Rosensweig J N, Omori M, Page K, Potter C J, Perlman E J, Thorgeirsson S S, Schwarz K B
Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, Maryland 21210, USA.
Pediatr Res. 1998 Sep;44(3):402-9. doi: 10.1203/00006450-199809000-00023.
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.
尽管几种儿童肝病，尤其是胆道闭锁（BA）和囊性纤维化（CF）肝病（CFLD）都以肝纤维化为特征，但这一过程的发病机制尚未完全明确。细胞因子转化生长因子-β1（TGF-β1）在实验动物的肝纤维化中发挥作用，在这些动物中，该细胞因子的肝脏表达和血浆浓度均升高。我们研究的目的是确定继发于BA和/或CFLD的肝纤维化患者中TGF-β1是否有类似变化。研究设计如下。在研究1中，通过酶联免疫吸附测定（ELISA）评估了9例接受肝移植的BA患儿、11例CFLD患者以及合适的对照受试者的血浆TGF-β1。在研究2中，由不知情的研究人员对10例BA患儿、10例CFLD患儿、10例肝组织学正常的大龄儿童以及4例各种病因的肝病患者的存档肝活检标本中TGF-β1蛋白的肝脏表达（通过免疫组织化学评估）和肝纤维化进行半定量评分，评分范围为1 - 3级。对8例肝病患者同时进行了血浆和肝脏TGF-β1研究。结果如下。健康受试者的血浆TGF-β1值与年龄呈负相关（r = -0.54，p < 0.0001）。与健康儿童（42±6 ng/mL，n = 10，p < 0.005）相比，BA患儿的血浆TGF-β1蛋白降低（13±2 ng/mL）。同样，与CF患儿且血清肝指标正常者（n = 14）相比，CFLD患者的血浆TGF-β1浓度也降低（2±1 ng/mL对12±1，p < 0.05）。然而，两名其他类型肝病患者的血浆TGF-β1浓度升高。在所研究的所有类型肝病中，肝纤维化存在时TGF-β1的肝脏表达均增加。46%的患者既有明显的肝纤维化又有明显的TGF-β1标记；86%无纤维化的样本未显示TGF-β1标记，p = 0.007。总之，这些研究证实了几种儿童常见肝病中肝脏TGF-β1蛋白与肝纤维化之间的关联。我们的数据还表明，在儿童中，血浆TGF-β1似乎并非该细胞因子肝脏表达的有用标志物。
