ANALYSIS OF RISK-FACTORS FOR THE DEVELOPMENT OF LIVER-DISEASE ASSOCIATED WITH CYSTIC-FIBROSIS

We prospectively screened for liver disease patients with cystic fibro sis who were more than 3 years of age and who were followed at the cys tic fibrosis center of the University of Milan. From January 1991 to D ecember 1992, we screened 189 patients; clinical, biochemical, and ech ographic abnormalities suggestive of overt liver disease were present in 34 (18%). To define risk factors for the development of liver disea se associated with cystic fibrosis, we evaluated the possible role of specific mutations of the CFTR (cystic fibrosis transmembrane regulato r) gene and of different clinical and demographic characteristics (sex , pancreatic status, meconium ileus or its equivalent) through a compa rison of patients with cystic fibrosis and overt liver disease (n = 34 ) and those without liver disease (n = 155). Genetic analysis failed t o reveal any significant difference in the allele frequencies of defin ed (Delta F508, 1717-1G-A, G542X, N1303K, W1282X, R553X) and undefined mutations of the CFTR gene in the two groups of patients; genotype fr equencies were also not significantly different. Pancreatic insufficie ncy was present in all patients with liver disease and in 87.3% of tho se without liver disease. A male predominance was found in the group w ith liver disease. The frequency of meconium ileus or its equivalent w as significantly higher in patients with cystic fibrosis and liver dis ease (35.3%) than in patients without river disease (12.3%) (p = 0.002 5). In the 31 patients with a history of meconium ileus or its equival ent, the following hepatic abnormalities occurred more frequently than in the 155 patients with cystic fibrosis who did not have meconium il eus: hepatomegaly, biochemical abnormalities, heterogeneous echographi c pattern of the liver, and microgallbladder. Twenty-four patients wit h a history of meconium ileus or its equivalent underwent hepatobiliar y scintigraphy (with technetium-labeled iminodiacetic acid derivatives ), which showed morphologic abnormalities suggestive of impaired bilia ry drainage in 21 patients and abnormalities in function in II. The ri sk of acquiring liver disease was increased almost fourfold in patient s with a history of meconium ileus or its equivalent, in comparison wi th patients who had cystic fibrosis but were unaffected by these compl ications (odds ratio, 3.9043; 95% confidence interval, 1.666 to 9.149) . We conclude that patients with cystic fibrosis and meconium ileus or its equivalent may benefit from prophylactic treatment with ursodeoxy cholic acid; genetic analysis of the major mutations present in this p opulation failed to provide evidence of the existence of a specific ge netic marker for the development of liver disease in patients with cys tic fibrosis.