Analysis of the Pathomorphology of the Intra- and Extrahepatic Biliary System in Biliary Atresia

Abstract

Objective: Aim of the study was to investigate the pathomorphological changes in the liver and triangular cord of the porta hepatis in biliary atresia and assess the relationship between the degree of differentiation of fibroblasts in the triangular cord of the porta hepatis and the liver fibrosis scores. Methods: From September 2005 to May 2006, 21 patients with biliary atresia (66 ± 20 days old) underwent a Kasai procedure. The liver biopsy and the remnant of the porta hepatis were conserved. Five cases with cholestasis syndrome and 10 cases with choledochal cyst were used as a control group. Liver biopsies were performed in the control group. The micro- and ultrastructure of the liver and the remnant of the porta hepatis were assessed in the biliary atresia and the control group. Ultrastructural features were examined by transmission electron microscopy. The semiquantitative differences in liver fibrosis grading between the biliary atresia and the control group was evaluated with a 3-grade staging system. The degree of differentiation of fibroblasts (FB) in the triangular cord of the porta hepatis was assessed as follows: 1) juvenile type: above 50 % FBs were juvenile, 2) senior type: above 50 % FBs were senior, 3) median type: between the former 2 types. The differentiation scores of FB in the porta hepatis were assessed in relation to the liver fibrosis score. Results: 1) The pathological changes with BA are characterized by inflammation and fibrosis in the hepatic portal area. The fibrosis scores in the biliary atresia group (I: 2 cases, II: 12 cases, III: 7 cases) were significantly higher than in the control group (I: 8 cases, II: 5 cases, III: 2 cases; p = 0.01. 2) In the biliary atresia group, the extrahepatic biliary system of all cases showed a triangular cord in the porta hepatis. The triangular cord of porta hepatis was characterized by hyperplasia of canaliculi, atresia or stenosis of the bile ducts, inflammation infiltration, cholestasis, and interstitial fibrosis. 3) The ultrastructural features of BA showed active fibroblasts, a loss of microvilli, dense deposits in the hepatocytes and liver sinusoid, and dilatation of canaliculi. 4) The differentiation scores of FB in the porta hepatis were positively related to the liver fibrosis score (p = 0.04). Conclusion: The main pathological changes of biliary atresia are inflammation and fibrosis in the hepatic portal area. The ultrastructural features of biliary atresia suggested that the differentiation scores of FB in the triangular cord of the porta hepatis were positively related to the liver fibrosis score.

Key words

biliary atresia - pathology - electron microscope - fibroblast

References

• 1 Alagille D. Extrahepatic biliary atresia.  Hepatology. 1984;  4 7-10
• 2 Bonacini M, Hadi G, Govindarajan S, Lindsay K L. Utility of a discriminant score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepatitis C virus infection.  Am J Gastroenterol. 1997;  92 1302-1304
• 3 Chen L, Goryachev A, Sun J, Kim P, Zhang H, Phillips M J, Macgregor P, Lebel S, Edwards A M, Cao Q, Furuya K N. Altered expression of genes involved in hepatic morphogenesis and fibrogenesis are identified by cDNA microarry analysis in biliary atresia.  Hepatology. 2003;  38 567-576
• 4 Domiati-Saod R, Dawson D B, Margraf L R, Finegold M J, Weinberg A G, Rogers B B. Cytomegalovirus and human herpesvirus 6, but not human papillomavirus, are present in neonatal giant cell hepatitis and extrahepatic biliary atresia.  Pediatr Dev Pathol. 2000;  3 367-373
• 5 Donaldson P T, Clare M, Constantini P K, Hadzic N, Mieli-Vergani G, Howard E, Kelley D. HLA and cytokine gene polymorphisms in biliary atresia.  Liver. 2002;  22 213-219
• 6 Feng J X, Li M J, Cai T, Gu W Z, Tang H F. Expression of Fsa, bcl-2 and bax genes in liver and bile ducts in Balb/c mice induced by cytomegalovirus.  Chin J Exp Surg. 2003;  20 719-722
• 7 Fischler B, Haglund B, Hjern A. A population-based study on the incidence and possible pre- and perinatal etiologic risk factors of biliary atresia.  J Pediatr. 2002;  141 217-222
• 8 Gamadia L E, Rentenaar R J, van Lier R A, ten Berge I J. Properties of CD4⁺ T cell in human cytomegalovirus Infection.  Hum Immun. 2004;  65 486-492
• 9 Hadzic N, Tizzard S, Davenport M, Singer J, Howard E R, Midi-Vergani G. Longterm survival following Kasai portoenterostomy: is chronic liver disease inevitable?.  J Pediatr Gastro Nutr. 2003;  37 403-433
• 10 Kobayashi H, Li Z, Yamataka A, Lane G J, Miyano T. Role of immunologic costimulatory factors in the pathogenesis of biliary atresia.  J Pediatr Surg. 2003;  38 892-896
• 11 Landing B H, Wells T R, Ramicone E. Time course of the intrahepatic lesion of extrahepatic biliary atresia: a morphometric study.  Pediatr Pathol. 1985;  4 309-319
• 12 Liu J C. Biliary atresia. Dong Q, Li L, Xiao XM Pediatrics Hepatobiliary Surgery. 1st ed. Beijing; People's Medical Publishing House 2005: 287-288
• 13 Mack C L, Sokol R J. Unraveling the pathogenesis and etiology of biliary atresia.  Pediatr Res. 2005;  57 87-94
• 14 McKiernan P J, Baker A J, Kelly D A. The frequency and outcome of biliary atresia in the UK and Ireland.  Lancet. 2000;  355 25-29
• 15 Moss P, Khan N. CD8+ T-cell immunity to cytomegalovirus.  Hum Immunol. 2004;  65 456-464
• 16 Nio M, Ohi R, Miyano T, Saeki M, Shiraki K, Tanaka K. Japanese Biliary Atresia Registry. Five and 10-year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry.  J Pediatr Surg. 2003;  38 997-1000
• 17 Petersen C, Ure B M. What's new in biliary atresia?.  Eur J Pediatr Surg. 2003;  13 1-6
• 18 Phillips M J, Azuma T, Meredith S L, Squire J A, Ackerlev C A, Pluthero F G, Roberts E A, Superina R A, Levv G A, Marsden P A. Abnormalities in villin gene expression and canalicular microvillus structure in progressive cholestatic liver disease of childhood.  Lancet. 2003;  362 1112-1119
• 19 Sheng C, Zheng S, Chen L. The relationship between the prognosis of biliary atresia and the infection of cytomegalovirus.  Clin J Obstet Gynecol Pediatr. 2005;  1 107-109
• 20 Shteyer E, Ramm G A, Xu C, White F V, Shepherd R W. Outcome after portoenterostomy in biliary atresia: pivotal role of degree of liver fibrosis and intensity of stellate cell activation.  J Pediatr Gastroenterol Nutr. 2006;  42 93-99
• 21 Wang W, Zheng S. Infection of cytomegalovirus exacerbated liver fibrosis in infants with biliary atresia.  Chin J Pediatr Surg. 2005;  6 464-466
• 22 Wang W, Zheng S. Studies of virus infection and immune system responses in biliary atresia.  Int J Pediatr. 2006;  33 27-271
• 23 Yu Z, Zhong C S. Connective cell. Lin YP, Yu Z The Ultrastructure of Cells and Transmission Electron Microscopy Technique. 2nd ed. Shanghai; Fudan University Press 2004: 82-86