medicine, were included in the study.
Nine were male and 5 were female; mean age: 2.5 ± 2.4 years. The control group consisted of 10 healthy
male children; mean age of 9.2 ± 6 years. Plasma endothelin-1 level was studied in DETAM Research
Institute, Istambul with RIA method. The patients were separated in two groups
according to the presence of cholestasis ( gamma glutamyl transpeptidase (GGT)
> 40 IU, total bilirubin (TB) > 1.5 mg/dl . Group-1 consisted of 9
children, 5 with portal hypertension
(PH) (PFIC, n= 4, BA, n= 1) and 4
without PH (AS, n= 1, BA, n=3). Group- 2 (non cholestatic) included 5 children
(BA, n=5) without PH. At the time of the study none of these patients had
ascites or hepatorenal syndrome. Plasma
endothelin-1 level did not differ between Group-1 and Group-2I, but it was
higher than the control group (
p<0.0001, p<.00007 respectively ).
Althought not statistically significant, plasma endothelin-1 level increase was
higher in children with cholestasis with PH than those without PH ( p>0.05
).
Key word : Children, cholestasis, endothelin-1
INTRODUCTION
Cholestatic liver diseases frequently start during the
neonatal period and may rapidly progress to cirrhosis and portal hypertension (
PH ). Among them, the most freqeuent is congenital biliary atresia (BA) which
is due to progressive destructive inflammatory process involving intra and/or
extrahepatic bile duct (1,2).
Endothelins are a group of peptides made of 21
aminoacid which are synthetised by endothelial cells. They have powerful
vasoconstrictor activity, ten times
higher than angiotensin (3). It was shown that in chronic liver disease with cirrhosis
with or without ascites, plasma endothelin-1 (ET-1) level is increased
(4,5,6,7). However, paediatric literature date about the relationship between
cholestasis and ET-1 are rare. In this
study we investigated plasma ET-1 level
in variety of cholestatic liver diseases and explored its prognostic value.
This study enrolled 9 children with BA, 4 with
PFIC, and 1 with Alagille syndrome (AS)
who were followed in the Paediatric
clinics, Cerrahpasa Faculty of Medicine, Istambul, Turkey. Nine children were
males, 5 females; mean age: 2.5±2.4 years. Ten healthy male children served as control group; mean age:
9.2 ± 6 years. None of the patients presented had ascites or hepatorenal
syndrome at the time of the study. The patients were separated in two groups
according to liver function tests, and the presence of jaundice and PH. .
Group-1
consisted of 9 children with cholestatic liver diseases. Five were diagnosed as
having PH ( 4 PFIC, 1 BA ). The remainder 4 without PH included one case AS (
syndromic congenital biliary hypoplasia ), and 3 operated patients of BA which were cholestatic but without
evidence of PH. . All children had
GGT> 40 IU/L, and total serum bilirubin (TB) > 1.5 mg/dl .
Group-2 included 5 cases operated of BA with good postoperative
biliary flow whith GGT<40 IU/L, and TB<1.5 mg/dl. They had no evidence of
PH.
Ten mililiter of blood was taken from each child and
placed into tubes with EDTA. They were
centrifuged at +2°C, 2000 cycles for 15 minutes.
Serum specimens were then put in Eppendorf tubes and kept at –20° C until they were analyzed.
The endothelin-1 analysis was done in Istanbul University Medical
Faculty, DETAM Research Institute, with RIA ( Euro-Diagnostica, Sweden).
Endothelin-1 from plasma samples kept in Eppendorf
tubes were let to settle at –20 C the colons of Sep-Pak C18 (Waters, Millipore
intertech corporation, P.O BOX 225, Bedford MM USA). One mililiter serum was
used for the analysis
Statistical Evaluation:
The Kruskal Wallis test and the Mann-Whitney-U test
were used for the statistical analysis between groups. Graphics were placed on
windows metafile .
Ethical Considerations:
The study was approved by Pediatric
Gastroenterology Department of Cerrahpasa Faculty of Medicine. Informed consent
was obtained from the parents of all children the analysis of sera .
Group-1 and Grup-2 plasma ET-1 levels were found to be higher than in the controls;
21.8 ± 5.4, 16.96 ± 2.3, and 9.61± 0.67 pmol/l respectively ( p<0.0001, p<0.0007 respectively ). The
plasma ET-1 level between Group-1 and Group-2 did not differ statistically
(p>0.08). Table 1. Figure 1. In Group-1, plasma ET-1 level
in children with PH was higher than in those who were not PH ( respectively 24.20+2.5,
18.97+2.3 pmol/1 respectively; p>0.05 ). However, the difference was
not found to be statistically significant. Figure
2.
There is plenty of evidence that endothelins have an
important in the pathogenesis of essential arterial hypertension, acute and
chronic kidney failure, acute myocardial infarction, pulmonary hypertension and
systemic sclerosis (8-10). Beside endothelial cells, endothelins are made by
neurons, heart, lung, pancreas, kidney, and smooth-muscle cells (11,12). They
exert powerful mytogenic activity acting on vascular smooth –muscle cells,
fibroblast, and glomeruler mesenchemical cells (13,14). Endothelins have an
important role in regulating hepatic stellate cell contraction which control
sinusoidal blood flow. In stellate cells endothelins are released by
transforming growth factor stimulus. In a case of active liver damage, ET-1 increases number of stellate cells,
contract them, and change them structurally and functionally, causing hepatic
fibrosis eventually. As a result, intrahepatic blood flow is further impaired
(15). In recent years, several animal and human studies demonstrated casual
connection between plasma ET-1 level and PH development in patients with
cirrhosis (4-7).
In 1995, Nozue reported that the plasma ET-1 concentration
is near normal in children with BA after succesfull portoenterostomy
(hepatico-jejunostomy according to Kasai), whereas in PFIC ET-1 tends to be
higher (16). Kabayoski et al. found higher
plasma ET-1 level in children with portoenterostomy presenting with
cirrhosis and PH, than in children
without cirrhosis and PH (17). They stated that
increased ET-1 level is possibly due to deterioration of liver function
and ET-1 monitoring can be helpful in the assessment of liver fibrosis
progression and the development of PH.
In our study, we found that in children with chronic
cholestatic liver diseases plasma ET-1 level is higher than in the control
group. In children with more severe liver damage, plasma ET-1 is higher than in
the group with more or less preserved liver functions and less severe liver
damage. In our study, the absence of
relationship between ET-I and prognosis of liver disease could be explained by
the fact that most of our patients with cholestasis were infants whose
portoenterostomies (hepatico-jejunostomies according to Kasai) were not
provided adequate biliary flow.
In conclusion, this very preliminary study
demonstrates that increased plasma ET-1 concentration reflects very early liver
damage in infants and small children with cholestatic liver diseases. ET-1
plasma concentration tends to be higher in portal hypertensive children
reflecting advanced liver fibrogenesis. Further studies are necessary to
determine the prognosic role of ET-1 in the development of PH and cirrhosis in
paediatric liver diseases.
Table-1 Plasma endothelin-1
concentrations in patients with cholestasis
|
Group I |
Group II |
Control |
P Group I-II Group I-Control Group II-Control 0.08 0.0001* 0.007* |
ET-1 |
21.8±5.4 |
16.96±2.3 |
9.61±0.67 |
P*<0.005 24 22 20 18 ET-1 16 14 12 10 8 Fig 1: Plasma endothelin-1(ET-1) concentrations in
patients with cholestasis
Nafiye
Urganci 25 20 15 ET-1 10 5 0 Fig 2: Plasma endothelin-1 (ET-1)
concentrations according to the precence of portal hypertension in patients
with cholestasis (Group-1)
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