Serum Transforming Growth Factor-β1 and Epidermal Growth Factor in Biliary Atresia

Abstract

Background and Aim: Biliary atresia (BA) is a serious liver disease in children. Since transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF) are involved in the hepatic reparative process, our objective was to investigate whether serum TGF-β1 and serum EGF levels were associated with therapeutic outcomes in BA. Methods: Serum levels of TGF-β1 and EGF were determined with the ELISA method in 67 postoperative BA patients with a median age of 7 years and in 10 age-comparable healthy children. The BA patients were then divided into two groups depending on their therapeutic outcome: good outcome (jaundice-free) and poor outcome (persistent jaundice). Clinical data, serum TGF-β1 and serum EGF levels were compared between the two groups of BA patients. Correlation analysis of serum TGF-β1 with serum EGF was carried out. Data are expressed as mean ± SD. Results: Serum TGF-β1 levels of BA patients were higher than those of controls (86.6 ± 15.7 vs. 75.7 ± 8.8 ng/ml, p = 0.0362). However, there was no difference in serum EGF between BA patients and controls (133.1 ± 66.6 vs. 125.4 ± 88.9 pg/ml, p = 0.744). Further subgroup analysis showed that patients with good outcomes (n = 40) had higher serum TGF-β1 and serum EGF levels than patients with poor outcomes (TGF-β1: 91.2 ± 16.5 vs. 79.6 ± 11.7 ng/ml, p = 0.002; EGF: 148.5 ± 65.0 vs. 110.3 ± 63.4 pg/ml, p = 0.02). In addition, serum TGF-β1 was positively correlated with serum EGF (Pearson's r = 0.3418, p = 0.0046). Conclusion: Elevated serum TGF-β1 and serum EGF levels were associated with a good outcome in BA patients. There was a positive correlation between serum TGF-β1 and serum EGF. This suggests that the resultant TGF-β1 and EGF pathways may be involved in the pathophysiological process in postoperative BA.

Key words

biliary atresia - TGF - EGF

References

• 1 Berlanga J, Caballero M E, Ramirez D. et al . Epidermal growth factor protects against carbon tetrachloride-induced hepatic injury.  Clin Sci (Lond). 1998;  94 219-223
• 2 Bissig K D, Marti U, Solioz M. et al . Epidermal growth factor is decreased in liver of rats with biliary cirrhosis but does not act as paracrine growth factor immediately after hepatectomy.  J Hepatol. 2000;  33 275-281
• 3 Deneme M A, Ok E, Akcan A, Akyildiz H, Soyuer I, Muhtaroglu S. Single dose of anti-transforming growth factor-beta1 monoclonal antibody enhances liver regeneration after partial hepatectomy in biliary-obstructed rats.  J Surg Res. 2006;  136 280-287
• 4 Hashimoto M, Kothary P C, Eckhauser F E, Raper S E. Treatment of cirrhotic rats with epidermal growth factor and insulin accelerates liver DNA synthesis after partial hepatectomy.  J Gastroenterol Hepatol. 1998;  13 1259-1265
• 5 Honsawek S, Chongsrisawat V, Vejchapipat P, Thawornsuk N, Tangkijvanich P, Poovorawan Y. Serum interleukin-8 in children with biliary atresia: relationship with disease stage and biochemical parameters.  Pediatr Surg Int. 2005;  21 73-77
• 6 Kayano K, Okita K. Does IL‐6 regulate liver fibrosis/cirrhosis directly and indirectly?.  J Gastroenterol. 2000;  35 250-251
• 7 Kelly D A, Davenport M. Current management of biliary atresia.  Arch Dis Child. 2007;  92 1132-1135
• 8 Kirmaz C, Terzioglu E, Topalak O. et al . Serum transforming growth factor-beta1(TGF-beta1) in patients with cirrhosis, chronic hepatitis B and chronic hepatitis C [corrected].  Eur Cytokine Netw. 2004;  15 112-116
• 9 Kiyama S, Yamada T, Iwata H. et al . Reduction of fibrosis in a rat model of non-alcoholic steatohepatitis cirrhosis by human HGF gene transfection using electroporation.  J Gastroenterol Hepatol. 2008;  23 e471-e576
• 10 Kobayashi H, Horikoshi K, Long L, Yamataka A, Lane G J, Miyano T. Serum concentration of adhesion molecules in postoperative biliary atresia patients: relationship to disease activity and cirrhosis.  J Pediatr Surg. 2001;  36 1297-1301
• 11 Kobayashi H, Hayashi N, Hayashi K, Yamataka A, Lane G J, Miyano T. Connective tissue growth factor and progressive fibrosis in biliary atresia.  Pediatr Surg Int. 2005;  21 12-16
• 12 Kobayashi H, Horikoshi K, Yamataka A. et al . Are stable postoperative biliary atresia patients really stable?.  Pediatr Surg Int. 2001;  17 104-107
• 13 Komuves L G, Feren A, Jones A L, Fodor E. Expression of epidermal growth factor and its receptor in cirrhotic liver disease.  J Histochem Cytochem. 2000;  48 821-830
• 14 Liu C, Chiu J-H, Chin T. et al . Expression of Fas ligand on bile ductule epithelium in biliary atresia – a poor prognostic factor.  J Pediatr Surg. 2000;  35 1591-1596
• 15 Malizia G, Brunt E M, Peters M G, Rizzo A, Broekelmann T J, McDonald J A. Growth factor and procollagen type I gene expression in human liver disease.  Gastroenterology. 1995;  108 145-156
• 16 Mitsue S, Hamanoue M, Tanabe G. et al . Expression of HGF and TGF-beta 1 mRNA after partial hepatectomy in rats with liver cirrhosis.  Surg Today. 1995;  25 237-243
• 17 Moreira R K. Hepatic stellate cells and liver fibrosis.  Arch Pathol Lab Med. 2007;  131 1728-1734
• 18 Napoli J, Prentice D, Niinami C, Bishop G A, Desmond P, McCaughan G W. Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor beta in a bile duct ligated rat model of cirrhosis.  Hepatology. 1997;  26 624-633
• 19 Ohi R. Biliary atresia. A surgical perspective.  Clin Liver Dis. 2000;  4 779-804
• 20 Ohi R. Surgery for biliary atresia.  Liver. 2001;  21 175-182
• 21 Ramm G A, Nair V G, Bridle K R, Shepherd R W, Crawford D H. Contribution of hepatic parenchymal and nonparenchymal cells to hepatic fibrogenesis in biliary atresia.  Am J Pathol. 1998;  153 527-535
• 22 Skov Olsen P, Boesby S, Kirkegaard P. et al . Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats.  Hepatology. 1988;  8 992-996
• 23 Uchida K, Inoue M, Otake K. et al . The significance of serum hepatocyte growth factor levels in planning follow-up of postoperative jaundice-free patients with biliary atresia.  J Pediatr Surg. 2006;  41 1657-1662
• 24 Ueno T, Nakamura T, Torimura T, Sata M. Angiogenic cell therapy for hepatic fibrosis.  Med Mol Morphol. 2006;  39 16-21
• 25 Vejchapipat P, Theamboonlers A, Chaokhonchai R, Chongsrisawat V, Chittmittrapap S, Poovorawan Y. Serum hepatocyte growth factor and clinical outcome in biliary atresia.  J Pediatr Surg. 2004;  39 1045-1049
• 26 Yang C, Zeisberg M, Mosterman B. et al . Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors.  Gastroenterology. 2003;  124 147-159
• 27 Yoshida S, Nio M, Hayashi Y, Ohi R, Kawamura I, Goto T. Serum insulinlike growth factor-I in biliary atresia.  J Pediatr Surg. 2003;  38 211-215