Myofibroblastic cell activation and neovascularization predict native liver survival and development of esophageal varices in biliary atresia.
OBJECTIVE
To study the relation between collagen 1, α-smooth muscle actin (α-SMA) and CD34 expression and the most essential portoenterostomy (PE) outcomes.


METHODS
Liver specimens were obtained at PE from 33 biliary atresia (BA) patients for immunohistochemical analysis of collagen 1, α-SMA and CD34. Liver biopsies from 35 organ donors were used as controls. Expression patterns were related to clinical data including age at PE, serum total and conjugated bilirubin concentration at the time of PE and during follow-up, incidence of esophageal varices in follow-up upper gastrointestinal endoscopies, and native liver survival as well as to detailed histopathological findings.


RESULTS
Collagen 1 (16.4% vs 4.5%, P < 0.0001), α-SMA (17.9% vs 4.6%, P < 0.0001) and CD34 (4.9% vs 3.8%, P = 0.017) were markedly overexpressed in BA patients compared with controls. Patients who underwent liver transplantation by age of two years had significantly higher expression of collagen 1 (18.6% vs 13.7%, P = 0.024), α-SMA (20.4% vs 15.4%, P = 0.009) and CD34 (5.9% vs 4.0%, P = 0.029) at PE compared with native liver survivors. CD34-positive microvessels were identified in the centrizonal region close to central vein in every BA patient. In majority of BA cases (56%) neovascularization was frequent as CD34-positive microvessels were observed in over half of the hepatic lobules. In controls, the CD34-positive microvessels were rare as they were completely absent in 40 % and were found in less than 5 % of the hepatic lobules in the rest. The difference between BA patients and controls was significant (P < 0.0001). Patients who developed esophageal varices by two years had significantly higher expression of CD34 at PE compared with patients without varices (5.6% vs 4.0%, P = 0.019). Expression of α-SMA (r = 0.758, P < 0.0001) and collagen 1 (r = 0.474, P = 0.016), and the amount of CD34-positive microvessels (r = 0.356, P = 0.047) were related to patient age at PE.


CONCLUSIONS
Hepatic myofibroblastic cell activation, fibrogenesis and neovascularization are enhanced in BA, progress with increasing PE age and relate to native liver survival and development of esophageal varices.
Janne S Suominen, Hanna Lampela, Mikko P Pakarinen, Department of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, 00290 Helsinki, Finland.
Janne S
JS
Suominen
Janne S Suominen, Hanna Lampela, Mikko P Pakarinen, Department of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, 00290 Helsinki, Finland.
Hanna
H
Lampela
Janne S Suominen, Hanna Lampela, Mikko P Pakarinen, Department of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, 00290 Helsinki, Finland.
Päivi
P
Heikkilä
Janne S Suominen, Hanna Lampela, Mikko P Pakarinen, Department of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, 00290 Helsinki, Finland.
Jouko
J
Lohi
Janne S Suominen, Hanna Lampela, Mikko P Pakarinen, Department of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, 00290 Helsinki, Finland.
Hannu
H
Jalanko
Janne S Suominen, Hanna Lampela, Mikko P Pakarinen, Department of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, 00290 Helsinki, Finland.
Mikko P
MP
Pakarinen
D000199:Actins / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D001656:Biliary Atresia / Q000473:pathology*; D001663:Bilirubin / Q000378:metabolism; D001706:Biopsy; D024042:Collagen Type I / Q000378:metabolism; D004932:Esophageal and Gastric Varices / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D007565:Jaundice / Q000628:therapy; D008099:Liver / Q000473:pathology*; D008833:Microcirculation; D009130:Muscle, Smooth / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology*; D011171:Portoenterostomy, Hepatic; D012189:Retrospective Studies; D016896:Treatment Outcome
D000199:Actins; D018952:Antigens, CD34; D024042:Collagen Type I; D001663:Bilirubin
Biliary atresia; CD34; Collagen 1; Liver fibrosis; Neovascularization; α-smooth muscle actin