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• W3206426385 abstract "Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. Cystic fibrosis-related liver disease (CFLD) is defined as the pathogenesis related to the underlying CFTR defect in biliary epithelial cells. CFLD needs to be distinguished from other liver manifestations that may not have any pathological significance. The clinical/histological presentation and severity of CFLD vary. The main histological presentation of CFLD is focal biliary fibrosis, which is usually asymptomatic. Portal hypertension develops in a minority of cases (about 10%) and may require specific management including liver transplantation for end-stage liver disease. Portal hypertension is usually the result of the progression of focal biliary fibrosis to multilobular cirrhosis during childhood. Nevertheless, non-cirrhotic portal hypertension as a result of porto-sinusoidal vascular disease is now identified increasingly more frequently, mainly in young adults. To evaluate the effect of new CFTR modulator therapies on the liver, the spectrum of hepatobiliary involvement must first be precisely classified. This paper discusses the phenotypic features of CFLD, its underlying physiopathology and relevant diagnostic and follow-up approaches, with a special focus on imaging. Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. Cystic fibrosis-related liver disease (CFLD) is defined as the pathogenesis related to the underlying CFTR defect in biliary epithelial cells. CFLD needs to be distinguished from other liver manifestations that may not have any pathological significance. The clinical/histological presentation and severity of CFLD vary. The main histological presentation of CFLD is focal biliary fibrosis, which is usually asymptomatic. Portal hypertension develops in a minority of cases (about 10%) and may require specific management including liver transplantation for end-stage liver disease. Portal hypertension is usually the result of the progression of focal biliary fibrosis to multilobular cirrhosis during childhood. Nevertheless, non-cirrhotic portal hypertension as a result of porto-sinusoidal vascular disease is now identified increasingly more frequently, mainly in young adults. To evaluate the effect of new CFTR modulator therapies on the liver, the spectrum of hepatobiliary involvement must first be precisely classified. This paper discusses the phenotypic features of CFLD, its underlying physiopathology and relevant diagnostic and follow-up approaches, with a special focus on imaging. Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. It is caused by pathogenic variants in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel expressed in epithelial cells. Liver involvement, which is reported in up to approximately 40% of patients with CF,[1]Boëlle P.-Y. Debray D. Guillot L. Clement A. Corvol H. Cystic fibrosis liver disease: outcomes and risk factors in a large cohort of French patients.Hepatology. 2019; 69: 1648-1656https://doi.org/10.1002/hep.30148Google Scholar includes all hepatic manifestations including clinical or biochemical liver abnormalities. These may be related to epiphenomena such as infectious episodes or drug hepatotoxicity, steatosis from diverse origins (diabetes, chronic diarrhoea, pancreatic insufficiency, malnutrition, obesity...) or hepatic congestion of cardio-pulmonary origin.[2]Lamireau T. Monnereau S. Martin S. Marcotte J.-E. Winnock M. Alvarez F. Epidemiology of liver disease in cystic fibrosis: a longitudinal study.J Hepatol. 2004; 41: 920-925https://doi.org/10.1016/j.jhep.2004.08.006Google Scholar,[3]Hillaire S. Cazals-Hatem D. Bruno O. Miranda S de Grenet D. Poté N. et al.Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy.Liver Transplant. 2017; 23: 1342-1347https://doi.org/10.1002/lt.24842Google Scholar Thus, liver involvement in these patients is not always CF-related liver disease (CFLD) which only includes disease due to the underlying CFTR defect. Until the pathogenic mechanisms of CFLD are better understood, a phenotypic approach seems to be the most appropriate way to analyse and report outcomes in these cases. The lexicon should follow the North American and European Societies for Paediatric Gastroenterology Hepatology and Nutrition which recommend the following phenotypic characterisation: multilobular cirrhosis with or without portal hypertension or liver failure, liver involvement with or without portal hypertension but without cirrhosis, or no evidence of liver involvement.[4]Debray D. Narkewicz M.R. Bodewes F.A.J.A. Colombo C. Housset C. de Jonge H.R. et al.Cystic fibrosis-related liver disease: research challenges and future perspectives.J Pediatr Gastroenterol Nutr. 2017; 65: 443-448https://doi.org/10.1097/MPG.0000000000001676Google Scholar This review article discusses the spectrum of CFLD and provides their radiological-pathological correlations. The absence of a precise definition of CFLD and increasingly frequent reports of cases of non-cirrhotic portal hypertension explain the significant epidemiological variations in the scientific literature.[2]Lamireau T. Monnereau S. Martin S. Marcotte J.-E. Winnock M. Alvarez F. Epidemiology of liver disease in cystic fibrosis: a longitudinal study.J Hepatol. 2004; 41: 920-925https://doi.org/10.1016/j.jhep.2004.08.006Google Scholar,[5]Colombo C. Battezzati P.M. Crosignani A. Morabito A. Costantini D. Padoan R. et al.Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.Hepatology. 2002; 36: 1374-1382https://doi.org/10.1053/jhep.2002.37136Google Scholar European criteria to define CFLD were historically based on the presence of at least 2 of the 3 following variables: abnormal physical examination, abnormal liver tests and abnormal liver ultrasound suggesting fibrosis or cirrhosis (excluding steatosis).[6]Debray D. Kelly D. Houwen R. Strandvik B. Colombo C. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease.J Cyst Fibros. 2011; 10: S29-S36https://doi.org/10.1016/S1569-1993(11)60006-4Google Scholar These criteria were used to perform most epidemiological studies. The cumulative incidence of CFLD was found to reach a plateau around the age of 18 with an incidence of 1.8% in patients with CF.[5]Colombo C. Battezzati P.M. Crosignani A. Morabito A. Costantini D. Padoan R. et al.Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.Hepatology. 2002; 36: 1374-1382https://doi.org/10.1053/jhep.2002.37136Google Scholar As patient management has improved (including for pulmonary involvement) and with the recent increase in life expectancy of patients with CF, studies have begun reporting liver disease in adults.[1]Boëlle P.-Y. Debray D. Guillot L. Clement A. Corvol H. Cystic fibrosis liver disease: outcomes and risk factors in a large cohort of French patients.Hepatology. 2019; 69: 1648-1656https://doi.org/10.1002/hep.30148Google Scholar,[7]Toledano M.B. Mukherjee S.K. Howell J. Westaby D. Khan S.A. Bilton D. et al.The emerging burden of liver disease in cystic fibrosis patients: a UK nationwide study.PLoS One. 2019; 14e0212779https://doi.org/10.1371/journal.pone.0212779Google Scholar A large prospective cohort study including 3,328 patients with CF recently reported an incidence of CFLD that increased by approximately 1% every year, reaching 32% by age 25, and an incidence of severe CFLD (i.e. cirrhosis or portal hypertension) that increased after the age of 5, reaching 10% by age 30.[1]Boëlle P.-Y. Debray D. Guillot L. Clement A. Corvol H. Cystic fibrosis liver disease: outcomes and risk factors in a large cohort of French patients.Hepatology. 2019; 69: 1648-1656https://doi.org/10.1002/hep.30148Google Scholar Portal hypertension, either as a direct complication of biliary cirrhosis and/or due to porto-sinusoidal vascular disease, plays a central role in CFLD because it is the main cause of morbidity (undernutrition, ascites, infection and variceal bleeding) and one of the leading causes of death after lung failure and lung transplantation[2]Lamireau T. Monnereau S. Martin S. Marcotte J.-E. Winnock M. Alvarez F. Epidemiology of liver disease in cystic fibrosis: a longitudinal study.J Hepatol. 2004; 41: 920-925https://doi.org/10.1016/j.jhep.2004.08.006Google Scholar,[5]Colombo C. Battezzati P.M. Crosignani A. Morabito A. Costantini D. Padoan R. et al.Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.Hepatology. 2002; 36: 1374-1382https://doi.org/10.1053/jhep.2002.37136Google Scholar,[8]Chryssostalis A. Hubert D. Coste J. Kanaan R. Burgel P.-R. Desmazes-Dufeu N. et al.Liver disease in adult patients with cystic fibrosis: a frequent and independent prognostic factor associated with death or lung transplantation.J Hepatol. 2011; 55: 1377-1382https://doi.org/10.1016/j.jhep.2011.03.028Google Scholar in these patients. In a large series of 905 patients with CF and cirrhosis,[9]Ye W. Narkewicz M.R. Leung D.H. Karnsakul W. Murray K.F. Alonso E.M. et al.Variceal hemorrhage and adverse liver outcomes in patients with cystic fibrosis cirrhosis.J Pediatr Gastroenterol Nutr. 2018; 66: 122-127https://doi.org/10.1097/MPG.0000000000001728Google Scholar the estimated 10-year cumulative rate of all liver-related adverse events (variceal haemorrhage, liver transplantation and death due to liver failure) was 20.4%. In another cohort including 561 patients with cirrhosis, CFLD-related complications appeared to be limited to patients with portal hypertension.[10]Stonebraker J.R. Ooi C.Y. Pace R.G. Corvol H. Knowles M.R. Durie P.R. et al.Features of severe liver disease with portal hypertension in patients with cystic fibrosis.Clin Gastroenterol Hepatol. 2016; 14: 1207-1215.e3https://doi.org/10.1016/j.cgh.2016.03.041Abstract Full Text Full Text PDF Scopus (61) Google Scholar A study from the European Liver Transplant Registry reported that before liver transplantation, 89% of patients with CF presented with oesophageal varices with at least 1 episode of gastrointestinal bleeding in 42% of cases, ascites in 44% and encephalopathy in 13%.[11]Melzi M.L. Kelly D.A. Colombo C. Jara P. Manzanares J. Colledan M. et al.Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry.Transpl Int. 2006; 19: 726-731https://doi.org/10.1111/j.1432-2277.2006.00344.xGoogle Scholar Although the progression of liver disease to liver failure is unpredictable, it rarely occurs during childhood.[12]Debray D. Lykavieris P. Gauthier F. Dousset B. Sardet A. Munck A. et al.Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension.J Hepatol. 1999; 31: 77-83Google ScholarKey pointCystic fibrosis-related liver disease, related to the underlying CFTR defect, includes two main, sometimes co-existing, manifestations: focal biliary fibrosis and porto-sinusoidal vascular disease. Cystic fibrosis-related liver disease, related to the underlying CFTR defect, includes two main, sometimes co-existing, manifestations: focal biliary fibrosis and porto-sinusoidal vascular disease. The pathogenesis of CFLD remains poorly understood. In the liver, CFTR chloride channel expression is restricted to the apical membrane of cholangiocytes lining the biliary ducts.[13]Cohn J.A. Strong T.V. Picciotto M.R. Nairn A.C. Collins F.S. Fitz J.G. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells.Gastroenterology. 1993; 105: 1857-1864https://doi.org/10.1016/0016-5085(93)91085-vGoogle Scholar CFTR is essential to maintain pH regulation and biliary HCO3− secretion. A proper alkaline balance, described by Beuers et al. as the 'bicarbonate umbrella', protects cholangiocytes against hydrophobic bile acids.[14]Beuers U. Hohenester S. de Buy Wenniger L.J.M. Kremer A.E. Jansen P.L.M. Elferink R.P.J.O. The biliary HCO(3)(-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.Hepatology. 2010; 52: 1489-1496https://doi.org/10.1002/hep.23810Google Scholar The primary hypothesis for the development of biliary fibrosis is based on a decreased or absent CFTR function in the bile duct, causing decreased transport of chloride, bicarbonate, and osmotically coupled water into the bile, leading to increased viscosity, reduced bile flow, and biliary obstruction with bile and mucoid secretions. This would cause retention of endogenous hydrophobic bile acids, cell membrane injury, peribiliary inflammation, and focal biliary fibrosis.[15]Feranchak A.P. Sokol R.J. Cholangiocyte biology and cystic fibrosis liver disease.Semin Liver Dis. 2001; 21: 471-488https://doi.org/10.1055/s-2001-19030Google Scholar However, this mechanism is not fully supported by relatively rare findings of inspissated bile secretions[16]Potter C.J. Fishbein M. Hammond S. McCoy K. Qualman S. Can the histologic changes of cystic fibrosis-associated hepatobiliary disease be predicted by clinical criteria?.J Pediatr Gastroenterol Nutr. 1997; 25: 32-36Google Scholar and is probably not the only cause. In addition, in Cftr knockout mouse models, a causal relationship has been identified between intestinal inflammation, which is a frequent finding in patients with CF, and biliary damage.[17]Debray D. Mourabit H.E. Merabtene F. Brot L. Ulveling D. Chrétien Y. et al.Diet-induced dysbiosis and genetic background synergize with cystic fibrosis transmembrane conductance regulator deficiency to promote cholangiopathy in mice.Hepatol Commun. 2018; 2: 1533-1549https://doi.org/10.1002/hep4.1266Google Scholar The innate immunity/gut dysbiosis axis could help further explain the pathogenesis of CFLD. Indeed, CFTR has been shown to play a role in regulating biliary innate immunity.[18]Fiorotto R. Strazzabosco M. Pathophysiology of cystic fibrosis liver disease: a channelopathy leading to alterations in innate immunity and in microbiota.Cell Mol Gastroenterol Hepatol. 2019; 8: 197-207https://doi.org/10.1016/j.jcmgh.2019.04.013Google Scholar More precisely, functional CFTR keeps inactivated Src tyrosine kinases at the apical membrane of cholangiocytes.[19]Fiorotto R. Villani A. Kourtidis A. Scirpo R. Amenduni M. Geibel P.J. et al.The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity.Hepatology. 2016; 64: 2118-2134https://doi.org/10.1002/hep.28817Google Scholar Thus, in the presence of a defective CFTR, Src tyrosine kinases can self-activate and lead to an inflammatory process via the phosphorylation of toll-like receptor 4 (TLR4), activation of NF-κB and the production of pro-inflammatory cytokines.[20]Fiorotto R. Scirpo R. Trauner M. Fabris L. Hoque R. Spirli C. et al.Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice.Gastroenterology. 2011; 141 (1508.e1-5): 1498-1508https://doi.org/10.1053/j.gastro.2011.06.052Google Scholar Gut dysbiosis, which is frequently reported in patients with CF, could trigger this dysregulated innate immunity.[21]Flass T. Tong S. Frank D.N. Wagner B.D. Robertson C.E. Kotter C.V. et al.Intestinal lesions are associated with altered intestinal microbiome and are more frequent in children and young adults with cystic fibrosis and cirrhosis.PLoS One. 2015; 10e0116967https://doi.org/10.1371/journal.pone.0116967Google Scholar,[22]Albillos A. de Gottardi A. Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy.J Hepatol. 2020; 72: 558-577https://doi.org/10.1016/j.jhep.2019.10.003Google Scholar Several explanations have been proposed for gut dysbiosis: prolonged intestinal transit, which is thought to favour bacterial overgrowth in the small intestine,[21]Flass T. Tong S. Frank D.N. Wagner B.D. Robertson C.E. Kotter C.V. et al.Intestinal lesions are associated with altered intestinal microbiome and are more frequent in children and young adults with cystic fibrosis and cirrhosis.PLoS One. 2015; 10e0116967https://doi.org/10.1371/journal.pone.0116967Google Scholar,[23]Lisowska A. Wójtowicz J. Walkowiak J. Small intestine bacterial overgrowth is frequent in cystic fibrosis: combined hydrogen and methane measurements are required for its detection.Acta Biochim Pol. 2009; 56: 631-634Google Scholar frequent exposure to antibiotics, pancreatic enzymes and/or proton pump inhibitors.[24]Li L. Somerset S. The clinical significance of the gut microbiota in cystic fibrosis and the potential for dietary therapies.Clin Nutr. 2014; 33: 571-580https://doi.org/10.1016/j.clnu.2014.04.004Google Scholar Altered microbiota are thought to be responsible for intestinal inflammation, damaging the tight and adherens junctions of epithelial intestinal cells and increasing intestinal permeability.25Bruzzese E. Raia V. Gaudiello G. Polito G. Buccigrossi V. Formicola V. et al.Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration.Aliment Pharmacol Ther. 2004; 20: 813-819https://doi.org/10.1111/j.1365-2036.2004.02174.xGoogle Scholar, 26Werlin S.L. Benuri-Silbiger I. Kerem E. Adler S.N. Goldin E. Zimmerman J. et al.Evidence of intestinal inflammation in patients with cystic fibrosis.J Pediatr Gastroenterol Nutr. 2010; 51: 304-308https://doi.org/10.1097/MPG.0b013e3181d1b013Google Scholar, 27De Lisle R.C. Disrupted tight junctions in the small intestine of cystic fibrosis mice.Cell Tissue Res. 2014; 355: 131-142https://doi.org/10.1007/s00441-013-1734-3Google Scholar Thus, the increased intestinal permeability associated with the more pathogenic strains of bacteria, which are also the result of altered microbiota,[21]Flass T. Tong S. Frank D.N. Wagner B.D. Robertson C.E. Kotter C.V. et al.Intestinal lesions are associated with altered intestinal microbiome and are more frequent in children and young adults with cystic fibrosis and cirrhosis.PLoS One. 2015; 10e0116967https://doi.org/10.1371/journal.pone.0116967Google Scholar,[28]Scanlan P.D. Buckling A. Kong W. Wild Y. Lynch S.V. Harrison F. Gut dysbiosis in cystic fibrosis.J Cystic Fibrosis. 2012; 11: 454-455https://doi.org/10.1016/j.jcf.2012.03.007Google Scholar could lead to the translocation of bacteria and bacterial products, including pathogen-associated molecular patterns (PAMPs).[26]Werlin S.L. Benuri-Silbiger I. Kerem E. Adler S.N. Goldin E. Zimmerman J. et al.Evidence of intestinal inflammation in patients with cystic fibrosis.J Pediatr Gastroenterol Nutr. 2010; 51: 304-308https://doi.org/10.1097/MPG.0b013e3181d1b013Google Scholar,[29]Hallberg K. Grzegorczyk A. Larson G. Strandvik B. Intestinal permeability in cystic fibrosis in relation to genotype.J Pediatr Gastroenterol Nutr. 1997; 25: 290-295Google Scholar Furthermore, altered microbiota also leads to disturbed bile acid homeostasis by disrupting the farnesoid X receptor (FXR) - fibroblast growth factor 19 (FGF19) activation pathway. Indeed, FXR is expressed in enterocytes and activates FGF19 synthesis, which circulates to the liver to act as a negative feedback regulator of cholesterol 7a-hydroxylase (Cyp7a1), the first enzyme of the bile acid synthesis pathway.[30]Kliewer S.A. Mangelsdorf D.J. Bile acids as hormones: the FXR-FGF15/19 pathway.DDI. 2015; 33: 327-331https://doi.org/10.1159/000371670Google Scholar Impaired bile acid homeostasis and the translocation of bacterial endotoxins and PAMPs into the portal-venous system and to the liver may trigger uncontrolled biliary inflammation by activating the dysregulated Src/NF-κB signalling pathway in CFTR-defective cholangiocytes. In addition, CFTR-deficient mice models have demonstrated a defect in peroxisome proliferator-activated receptor γ (PPARγ) function, whose stimulation could downregulate NF-κB-mediated inflammation.[31]Scirpo R. Fiorotto R. Villani A. Amenduni M. Spirli C. Strazzabosco M. Stimulation of nuclear receptor peroxisome proliferator–activated receptor-γ limits NF-κB-dependent inflammation in mouse cystic fibrosis biliary epithelium.Hepatology. 2015; 62: 1551-1562https://doi.org/10.1002/hep.28000Google Scholar,[32]Harmon G.S. Dumlao D.S. Ng D.T. Barrett K.E. Dennis E.A. Dong H. et al.Pharmacological correction of a defect in PPAR-γ signaling ameliorates disease severity in Cftr-deficient mice.Nat Med. 2010; 16: 313-318https://doi.org/10.1038/nm.2101Google Scholar On the other hand, the pathogenesis of porto-sinusoidal vascular disease has not been clarified. The anatomical proximity of the portal system to the bile ducts and the pro-inflammatory state resulting from CFTR-defective cholangiocytes have not been explored. One hypothesis is that the intrahepatic portal system is involved secondary to the pro-inflammatory state in the bile ducts. Two factors could explain the proposed pathogenesis: micro-thrombotic phenomena due to platelet activation and CFTR defect-related endothelial lesions. Indeed, CFTR is both expressed and functional in cell types other than cholangiocytes, including platelets, endothelial cells and smooth muscle cells.[33]Tousson A. Van Tine B.A. Naren A.P. Shaw G.M. Schwiebert L.M. Characterization of CFTR expression and chloride channel activity in human endothelia.Am J Physiol. 1998; 275: C1555-C1564https://doi.org/10.1152/ajpcell.1998.275.6.C1555Google Scholar,[34]Poore S. Berry B. Eidson D. McKie K.T. Harris R.A. Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis.Chest. 2013; 143: 939-945https://doi.org/10.1378/chest.12-1934Google Scholar Recent studies have suggested that the CFTR defect promotes platelet activation, resulting in increased platelet aggregation.[35]Lindberg U. Svensson L. Hellmark T. Segelmark M. Shannon O. Increased platelet activation occurs in cystic fibrosis patients and correlates to clinical status.Thromb Res. 2018; 162: 32-37https://doi.org/10.1016/j.thromres.2017.12.012Google Scholar Moreover, platelet function, which plays a key role in the downregulation of inflammation,[36]von Hundelshausen P. Weber C. Platelets as immune cells.Circ Res. 2007; 100: 27-40https://doi.org/10.1161/01.RES.0000252802.25497.b7Google Scholar also seems to be affected by the CFTR defect which might lead to a pro-inflammatory state.37Ortiz-Muñoz G. Yu M.A. Lefrançais E. Mallavia B. Valet C. Tian J.J. et al.Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.J Clin Invest. 2020; 130: 2041-2053https://doi.org/10.1172/JCI129635Google Scholar, 38O’Sullivan B.P. Michelson A.D. The inflammatory role of platelets in cystic fibrosis.Am J Respir Crit Care Med. 2006; 173: 483-490https://doi.org/10.1164/rccm.200508-1243PPGoogle Scholar, 39Mattoscio D. Evangelista V. Cristofaro R.D. Recchiuti A. Pandolfi A. Silvestre S.D. et al.Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response.FASEB J. 2010; 24: 3970-3980https://doi.org/10.1096/fj.10-159921Google Scholar The role of CFTR in endothelial dysfunction is not well understood.[40]Declercq M. Zeeuw P de Conchinha N.V. Geldhof V. Ramalho A.S. García-Caballero M. et al.Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype.Eur Respir J. 2021; 57https://doi.org/10.1183/13993003.00261-2020Google Scholar The CFTR defect leads to decreased nitric oxide,[34]Poore S. Berry B. Eidson D. McKie K.T. Harris R.A. Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis.Chest. 2013; 143: 939-945https://doi.org/10.1378/chest.12-1934Google Scholar decreased endothelium-dependent relaxation and increased arterial stiffness (increased vasoconstriction in response to vasoactive agents and impaired cAMP-dependent vasorelaxation due to the altered mechanical properties of smooth muscle cells).[41]Buehler T. Steinmann M. Singer F. Regamey N. Casaulta C. Schoeni M.H. et al.Increased arterial stiffness in children with cystic fibrosis.Eur Respir J. 2012; 39: 1536-1537https://doi.org/10.1183/09031936.00212511Google Scholar,[42]Robert R. Norez C. Becq F. Disruption of CFTR chloride channel alters mechanical properties and cAMP-dependent Cl− transport of mouse aortic smooth muscle cells.J Physiol. 2005; 568: 483-495https://doi.org/10.1113/jphysiol.2005.085019Google Scholar It could also lead to increased oxidative stress (reactive oxygen species),[43]Khalaf M. Scott-Ward T. Causer A. Saynor Z. Shepherd A. Górecki D. et al.Cystic fibrosis transmembrane conductance regulator (CFTR) in human lung microvascular endothelial cells controls oxidative stress, reactive oxygen-mediated cell signaling and inflammatory responses.Front Physiol. 2020; 11: 879https://doi.org/10.3389/fphys.2020.00879Google Scholar a pro-inflammatory state (vascular cell adhesion molecule-1, intercellular adhesion molecule-1, pro-inflammatory interleukins, transforming growth factor-β (TGFβ), CD40-L, …),[40]Declercq M. Zeeuw P de Conchinha N.V. Geldhof V. Ramalho A.S. García-Caballero M. et al.Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype.Eur Respir J. 2021; 57https://doi.org/10.1183/13993003.00261-2020Google Scholar,44Nowak J.K. Wojsyk-Banaszak I. Mądry E. Wykrętowicz A. Krzyżanowska P. Drzymała-Czyż S. et al.Increased soluble VCAM-1 and normal P-selectin in cystic fibrosis: a cross-sectional study.Lung. 2017; 195: 445-453https://doi.org/10.1007/s00408-017-0029-yGoogle Scholar, 45Sprague A.H. Khalil R.A. Inflammatory cytokines in vascular dysfunction and vascular disease.Biochem Pharmacol. 2009; 78: 539-552https://doi.org/10.1016/j.bcp.2009.04.029Google Scholar, 46Falco A. Romano M. Iapichino L. Collura M. Davì G. Increased soluble CD40 ligand levels in cystic fibrosis.J Thromb Haemost. 2004; 2: 557-560https://doi.org/10.1111/j.1538-7836.2004.00683.xGoogle Scholar increased membrane permeability (due to altered distribution of transmembrane protein vascular endothelial cadherin and p120-catenin leading to impaired intercellular adherens junctions)[47]Totani L. Plebani R. Piccoli A. Di Silvestre S. Lanuti P. Recchiuti A. et al.Mechanisms of endothelial cell dysfunction in cystic fibrosis.Biochim Biophys Acta (BBA) - Mol Basis Dis. 2017; 1863: 3243-3253https://doi.org/10.1016/j.bbadis.2017.08.011Google Scholar and a pro-coagulant state.[48]Romano M. Collura M. Iapichino L. Pardo F. Falco A. Chiesa P.L. et al.Endothelial perturbation in cystic fibrosis.Thromb Haemost. 2001; 86: 1363-1367https://doi.org/10.1055/s-0037-1616736Google Scholar,[49]Serisier D.J. Carroll M.P. Catheter-related thrombosis associated with elevated factor VIII levels in cystic fibrosis.J Cystic Fibrosis. 2006; 5: 201-204https://doi.org/10.1016/j.jcf.2006.02.003Google Scholar Once again, bacterial endotoxins in the gut could play a role in the pathogenesis of endothelial lesions. However, it is not clear why CFLD only develops in a minority of patients (about one third), with varying degrees of severity. The progression from focal biliary fibrosis to multilobular cirrhosis is a slow and unpredictable process.[2]Lamireau T. Monnereau S. Martin S. Marcotte J.-E. Winnock M. Alvarez F. Epidemiology of liver disease in cystic fibrosis: a longitudinal study.J Hepatol. 2004; 41: 920-925https://doi.org/10.1016/j.jhep.2004.08.006Google Scholar,[5]Colombo C. Battezzati P.M. Crosignani A. Morabito A. Costantini D. Padoan R. et al.Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.Hepatology. 2002; 36: 1374-1382https://doi.org/10.1053/jhep.2002.37136Google Scholar,[50]van de Peppel I.P. Bertolini A. Jonker J.W. Bodewes F.A.J.A. Verkade H.J. Diagnosis, follow-up and treatment of cystic fibrosis-related liver disease.Curr Opin Pulm Med. 2017; 23: 562-569https://doi.org/10.1097/MCP.0000000000000428Google Scholar,[51]Calvopina D.A. Noble C. Weis A. Hartel G.F. Ramm L.E. Balouch F. et al.Supersonic shear-wave elastography and APRI for the detection and staging of liver disease in pediatric cystic fibrosis.J Cyst Fibros. 2019; https://doi.org/10.1016/j.jcf.2019.06.017Google Scholar The severity of histological lesions does not appear to be correlated to age or progression over time.[16]Potter C.J. Fishbein M. Hammond S. McCoy K. Qualman S. Can the histologic changes of cystic fibrosis-associated hepatobiliary disease be predicted by clinical criteria?.J Pediatr Gastroenterol Nutr. 1997; 25: 32-36Google Scholar,[52]Lindblad A. Glaumann H. Strandvik B. Natural history of liver disease in cystic fibrosis.Hepatology. 1999; 30: 1151-1158https://doi.org/10.1002/hep.510300527Google Scholar While the presence of CFLD appears to be limited to severe genotypes (class I, II or III mutations in both alleles, resulting in a lack of synthesis or total loss of CFTR function[1]Boëlle P.-Y. Debray D. Guillot L. Clement A. Corvol H. Cystic fibrosis liver disease: outcomes and risk factors in a large cohort of French patients.Hepatology. 2019; 69: 1648-1656https://doi.org/10.1002/hep.30148Google Scholar,[5]Colombo C. Battezzati P.M. Crosignani A. Morabito A. Costantini D. Padoan R. et al.Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.Hepatology. 2002; 36: 1374-1382https://doi.org/10.1053/jhep.2002.37136Google Scholar,53Rowe S.M. Miller S. Sorscher E.J. Cystic fibrosis.N Engl J Med. 2005; 352: 1992-2001https://doi.org/10.1056/NEJMra043184Google Scholar, 54Zeitlin P.L. Pharmacologic restoration of αδF508 CFTR-mediated chloride current.Kidney Int. 2000; 57: 832-837https://doi.org/10.1046/j.1523-1755.2000.00922.xGoogle Scholar, 55Slieker M.G. Deckers-Kocken J.M. U" @default.
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