Subsequently, periportal fibrosis develops and, eventually, focal biliary cirrhosis appears. This then leads to inflammation and duct injury ( 17). It is thought that the abnormal function of CFTR impacts the secretion of bile and its alkalinization, leading to obstruction of biliary ductules by hyperviscous bile. The CFTR protein is present on the apical membrane of cholangiocytes ( 16), where it serves as an ATP-dependent channel for the transport of chloride ions. CFTR is expressed in the bile duct cells as well as in the gallbladder, but not in hepatocytes. The pathogenesis of CFLD remains poorly understood. Recently, new data accumulated on the use of transient elastography or serum markers have challenged the Debray criteria ( 15). A liver biopsy is required if uncertainty remains and is judged to be clinically relevant, while keeping in mind possible sampling errors due to the non-uniform nature of CFLD. The diagnostic criteria proposed by Debray et al in 2011 ( 14) currently serve as the most commonly used definition, requiring the identification of at least two of the following: 1) evidence of hepatomegaly or splenomegaly (confirmed by ultrasound) 2) AST, ALT, or GGT elevation above the normal limit on three consecutive occasions over 12 months or 3) ultrasonic evidence of liver involvement, portal hypertension, or biliary involvement. Variable definitions have been used throughout time and in the available literature, showcasing the difficulty in describing CFLD. The definition of CFLD is controversial and expert panels have highlighted that there is an ongoing need to clarify disease staging and to identify relevant biomarkers to assess disease severity ( 13). Environmental factors, while yet to be determined specifically, are thought to play a role as suggested by the discordance in the clinical expression of liver disease in siblings ( 12). Non-CFTR polymorphisms such as SERPINA1Z allele of the α1-antitrypsin gene ( 11) have been associated with a greater risk of developing portal hypertension in CFLD. It remains unknown why certain patients develop severe liver involvement: in particular, no specific CFTR mutation has been clearly associated with CFLD ( 9, 10).
While the most prominent clinical manifestations of CF are pulmonary, liver involvement has been described in about 30% of cases in prospective pediatric cohorts ( 4, 6, 7) with a similar prevalence in adult retrospective cohorts ( 7, 8). Liver involvement is thought to be more prevalent in individuals of Latin American origin ( 5). Besides mutations, it is known that pancreatic insufficiency, meconial ileus and younger age at diagnosis have been associated with the occurrence of CFLD ( 3, 4).
Classes I, II and III, often described as severe, are associated with CFLD. CFTR mutations are separated into classes according to their clinical impact. The most common mutation is the F508del, which is frequent in Caucasians however, CF can affect all ethnicities. Therefore, particular attention has to be paid to the transition of care from pediatric into adult medicine and to liver involvement in adult CF patients.ĬF, an autosomal recessive disorder, is caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR).
Historically the majority of the research in this field has been done in children with a relative paucity of data in the adult literature. Long thought to be primarily an issue of childhood, cystic fibrosis–associated liver disease (CFLD) has become a concern in adults due to recent advances in extending life expectancy in North American CF patients, who can now expect to live beyond 40 years of age ( 2). Liver disease in cystic fibrosis (CF) represents the third leading cause of mortality in cystic fibrosis patients ( 1).
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