Institutional members access full text with Ovid®

Share this article on:

Transcriptional Basis for Hepatic Fibrosis in Cystic Fibrosis–associated Liver Disease

Pereira, Tamara N.*; Lewindon, Peter J.*; Greer, Ristan M.; Hoskins, Anita C.*; Williamson, Richard M.; Shepherd, Ross W.*; Ramm, Grant A.*

Journal of Pediatric Gastroenterology and Nutrition: March 2012 - Volume 54 - Issue 3 - p 328–335
doi: 10.1097/MPG.0b013e3182432034
Original Articles: Hepatology and Nutrition

Objectives: Liver disease contributes to significant morbidity and mortality in cystic fibrosis (CF). Although all patients with CF express the defective CF transmembrane conductance regulator in cholangiocytes, many develop asymptomatic fibrosing liver disease. Only some develop cirrhosis, with pathogenesis remaining enigmatic. Available noninvasive diagnostic tools do not identify patients at risk before development of advanced fibrosis. We conducted a pilot study to identify genes associated with hepatic injury and fibrosis on liver biopsy that may help elucidate determinants of CF-associated liver disease (CFLD).

Methods: Liver tissue from children with CFLD with various stages of hepatic fibrosis was compared with pediatric controls using cDNA array analysis. Differential expression of genes of interest was then assessed relative to pediatric control liver and non-CF cholestatic disease control liver from patients with biliary atresia, using both real-time reverse transcription-polymerase chain reaction and immunohistochemistry.

Results: cDNA array demonstrated differential expression of numerous genes associated with hepatic fibrogenesis including collagens, matrix metalloproteinases, and chemokines in CFLD versus normal controls, particularly decreased expression in tissue remodeling genes including plasminogen activator inhibitor-1 (PAI-1, up to 25-fold) and tissue inhibitor of metalloproteinase-1 (TIMP-1); this was validated by real-time reverse transcription-polymerase chain reaction (PAI-1, P = 0.004; TIMP-1, P = 0.019). No significant decrease in PAI-1 or TIMP-1 mRNA was observed in biliary atresia versus normal control. Immunohistochemistry confirmed the decreased expression of hepatic PAI-1 and TIMP-1 protein in CFLD versus both normal and biliary atresia disease controls.

Conclusions: The coordinated differential expression of these genes associated with liver fibrosis provides evidence for a transcriptional basis for the pathogenesis of CFLD and provides avenues for further study. Clarifying the pathogenesis of CFLD will facilitate techniques for early, precirrhotic detection and targeted interventions.

Supplemental Digital Content is available in the text

*Hepatic Fibrosis Group, The Queensland Institute of Medical Research

School of Veterinary Science

Department of Pathology, The University of Queensland, Brisbane, Australia.

Address correspondence and reprint requests to Dr Grant A. Ramm, Hepatic Fibrosis Group, The Queensland Institute of Medical Research, PO Box Royal Brisbane and Women's Hospital, Herston, Brisbane QLD 4029, Australia (e-mail:

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

Received 10 February, 2011

Accepted 21 November, 2011

Drs Pereira and Lewindon participated equally in this study.

This research was supported by research grants from the National Health and Medical Research Council (NHMRC) of Australia (grant no. 290220 and 496602 to G.A.R., P.J.L., and R.W.S.) and the Royal Children's Hospital Foundation, Brisbane, Australia (grant no. 913-003, 913-005, 972-011, 972-017 to G.A.R., P.J.L., and R.W.S.). T.N.P. is supported by the Bushell Foundation Post-Doctoral Research Fellowship from the Gastroenterological Society of Australia and G.A.R. is supported by a senior research fellowship from the NHMRC of Australia (grant no. 552409).

The authors report no conflicts of interest.

Copyright 2012 by ESPGHAN and NASPGHAN