Focal biliary cirrhosis causes significant morbidity and mortality in cystic fibrosis (CF). Although the mechanisms of pathogenesis remain unclear, bile acids have been proposed as potential mediators of liver injury. This study examined bile acid composition in CF and assessed altered bile acid profiles to determine if they are associated with incidence and progression of liver injury in CF-associated liver disease (CFLD). Bile acid composition was determined by gas-liquid chromatography/mass spectrometry in bile, urine, and serum samples from 30 children with CFLD, 15 children with CF but without liver disease (CFnoLD), and 43 controls. Liver biopsies from 29 CFLD subjects were assessed histologically by grading for fibrosis stage, inflammation, and disruption of the limiting plate. A significantly greater proportion of endogenous biliary ursodeoxycholic acid (UDCA) was demonstrated in CFnoLD subjects vs. both CFLD subjects and controls (2.4-and 2.2-fold, respectively; ANOVA, P β«Ψβ¬ .04), and a 3-4 fold elevation in endogenous serum UDCA concentration was observed in both CFLD subjects and CFnoLD subjects vs. controls (ANOVA, P < .05). In CFLD, there were significant correlations between serum cholic acid and hepatic fibrosis, inflammation, and limiting plate disruption as well as the ratio of serum cholic acid/chenodeoxycholic acid to hepatic fibrosis, inflammation, and limiting plate disruption. In conclusion, elevated endogenous UDCA in CFnoLD suggests a possible protective role against liver injury in these patients. The correlation between both cholic acid and cholic acid/chenodeoxycholic acid levels with histological liver injury and fibrosis progression suggests a potential monitoring role for these bile acids in CFLD. (HEPATOLOGY 2004;39: 1673-1682.)
A dvances in pulmonary and nutritional strategies for patients with cystic fibrosis (CF) have significantly improved life expectancy and quality over the last 30 years. Although pulmonary complications still account for the greatest mortality and morbidity among these patients, clinically significant fibrosing CF-associated liver disease (CFLD) has a prevalence of 13%-17%. [1][2][3][4][5][6][7] Onset and progression is during childhood; clinical signs appear late, when fibrosis is advanced. With no reliable predictors or disease markers, early interventions cannot be adequately evaluated. The abnormal CF transmembrane conductance regulator (CFTR) protein was identified in the biliary epithelium and characterized more than a decade ago, 8 yet treatments to prevent progression or initiate regression of CFLD remain elusive. Bile acid therapy with ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases, and improvements in serum parameters, hepatic excretory function, and liver histology 9 -17 have been reported in patients with CFLD. However, while the physiological benefits of UDCA are known in stimulating bile flow and non-CFTR biliary chloride channels and protecting hepatocytes from toxicity of other bile acids, the efficacy of UCDA to alter the natural history of CFLD is not proven. 18 A role for bile acids in the pathogenesis of CFLD was first proposed more than 30 years ago by Sandberg 19 and Weber et al. 20 Since then, the absence of bile acid data obtained during the critical childhood period of disease