Cholangiocyte Biology and Cystic Fibrosis Liver Disease

Abstract

Cystic fibrosis (CF) is one of the most common inherited diseases in the white population. The disease results from mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). How this gene defect leads to the clinical manifestations of the disease, however, is not entirely clear. CFTR functions as a Cl(-) channel in the apical membrane of most secretory epithelia, including biliary epithelial cells, or cholangiocytes. In cholangiocytes, CFTR appears to be an important determinant of biliary secretion and bile flow. Additionally, recent evidence suggests that CFTR regulates other membrane transporters, channels, and proteins. Improving life expectancy has led to an increasing recognition of hepatobiliary complications from CF. The true prevalence of CF liver disease is unknown, but may affect up to 17-25% of CF patients. Clinical manifestations include hepatic steatosis, neonatal cholestasis, focal nodular cirrhosis, multilobular cirrhosis, and biliary tract complications. Why only a subset of CF patients develops severe liver disease and others with the same genotype do not is one of the many scientific curiosities of this disease. This review focuses on the function of CFTR in cholangiocytes with emphasis on ductular bile formation as well as the clinical consequences of abnormal CFTR, namely CF-associated liver disease. Data on the pathogenesis, prevalence, clinical course, and treatment of CF liver disease will be reviewed.

Identification and Functional Characterization of TMEM16A, a Ca2+-activated Cl− Channel Activated by Extracellular Nucleotides, in Biliary Epithelium

“…Furthermore, many of the effects of cAMP on bile formation appear to be mediated by ATP release into the duct lumen and subsequent activation of apical P2 receptors (9,10). These general findings are consistent with the clinical observation that only 10 -20% of patients with cystic fibrosis (CF) develop clinically significant liver disease despite absent or abnormal CFTR in biliary epithelium (11,12). Furthermore, in cells with the CF phenotype, activation of P2 receptors still elicits potent secretory responses (13,14).…”

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

“…Elevated levels in liver function tests (LFTs: alanine transaminase, aspartate transaminase, γ-glutamyltransferase, and bilirubin) are commonly observed in the majority of newborn CF infants (41,42,57) and newborn CF ferrets (40). Neonatal elevations in LFTs observed in CF infants are generally thought to reflect cholestasis due to thickening of bile (42,57,58). However, when liver biopsies were evaluated in CF neonates, there was no direct correlation between LFTs and histologic cholestasis (41).…”

“…Fatty liver disease is not uncommon in human CF (41,58), and liver dysfunction (including fatty liver) is often associated with insulin resistance and abnormal glucose metabolism in humans and mice (49,59). Fatty liver (or steatosis) is characterized by excessive triglyceride deposition.…”

Diagnostik cholestatischer Erkrankungen

“…In kurzer Zeit konnten mittlerweile bereits hunderte Polymorphismen in den Transportergenen BSEP und MRP2 der gesunden Bevöl-kerung identifiziert werden, deren pathogenetische Bedeutung bislang unklar ist [70,71]. Auch auf der Ebene der Gallengangszellen ist es in den letzten Jahren durch Entdeckung von Mutationen im CFTR-Gen bei zystischer Fibrose (am häufigsten (⌬F508 mit Trafficking-Defekt) und im JAG1-Gen bei Alagille-Syndrom zu Fortschritten im Verständnis der molekularen Pathogenese der Cholestase gekommen [72,73]. Die molekulargenetische Diagnostik könnte in Zukunft zur routinemäßi-gen Identifikation hereditärer Cholestasesyndrome beitragen.…”