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    • metabolic enzymes CF patients can suffer from a multitude of

    2021-10-16

    CF patients can suffer from a multitude of hepatobiliary problems including gall stones, hepatitis, steatosis and cirrhosis. Hepatobiliary problems are common in pediatric CF patients with reported prevalence rates up to 25% [12,13]. Cystic fibrosis related liver disease (CFLD) was thought to develop mainly in early childhood. However, a recent follow-up study of a cohort of CF patients into adulthood incorporated novel markers into the CFLD diagnostic algorithm and suggests an additional wave of adult-onset CFLD with a median age of 37 years [14]. Another recent study that assessed a large retrospective cohort of French CF patients found that CFLD incidence increased by approximately 1% every year reaching 32.2% by the age of 25 [13]. In the liver, CFTR is exclusively expressed at the apical membrane of cholangiocytes lining the bile ducts [15]. CFLD is characterized by focal biliary cirrhosis which can lead to multilobular cirrhosis and portal metabolic enzymes in 1–10% of patients [16]. The pathophysiology of biliary cirrhosis has been hypothesized to be secondary to occlusion of small bile ducts and/or to increased bile toxicity. In CF mouse models, however, evidence to support the hypothesis that increased bile toxicity contributes to CFLD has not been reported [17]. Luminal GI complications are highly prevalent in CF. Approximately 15–20% of CF infants present with meconium ileus, an obstruction of the distal small intestine by dehydrated mucofeculent material [18]. After the neonatal phase, acute fecal obstruction of the ileocecum known as DIOS can occur and incidence increases with age [19,20]. Nearly half of pediatric CF patients suffer from constipation and this is even more prevalent in adulthood [21]. Another common luminal GI feature of CF is a change in intestinal microbiota characterized by small intestinal bacterial overgrowth (SIBO) and colonic dysbiosis [22]. Important contributing factors include delayed intestinal transit time, luminal hyperacidity due to decreased bicarbonate secretion by pancreas and intestinal epithelium, frequent antibiotic use and inspissated mucus. Intestinal microbial composition is important for immune function and various metabolic processes in the body [23]. Its disruption in CF is therefore likely to contribute to various aspects of the phenotype [24]. Along with the increased life expectancy the CF population has been shown to become exposed to an increased risk of malignant tumors especially of the small intestine and colon [22,25,26], possibly due to an increased proliferation rate of epithelial cells and disruption of anti-apoptotic pathways [27]. Additionally, a recent study has shown a direct role of CFTR as a tumor suppressor gene in intestinal cancer [28]. After lung transplantation the risk for malignancies in CF patients is even further increased due to the use of immunosuppressant drugs [25,29].
    Impaired bile acid homeostasis and farnesoid X receptor signaling in cystic fibrosis One of the hallmarks of the GI complications in CF patients as well as in murine CF models is an up to 3-fold increase in fecal bile acid (BA) excretion [2,[30], [31], [32]]. This increase is independent of exocrine pancreatic insufficiency and fat malabsorption. In the physiological situation the enterohepatic circulation of BAs is a tightly regulated system in which ~95% of total BAs are reabsorbed and the remaining ~5% is excreted via the feces (Fig. 1). Reabsorption mainly takes place by active transport of conjugated BAs into the ileal enterocyte by the apical sodium-dependent bile acid transporter (ASBT, SLC10A2) [33]. In the ileal enterocyte BAs activate the farnesoid X receptor (FXR), a ligand-activated transcription factor of the family of nuclear receptors, which leads to increased expression and subsequent release of fibroblast growth factor 19 (FGF19, Fgf15 in mice) in the circulation [34]. In the liver FGF19 can bind to and activate the FGF receptor 4 (FGFR4)/β-Klotho complex which in turn exerts negative feedback on the rate controlling enzyme of BA synthesis, cholesterol 7α-hydroxylase (CYP7A1). Reabsorbed BAs can also cause negative feedback by directly activating hepatic FXR. However, organ specific Fxr knockout studies in mice indicated a much more prominent role for the FXR-FGF15/19 axis in CYP7A1 repression [35].