Liver Disease in Cystic Fibrosis

Incidence and Demographics

Cystic fibrosis is the most common life-threatening autosomal recessive disease affecting Caucasians, occurring in approximately 1 in 3500 newborns. Retrospective epidemiologic studies suggest that the frequency of CF is between 1 in 2000 and 1 in 4000 live births in most European-derived populations, with a higher frequency in certain groups such as French-Canadians in the Saguenay-Lac St. Jean region of Quebec. Only about 1 in 15,000 African-American infants are affected, and the disease is even rarer in Asians. The carrier frequency is estimated to be about 1 in 20 among Caucasians. Patients with CF appear to be at increased risk for cancers of the esophagogastric junction, the small bowel, colon and biliary tree, along with a higher risk of testicular cancer and leukemia. The risk of digestive tract cancer appears to be more pronounced in these patients after lung transplantation.

Genetics

The CFTR gene is located on chromosome 7, and since it was cloned in 1989, more than 1900 disease-associated mutations have been identified, only a small percentage of which are proven to cause CF, with most having unknown physiologic consequences. CFTR mutations have been grouped into six different classes. Class I mutations affect synthesis and result in total or partial absence of the protein, class II mutations result in defective maturation and class III mutations result in a nonfunctional protein; these three classes are associated with the classic severe clinical phenotype. The most common mutation, the ΔF508 mutation, accounting for about 70% of CF mutations worldwide, is a class II mutation resulting in defective processing of the protein with subsequent premature intracellular degradation and complete absence of the protein at the surface of epithelial cells. Classes IV to VI result in decreased quantity, decreased function or decreased stability of the CFTR protein, and are associated with milder forms of the disease. CFTR is part of a multiprotein assembly, linked by its carboxyl terminal to other cellular proteins, including membrane and signaling proteins. The absence of CFTR may also alter expression of these proteins, including proteins regulating glutathione, ATP permeability, and cell signaling and inflammatory response, in addition to its effect on ion transport. Altered expression or function of these proteins may act as modifiers of the CF phenotype. There is also increasing evidence that genes other than CFTR modify the frequency and the severity of the clinical phenotypes of CF. For example, polymorphisms in the MBL2 gene, an effector of innate immunity, and the TNFα and TGFβ1 genes are associated with more severe pulmonary disease and increased incidence of cirrhosis. Recently, the SERPINA1 Z allele was found to be significantly associated with severe liver disease, possibly linking CF liver disease to the widening spectrum of diseases related to mutations in the SERPIN ( ser ine p rotease in hibitor) family of genes, which includes alpha-1 antitrypsin deficiency.

Pathophysiology

The polypeptide product of the CF gene, named CFTR, is part of the ATP-binding cassette (ABC) family of transmembrane proteins, and contains 1480 amino acids, including two membrane-spanning domains, two nucleotide-binding domains, and a carboxyl terminal (TRL).

In eccrine glands, CFTR appears to be the major pathway for Cl ⁻ absorption. Diminished Cl ⁻ absorption in the face of continued sodium uptake leads to an elevated transmembrane potential with a more negatively charged lumen, and eventually decreased sodium reabsorption with increased salt retention within sweat. In the airway both sodium and chloride ions may be hyperabsorbed, leading to a depletion of the volume of airway surface liquid, resulting in distal airway obstruction by thick tenacious mucus. This thick mucus plasters the airway surface with mucopurulent debris, within which pathogens such as Staphylococcus aureus, Haemophilus influenza, Pseudomonas aeruginosa, and Burholderia cepacia become established, resulting in bronchiectasis and chronic lung infections. Impaction of pancreatic ducts leads to chronic inflammation, fibrosis, and fatty replacement of the exocrine pancreas, causing malabsorption and nutritional problems such as failure to thrive and complications because of deficiencies of fat-soluble vitamins. Nearly 10% of patients with CF are born with intestinal obstruction (meconium ileus). Men with CF are frequently infertile because of obstruction of the vas deferens in utero, resulting in involution of the Wolffian duct and vas deferens. An increased risk of digestive tract cancers, particularly of the small bowel, colon, and biliary tree, has been reported in adult CF patients, the risk being more pronounced in nontransplanted patients.

In the liver and biliary tree, CFTR is located on the apical membrane of cholangiocytes and gallbladder epithelium, where it functions as a c-AMP-activated Cl ⁻ channel. Binding of agonists such as secretin to basolateral receptors appears to result in increased intracellular c-AMP and activation of CFTR. Aberrant cytoplasmic localization of the CFTR product in patients with the Δ508 mutation has been demonstrated in biliary epithelium by immunohistochemistry. The conventional model proposes that an abnormal or absent CFTR in the cholangiocyte membrane would result in decreased Cl ⁻ and HCO ₃ ⁻ secretion, and diminished bile flow with bile “plugging”, followed by cholangiocyte and hepatocellular injury, concomitant stellate cell activation, and subsequent fibrosis. In a murine model, elevated fecal bile acid loss resulted in increased biliary secretion of more hydrophobic bile salts, increasing the bile salt-to-phospholipid ration, causing intrahepatic bile duct damage.