TRANSFORMING GROWTH-FACTOR-BETA-1 IN PLASMA AND LIVER OF CHILDREN WITH LIVER-DISEASE

Although several liver diseases of childhood, particularly biliary atr esia (BA) and cystic fibrosis (CF) liver disease (CFLD) are characteri zed by hepatic fibrosis, the pathogenesis of this process is incomplet ely understood. The cytokine transforming growth factor-beta 1 (TGF-be ta 1) 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 w hether there are similar alterations of TGF-beta 1 in patients with he patic fibrosis secondary to either BA and/or CFLD. The study design wa s as follows. In study 1, plasma TGF-beta 1 was assessed by ELISA in 9 children with BA undergoing Liver transplantation, 11 patients with C FLD, and appropriate control subjects. In study 2, hepatic expression of TGF-beta 1 protein (assessed immunohistochemically) and hepatic fib rosis were scored semiquantitatively, on a 1-3 scale, by blinded inves tigators, in archival liver biopsy specimens from 10 children with BA, 10 with CFLD, and from 10 older children with normal hepatic histolog y, as well as in 4 patients with Liver diseases of various etiologies. Simultaneous plasma and liver TGF-beta 1 studies were performed in 8 patients with Liver disease. Results were as follows. Plasma TGF-PL va lues were inversely correlated with age in healthy subjects (r = -0.54 , p < 0.0001). The plasma TGF-beta 1 protein of children with BA was d ecreased (13 +/- 2 ng/mL) compared with values for healthy children (4 2 +/- 6 ng/mL, n = 10, p < 0.005). Similarly, the plasma TGF-beta 1 co ncentration in patients with CFLD was also decreased compared with val ues 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-beta 1 concentration was increased in two patients with other types of liver disease. The hepatic expression of TGF-beta 1 was increased in the pre sence of hepatic fibrosis in all types of liver diseases studied. Fort y-six percent of patients had both marked hepatic fibrosis and marked TGF-beta 1 labeling; 86% of samples without fibrosis showed no TGF-bet a 1 labeling, p = 0.007. In conclusion, these studies have established the association of hepatic TGF-beta 1 protein and hepatic fibrosis in several common liver diseases of childhood. Our data also suggest tha t, in children, plasma TGF-beta 1 does not appear to be a useful marke r of hepatic expression of this cytokine.