Liver disease in cystic fibrosis

Abstract

The most common cause of death in cystic fibrosis (CF) is respiratory failure caused by the chronic lung infection. Approximately 5% die due to liver failure or bleeding varices caused by the CF-associated liver disease. Due to centralised care and more efficient treatment, the expected median survival age is now between 30 and 40 years. This increased survival might make the complications of the liver disease more common as it gives the liver disease more time to progress. The thesis aims to describe the development of liver disease in a well-defined CF-population during the period 1976-1993 with special attention to the age of the patients, different potential risk factors and treatment with ursodeoxycholic acid (UDCA). One hundred and twenty-four patients were followed yearly with liver function tests during the observation period. Between 1989 and 1993 41 patients had at least one liver biopsy. The median age increased from 11 to 15 years during the period. Despite this the percentage of patients having biochemical liver disease (20-30%) did not increase. 4% developed multilobular cirrhosis including portal hypertension and <10% had cirrhosis or severe fibrosis at liver biopsy. This is similar to or less than in other studies. Liver function tests were sensitive in detecting severe liver disease (100%) but not specific. Out of 15 patients who underwent liver biopsy twice with a mean follow-up time of 13 years, only three had progressive liver disease. Meconium ileus, gallbladder disease, lung function and genotype were not risk factors for liver disease in our study. The fatty infiltration of the liver was significantly related to the serum levels of linoleic acid (p<0.05). In ten patients the portal zones were investigated by electron microscopy. Most patients (8/10) had increased collagen deposition around the bile ducts with activated stellate cells with few inflammatory cells in the portal area. This was also found in patients with normal liver function tests. No bile stasis was noted. Seven patients were investigated for bile lipid composition and bile acid kinetics. In no case was the bile lithogenic and the concentration of duodenal bile acids was normal. The sizes of the pools of cholic acid and chenodeoxycholic acid were normal. The proportion of cholic acid was increased (63%, p<0.001) and chenodeoxycholic acid and deoxycholic acid decreased (28%, p<0.05 and 8%, p<0.01, respectively). Vitamin A in liver tissue was analysed in 15 patients. The concentration of vitamin A in the liver decreased with age. In no case were the levels toxic. There was no correlation between the level of vitamin A in the liver and degree of liver fibrosis. In five patients who were followed consecutively by liver biopsy the biopsies were prepared for electron microscopy. The biopsies were analysed regarding fatty infiltration and lysosomal changes in the hepatocytes and related to aminoglycoside administration. No changes could be related to concomitant intravenous aminoglycoside administration or to the total amount of aminoglycoside given. Ten patients were treated with UDCA due to liver disease. Only one had clinical signs of progression of the liver disease and he was the only patient who did not respond with normalisation of the liver function tests. The endoscopic retrograde cholangiography was unchanged after 1 year of treatment and there was a tendency to improved liver histopathology after two yearsí treatment. The urinary excretion of lithocholic acid did not increase during treatment. Urinary UDCA was mainly conjugated with N-acetylglucosamine and glycine. In conclusion, no patients developed liver cirrhosis as adults and liver disease did not seem to become more common with increasing age. No special risk factors for developing liver cirrhosis could be identified. UDCA seemed to decrease fibrosis, bile duct proliferation and inflammation after two years of treatment.