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CYSTIC FIBROSIS

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Cystic fibrosis (CF) is a genetic multisystem disorder that is discussed in greater detail in Chapter 507.

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PATHOGENESIS AND EPIDEMIOLOGY

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Cystic fibrosis transmembrane regulator (CFTR) is a chloride channel on epithelial cells. In the liver, it is expressed on biliary tract cells and is involved in chloride and water secretion into bile. There are no clear genotype associations with CF liver disease, although it is less common in patients with pancreatic sufficiency. The factors that initiate, accentuate, and perpetuate the development of liver disease in patients with CF have not been identified. A 3:1 male preponderance is seen in patients with CF-associated liver disease (CFLD).

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The CFTR defect in the liver results in the production of thick, tenacious secretions in the hepatobiliary system. Secretion of viscous bile results in impaired bile flow and consequent sludge and potential gallstone formation. Over time, these abnormalities in bile lead to persistent focal microscopic or macroscopic obstructions in the intrahepatic biliary tree causing chronic inflammation, bile duct proliferation, and fibrosis with extension and coalescence. The resulting lesion is called focal biliary cirrhosis.

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Advanced CFLD, defined as CFLD with portal hypertension, occurs early in life in patients with bi-allelic loss-of-function (pancreatic insufficient) mutations in CFTR. A large study of CFLD focused on 5 candidate genes that had previously been studied in CFLD, but not all patients in the previous studies had portal hypertension. There was a strong association of the Z-allele of the α1-antiprotease (SERPINA1) gene, the gene associated with α1-antitrypsin deficiency, with CFLD. The mechanism is unclear but probably does not reflect cumulative effects of the folding mutations in CFTR (ΔF508) and SERPINA1 (Z-allele), because these 2 are predominately expressed in 2 different cell types (cholangiocytes and hepatocytes, respectively) in the liver. The variability in time of presentation, severity of liver disease, and rate of progression may be due to as yet unknown polymorphisms for other genes.

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CFLD is increasingly recognized as mortality from lung disease decreases. In many cases, the course is benign and does not contribute significantly to morbidity or mortality. However, in a minority of CF patients, liver disease may directly affect survival. The prevalence varies by study and detection method. According to several reports, symptomatic liver disease is observed in 20% to 50% of patients; another study reports an incidence of 2.5 cases per 100 patient-years during the first 10 years of life. The incidence of CFLD appears to peak during adolescence, and it is rare for liver disease to have its onset after 20 years of age. Pathologic evidence of liver disease is found at autopsy in more than 75% of patients. CFLD may be the presenting or dominant feature of CF. Cirrhosis complicates CF in 5% to 10% of patients and accounts for virtually all nonpulmonary causes of death in patients with CF.

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