Clinical signs or elevated

serum aminotransferases may vary over time or may be absent in patients with advanced cirrhosis.2, 4 Ultrasound (US) is widely used5-8 but may not distinguish liver fibrosis from steatosis.8 Although these tests are widely employed in CFLD evaluation, their value in predicting significant liver disease has not been determined to date by a prospective study. Liver biopsy is not widely used and has not been systematically evaluated in this clinical Proteasome inhibitor context. There are perceived but poorly tested issues of sampling error in CFLD, and only limited studies have included histology in diagnosis, management, or the study of putative therapies.8-10 However, liver pathology is being characterized in CFLD, and the importance of hepatic fibrogenesis is generating interest in the role of liver biopsy in clinical

practice. The CF transmembrane regulator protein is expressed in the cholangiocyte.11 Altered biliary transport12 appears to lead to focal obstruction of bile flow, retention of toxic bile acids,13 up-regulation of key chemokines,13 selleck chemical induction of hepatic stellate cell chemotaxis and proliferation, and peribiliary fibrogenesis,13, 14 which is the key event leading to the pathognomonic focal biliary fibrosis Rho of CFLD.14 Some but not all cases progress to multilobular biliary cirrhosis via bile duct and hepatocyte injury and active fibrogenesis along the expanding

scar interface13, 14; this is reflected also by the appearance of potential biomarkers in the serum.12, 13, 15, 16 Recent studies have suggested that the Z allele of the serpin peptidase inhibitor clade A member 1 gene is a risk factor for cirrhosis in CF, although the role of this and other potential genetic modifiers in CFLD requires further mechanistic evaluation.17 Here we evaluate dual-pass liver biopsy and the commonly used clinical tools available to clinicians when they are confronted with a patient with suspected CFLD. We look at the ability of the latter to predict hepatobiliary fibrosis on biopsy, and we compare the value of biopsy to the value of clinical modalities currently used to predict adverse outcomes (i.e., PHT and/or liver failure) and mortality over prolonged clinical follow-up (up to 12 years). We hypothesized that hepatic fibrosis on biopsy best predicts clinically significant CFLD and that the evaluation of dual-pass liver biopsy pairs improves diagnostic accuracy.