Ursodeoxycholic Acid in Cystic Fibrosis-Related Liver Disease: A Systematic Review
Authors: Katharine Cheng, Deborah Ashby, Rosalind Smyth
Journal: Journal of the Royal Society of Medicine (1997)

Treatment of progressive lung disease in cystic fibrosis (CF) has improved greatly over the last 30 years, leading to improvement in survival well into adult lifel. This has led to clinicians paying increasing attention to both treating and delaying progression of disease in other affected organs. A recent epidemiological study2 reported that the clinical prevalence of cystic fibrosis-related liver disease is relatively uncommon in young children but rises to a peak in adolescence. The pathogenesis of liver involvement in CF remains unclear, partly because there are still insufficient long-term data on large numbers of patients. The end point seen at post-mortem is focal biliary cirrhosis which is the typical histological lesion found in those CF patients with liver disease and is characterized by portal ducts containing an inspissated granular eosinophilic material, bile duct proliferation, chronic inflammatory infiltration and some fibrosis3. This may progress to multilobular cirrhosis which has a reported incidence of up to 4% in one clinic4. Periportal changes were also seen with excessive mucus in the biliary tract3. These observations led to the suggestion that the development of focal biliary cirrhosis may be related to mucus obstruction in the intrahepatic ducts3 but this remains uncertain. Recently, the cystic fibrosis transmembrane regulator (CFTR) was found to be located at or near the apical membrane of the intrahepatic bile duct epithelium5. This observation has been followed by a hypothesis that a primary defect in biliary chloride transport may cause abnormal bile flow and thus contribute to the pathophysiology. In CF the faecal losses of bile acids and taurine (a bile acid conjugate) are high, resulting in a greater proportion of glycine-conjugated bile acids which are potentially more hepatotoxic than taurine-conjugated bile acids and may contribute to the bile duct injury6. It is likely that these mechanisms may lead eventually to intrahepatic bile duct irregularities seen at endoscopic retrograde cholangiography7 and to the observed post-mortem findings of CF liver disease. No association between genotype and development of liver disease has been found so far. A recent study analysing the risk factors for the development of liver disease associated with CF showed no difference in allele frequencies between those with and those without liver involvement8. Early detection and assessment of progression of CFliver disease can be difficult. By the time clinical liver disease is evident, usually portal hypertension and cirrhosis have already developed. At this stage, the only potentially curative treatment may be liver transplantation9. Biochemical markers of liver function may not be useful in the assessment of liver involvement because any hepatocyte dysfunction is due to the secondary effect of the primary intrahepatic ductal lesion and the level of abnormality does not always correlate with clinical evidence of liver disease6. Abnormalities of these tests may also be due to an effect other than CF liver disease such as an adverse effect of a drug treatment or bacterial infectionl. Ultrasound appearances of liver size and irregular texture, as well as Doppler studies of altered direction and velocity of portal vein flow can be used to assess the presence and progression of liver disease or portal hypertension1 1. A recent study has suggested that measuring biliary excretion of disopropylphenyl-carboxymethyl iminodiacetic acid (DISIDA) by radioisotope scanning with hepatic scintigraphy may be useful in assessing early liver involvement12. Recent developments in therapy have been directed towards attempting to improve biliary secretion and bile acid composition. Ursodeoxycholic acid (UDCA) is a naturally occurring hydrophilic bile acid which constitutes less than 4% of the total bile acid pool. In 1990, Erlinger et al. 13 showed that UDCA improves bile acid flow by inducing an increased bicarbonate-rich bile flow. Hydrophilic UDCA is less hepatotoxic than primary bile acids10. Initially UDCA was used to dissolve gallstones but more recently has been used as a possible treatment for other adult chronic cholestatic liver diseases such as primary biliary cirrhosis14 and primary sclerosing cholangitis1 . Following these trials, UDCA was found to improve liver function tests in CF liver disease16 and has since been used in the treatment of and hopefully in the prevention of progressive liver disease in CF in recent years. 6 'Respiratory Unit, Alder Hey Children's Hospital, Eaton Road, Liverpool L12 2AP; 2Department of Mathematical Sciences, University of Liverpool L69 3BX, England