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Transforming growth factor-beta1 in plasma and liver of children with liver disease
J N Rosensweig1, M Omori, K Page
1Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, Maryland 21210, USA.
Insights
Transforming growth factor-beta1 (TGF-beta1) hepatic expression is linked to liver fibrosis in children with biliary atresia and cystic fibrosis liver disease. However, plasma TGF-beta1 levels do not accurately reflect hepatic TGF-beta1 in pediatric liver disease.
Area of Science:
- Pediatric Hepatology
- Fibrosis Pathogenesis
- Cytokine Signaling
Background:
- Hepatic fibrosis in pediatric liver diseases like biliary atresia (BA) and cystic fibrosis liver disease (CFLD) has an incompletely understood pathogenesis.
- Transforming growth factor-beta1 (TGF-beta1) is implicated in hepatic fibrosis, with increased hepatic expression and plasma levels observed in animal models.
Purpose of the Study:
- To investigate alterations in TGF-beta1 in children with hepatic fibrosis secondary to BA and/or CFLD.
- To determine if TGF-beta1 shows similar changes in pediatric liver fibrosis as observed in animal studies.
Main Methods:
- Plasma TGF-beta1 levels were measured using ELISA in children with BA, CFLD, and controls.
- Hepatic TGF-beta1 protein expression and fibrosis were semiquantitatively scored via immunohistochemistry in archival liver biopsy specimens.
- Simultaneous plasma and liver TGF-beta1 assessments were conducted in a subset of patients.
Main Results:
- Plasma TGF-beta1 was decreased in children with BA and CFLD compared to healthy controls.
- Plasma TGF-beta1 showed an inverse correlation with age in healthy subjects.
- Hepatic TGF-beta1 expression was significantly increased in the presence of hepatic fibrosis across various pediatric liver diseases (p=0.007).
Conclusions:
- Hepatic TGF-beta1 protein expression is associated with hepatic fibrosis in common childhood liver diseases.
- Plasma TGF-beta1 levels in children do not appear to be a reliable indicator of hepatic TGF-beta1 expression.
- Further research is needed to elucidate the role of TGF-beta1 in pediatric liver fibrosis pathogenesis.
Abstract:
Although several liver diseases of childhood, particularly biliary atresia (BA) and cystic fibrosis (CF) liver disease (CFLD) are characterized by hepatic fibrosis, the pathogenesis of this process is incompletely understood. The cytokine transforming growth factor-beta1 (TGF-beta1) has been implicated in hepatic fibrosis in experimental animals, in which both the hepatic expression and plasma concentration of this cytokine are increased. The objective of our study was to determine whether there are similar alterations of TGF-beta1 in patients with hepatic fibrosis secondary to either BA and/or CFLD. The study design was as follows. In study 1, plasma TGF-beta1 was assessed by ELISA in 9 children with BA undergoing liver transplantation, 11 patients with CFLD, and appropriate control subjects. In study 2, hepatic expression of TGF-beta1 protein (assessed immunohistochemically) and hepatic fibrosis were scored semiquantitatively, on a 1-3 scale, by blinded investigators, in archival liver biopsy specimens from 10 children with BA, 10 with CFLD, and from 10 older children with normal hepatic histology, as well as in 4 patients with liver diseases of various etiologies. Simultaneous plasma and liver TGF-beta1 studies were performed in 8 patients with liver disease. Results were as follows. Plasma TGF-beta1 values were inversely correlated with age in healthy subjects (r=-0.54, p < 0.0001). The plasma TGF-beta1 protein of children with BA was decreased (13+/-2 ng/mL) compared with values for healthy children (42+/-6 ng/mL, n=10, p < 0.005). Similarly, the plasma TGF-beta1 concentration in patients with CFLD was also decreased compared with values for children with CF and normal serum liver profiles (n=14) (2+/-1 ng/mL versus 12+/-1, p < 0.05). However, the plasma TGF-beta1 concentration was increased in two patients with other types of liver disease. The hepatic expression of TGF-beta1 was increased in the presence of hepatic fibrosis in all types of liver diseases studied. Forty-six percent of patients had both marked hepatic fibrosis and marked TGF-beta1 labeling; 86% of samples without fibrosis showed no TGF-beta1 labeling, p=0.007. In conclusion, these studies have established the association of hepatic TGF-beta1 protein and hepatic fibrosis in several common liver diseases of childhood. Our data also suggest that, in children, plasma TGF-beta1 does not appear to be a useful marker of hepatic expression of this cytokine.