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Cystic Fibrosis–associated Liver Disease: When Will the Future Be Now?

Rudnick, David A.

Journal of Pediatric Gastroenterology and Nutrition: March 2012 - Volume 54 - Issue 3 - p 312
doi: 10.1097/MPG.0b013e3182309fd0
Invited Commentaries

Departments of Pediatrics and Developmental Biology, Washington University School of Medicine, St Louis, MO.

Address correspondence and reprint requests to David A. Rudnick, MD, PhD, Departments of Pediatrics and Developmental Biology, Washington University School of Medicine, 660 S Euclid Ave, Box 8208, St Louis, MO 63110 (e-mail:

Received 19 July, 2011

Accepted 25 July, 2011

The author reports no conflicts of interest.

See “Transcriptional Basis for Hepatic Fibrosis in Cystic Fibrosis–associated Liver Disease” by Pereira et al on page 328.

In the present issue of JPGN, Pereira et al (1) report their efforts to identify genes whose hepatic expression correlates with severity of fibrosis in patients with cystic fibrosis–associated liver disease (CFLD), in the hope that such data may lead to improved clinical management. The incidence of CFLD is highest in the first decade of life, with an estimated 3% to 10% of patients with cystic fibrosis (CF) developing severe liver disease characterized by cirrhosis with portal hypertension (2,3). CFLD is responsible for 2% to 3% of CF mortality, making it the third leading and most important nonpulmonary cause of CF-related death (2,3). There is no association between specific CF transmembrane conductance regulator (CFTR) mutations and CFLD (2,3). Thus, non-CFTR genetic variation, environmental exposures, or both must contribute to the development of liver disease in these patients. Consistent with this conclusion, the α1-antitrypsin (SERPINA1) Z allele was recently identified as a risk factor for CFLD (4). Of note, polymorphisms in several other genes previously associated with CFLD (5–7) were not confirmed in the more recent study (4). Despite these observations, early, reliable prediction of risk for development of CFLD is not possible. Present practice relies on serial clinical, biochemical, imaging, and histological evaluation (3). With respect to management, ursodeoxycholic acid has been reported to prevent clinical deterioration and improve biochemical parameters at 1 year in patients with CFLD; however, the effects of ursodeoxycholic acid on the likelihood of death or liver transplantation are unknown (8). Together, these considerations emphasize that existing diagnostic and therapeutic options to identify and prevent or reverse CFLD are inadequate. Based on this, CFLD was the focus of a recent National Institutes of Health–sponsored clinical research workshop (9).

Pereira et al conducted cDNA array analysis of gene expression on liver tissue from 14 pediatric patients with CFLD with various stages of hepatic fibrosis, and compared the results with analyses of normal and non-CF cholestatic patients. Because of limited tissue, samples were pooled from patients by fibrosis category. The results showed differential expression of numerous genes associated with hepatic fibrogenesis. To validate these findings, they performed semiquantitative real-time reverse transcriptase-polymerase chain reaction on another 18 patients and immunohistochemical analysis of protein expression on some for a subset of the genes identified by the array. The results showed downregulation of plasminogen activator inhibitor 1 (PAI1) and tissue inhibitor of metalloproteinase 1 (TIMP) hepatic mRNA expression in patients with CFLD.

These data begin to define patterns of hepatic gene expression associated with CFLD. Nevertheless, much more work will be required before such findings can be translated into improved strategies for identification or intervention in CFLD. The experiences with polymorphism analyses noted above obligate efforts to validate the findings reported here in individual patients with CFLD from an independent cohort. Furthermore, the possibility of a causal relation between the identified alterations in gene expression and CFLD requires experimental investigation. For example, the identified differences in gene expression may be markers of or even an adaptive response to CFLD. If so, efforts to target the molecular pathways implicated by the gene expression data in patients at risk for CFLD may be ineffective or, even worse, harmful. Still, if the reported changes in gene expression are reliable markers of CFLD, their identification may lead to improved strategies for predicting development or progression of CFLD, particularly if future studies show the ability to detect the corresponding protein products in blood. Such a tool would be invaluable to identify at-risk patients for future clinical intervention trials.

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