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Liver Disease in Cystic Fibrosis

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Diseases of the Liver and Biliary Tree

Abstract

Cystic fibrosis (CF) is a severe autosomal recessive genetic disorder caused by mutations of the CF Transmembrane Conductance Regulator (CFTR) gene, which encodes for the CFTR protein, a chloride channel located at the apical membrane of epithelial cells. CF is a multiorgan disease affecting mostly the lungs, the pancreas, liver, intestine and sweat glands. With advances in medical care, a remarkable increase in survival has occurred, from 16 years in 1970 to 47.7 years in 2016. Further improvements are predicted in the near future due to the recent availability of an increasing number of innovative drugs targeting the CF basic defect (CFTR modulators) [1].

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References

  1. Bell SC, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2020;8(1):65–124.

    Article  CAS  PubMed  Google Scholar 

  2. Collawn JF, Matalon S. CFTR and lung homeostasis. Am J Phys Lung Cell Mol Phys. 2014;307(12):L917–23.

    CAS  Google Scholar 

  3. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation patient registry. Annual data report 2018. Bethesda, MD: Cystic Fibrosis Foundation; 2018.

    Google Scholar 

  4. Cohn JA, Strong T, Picciotto MR, et al. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology. 1993;105(6):1857–64.

    Article  CAS  PubMed  Google Scholar 

  5. Martínez-Ansó E, Castillo JE, Díez J, Medina JF, Prieto J. Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver. Hepatology. 1994;19(6):1400–6.

    Article  PubMed  Google Scholar 

  6. Flass T, Narkewicz MR. Cirrhosis and other liver disease in cystic fibrosis. J Cyst Fibros. 2013;12(2):116–24.

    Article  PubMed  Google Scholar 

  7. Lazaridis KN, Strazzabosco M, Larusso N. The cholangiopathies: disorders of biliary epithelia. Gastroenterology. 2004;127:1565–77.

    Article  CAS  PubMed  Google Scholar 

  8. Staufer K, Halilbasic E, Trauner M, Kazemi-Shirazi L. Cystic fibrosis related liver disease--another black box in hepatology. Int J Mol Sci. 2014;15(8):13529–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rogers GB, Narkewicz MR, Hoffman LR. The CF gastrointestinal microbiome: structure and clinical impact. Pediatr Pulmonol. 2016;51(S44):S35–44.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hallberg K, Grzegorczyk A, Larson G, Strandvik B. Intestinal permeability in cystic fibrosis in relation to genotype. J Pediatr Gastroenterol Nutr. 1997;25(3):290–5.

    Article  CAS  PubMed  Google Scholar 

  11. Demeyer S, De Boeck K, Witters P, Cosaert K. Beyond pancreatic insufficiency and liver disease in cystic fibrosis. Eur J Pediatr. 2016;175(7):881–94.

    Article  CAS  PubMed  Google Scholar 

  12. Werlin SL, Benuri-Silbiger I, Kerem E, et al. Evidence of intestinal inflammation in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;51(3):304–8.

    CAS  PubMed  Google Scholar 

  13. Manor O, Levy R, Pope C, et al. Metagenomic evidence for taxonomic dysbiosis and functional imbalance in the gastrointestinal tracts of children with cystic fibrosis. Sci Rep. 2016;6:22493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schippa S, Iebba V, Santangelo F, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients. PLoS One. 2013;8:e61176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Flass T, Tong S, Frank DN, 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;10:e0116967.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Hillaire S, Cazals-Hatem D, Bruno O, de Miranda S, Grenet D, Poté N, Soubrane O, Erlinger S, Lacaille F, Mellot F, Vilgrain V, Paradis V. Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy. Liver Transpl. 2017;23(10):1342–7.

    Article  PubMed  Google Scholar 

  17. Witters P, Libbrecht L, Roskams T, et al. Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension. J Cyst Fibros. 2017;16:e11–3.

    Article  PubMed  Google Scholar 

  18. Koh C, Sakiani S, Surana P, Zhao X, Eccleston J, Kleiner DE, et al. Adult-onset cystic fibrosis liver disease: diagnosis and characterization of an underappreciated entity. Hepatology. 2017;66(2):591–601.

    Article  CAS  PubMed  Google Scholar 

  19. Boëlle PY, Debray D, Guillot L, Clement A, Corvol H, French CF, Modifier Gene Study Investigators. Cystic fibrosis liver disease: outcomes and risk factors in a large cohort of french patients. Hepatology. 2019;69(4):1648–56.

    Article  PubMed  CAS  Google Scholar 

  20. Colombo C, Battezzati PM, Crosignani A, et al. Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome. Hepatology. 2002;36(6):1374–82.

    Article  PubMed  Google Scholar 

  21. Lindblad A, Glaumann H, Strandvik B. Natural history of liver disease in cystic fibrosis. Hepatology. 1999;30(5):1151–8.

    Article  CAS  PubMed  Google Scholar 

  22. Lamireau T, Monnereau S, Martin S, et al. Epidemiology of liver disease in cystic fibrosis: a longitudinal study. J Hepatol. 2004;41(6):920–5.

    Article  PubMed  Google Scholar 

  23. Wilschanski M, Rivlin J, Cohen S, et al. Clinical and genetic risk factors for cystic fibrosis-related liver disease. Pediatrics. 1999;103(1):52–7.

    Article  CAS  PubMed  Google Scholar 

  24. Chryssostalis A, Hubert D, Coste J, Kanaan R, Burgel PR, Desmazes-Dufeu N, Soubrane O, Dusser D, Sogni P. Liver disease in adult patients with cystic fibrosis: a frequent and independent prognostic factor associated with death or lung transplantation. J Hepatol. 2011;55(6):1377–82.

    Article  PubMed  Google Scholar 

  25. Norsa L, Nicastro E, Di Giorgio A, Lacaille F, D’Antiga L. Prevention and treatment of intestinal failure-associated liver disease in children. Nutrients. 2018;10(6):664.

    Article  PubMed Central  CAS  Google Scholar 

  26. Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B, Castaldo G, Castellani C, Cipolli M, Colombo C, et al. Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA. 2009;302(10):1076–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nash KL, Allison ME, McKeon D, Lomas DJ, Haworth CS, Bilton D, Alexander GJ. A single centre experience of liver disease in adults with cystic fibrosis 1995-2006. J Cyst Fibros. 2008;7(3):252–7.

    Article  CAS  PubMed  Google Scholar 

  28. Desmond CP, Wilson J, Bailey M, Clark D, Roberts SK. The benign course of liver disease in adults with cystic fibrosis and the effect of ursodeoxycholic acid. Liver Int. 2007;27(10):1402–8.

    CAS  PubMed  Google Scholar 

  29. Melzi ML, Kelly DA, Colombo C, et al. Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry. Transpl Int. 2006;19(9):726–31.

    Article  PubMed  Google Scholar 

  30. Cipolli M, Fethney J, Waters D, Zanolla L, Meneghelli I, Shoma D, Assael Baroukh M, Gaskin KJ. Occurrence, outcomes and predictors of portal hypertension in cystic fibrosis: a longitudinal prospective birth cohort study. J Cyst Fibros. 2020;19(3):455–9.

    Article  PubMed  Google Scholar 

  31. Ye W, Narkewicz MR, Leung DH, Karnsakul W, Murray KF, Alonso EM, Magee JC, Schwarzenberg SJ, Weymann A, Molleston JP, CFLD Net Research Group. Variceal hemorrage and adverse liver outcomes in patients with Cystic Fibrosis cirrhosis. J Pediatr Gastroenterol Nutr. 2018;66:122–7.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Breuer O, Shteyer E, Wilschanski M, Perles Z, Cohen-Cymberknoh M, Kerem E, Shoseyov D. Hepatopulmonary syndrome in patients with Cystic Fibrosis and liver disease. Chest. 2016;149(2):e35–8.

    Article  PubMed  Google Scholar 

  33. 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(Suppl 2):S29–36.

    Article  PubMed  Google Scholar 

  34. Bianchi M, Romano G, Saraifoger S, Costantini D, Limonta C, Colombo C. BMD and body composition in children and young patients affected by cystic fibrosis. J Bone Miner Res. 2006;21(3):388–96.

    Article  PubMed  Google Scholar 

  35. Minicucci L, Lorini R, Giannattasio A, Colombo C, Iapichino L, Reali MF, Padoan R, Calevo MG, De Alessandri A, Haupt R. Liver disease as risk factor for cystic fibrosis-related diabetes development. Acta Paediatr. 2007;96(5):736–9.

    Article  CAS  PubMed  Google Scholar 

  36. Pals FH, Verkade HJ, Gulmans VAM, et al. Cirrhosis associated with decreased survival and a 10-year lower median age at death of cystic fibrosis patients in the Netherlands. J Cyst Fibros. 2019;18(3):385–9.

    Article  CAS  PubMed  Google Scholar 

  37. Bodewes FA, van der Doef HP, Houwen RH, Verkade HJ. Increase of serum γ-glutamyltransferase associated with development of cirrhotic cystic fibrosis liver disease. J Pediatr Gastroenterol Nutr. 2015;61(1):113–8.

    CAS  PubMed  Google Scholar 

  38. Leung DH, Narkewicz MR. Cystic fibrosis-related cirrhosis. J Cyst Fibros. 2017;16(Suppl 2):S50–61.

    Article  PubMed  Google Scholar 

  39. Kondo T, Maruyama H, Sekimoto T, et al. Reversed portal flow: clinical influence on the long-term outcomes in cirrhosis. World J Gastroenterol. 2015;21(29):8894–902.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ling SC, Ye W, Leung DH, et al. Liver ultrasound patterns in children with cystic fibrosis correlate with noninvasive tests of liver disease. J Pediatr Gastroenterol Nutr. 2019;69(3):351–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Durieu I, Pellet O, Simonot L, Durupt S, Bellon G, Durand DV, Minh VA. Sclerosing cholangitis in adults with cystic fibrosis: a magnetic resonance cholangiographic prospective study. J Hepatol. 1999;30(6):1052–6.

    Article  CAS  PubMed  Google Scholar 

  42. Lemaitre C, Dominique S, Billoud E, et al. Relevance of 3D cholangiography and transient elastography to assess cystic fibrosis-associated liver disease. Can Respir J. 2016;2016:4592702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lewindon PJ, Shepherd RW, Walsh MJ, et al. Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy. Hepatology. 2011;53(1):193–201.

    Article  CAS  PubMed  Google Scholar 

  44. Leung DH, Khan M, Minard CG, Guffey D, Ramm LE, Clouston AD, Miller G, Lewindon PJ, Shepherd RW, Ramm GA. Aspartate aminotransferase to platelet ratio and fibrosis-4 as biomarkers in biopsy validated pediatric cystic fibrosis liver disease. Hepatology. 2015;62:1576–83.

    Article  CAS  PubMed  Google Scholar 

  45. Stonebraker JR, Ooi CY, Pace RG, Corvol H, Knowles MR, Durie PR, Ling SC. Features of severe liver disease with portal hypertension in patients with cystic fibrosis. Clin Gastroenterol Hepatol. 2016;14(8):1207–15.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Friedrich-Rust M, Schlueter N, Smaczny C, Eickmeier O, Rosewich M, Feifel K, Herrmann E, Poynard T, Gleiber W, Lais C, Zielen S, Wagner TO, Zeuzem S, Bojunga J. Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis. J Cyst Fibros. 2013;12(5):431–9.

    Article  PubMed  Google Scholar 

  47. Gominon AL, Frison E, Hiriart JB, Vergniol J, Clouzeau H, Enaud R, Bui S, Fayon M, de Ledinghen V, Lamireau T. Assessment of liver disease progression in cystic fibrosis using transient elastography. J Pediatr Gastroenterol Nutr. 2018;66(3):455–60.

    Article  PubMed  Google Scholar 

  48. Calvopina DA, Chatfield MD, Weis A, et al. MicroRNA sequencing identifies a serum microRNA panel, which combined with aspartate aminotransferase to platelet ratio index can detect and monitor liver disease in pediatric cystic fibrosis. Hepatology. 2018;68(6):2301–16.

    Article  CAS  PubMed  Google Scholar 

  49. Colombo C, Battezzati PM, Podda M, Bettinardi N, Giunta A. Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis. Hepatology. 1996;23(6):1484–90.

    Article  CAS  PubMed  Google Scholar 

  50. Colombo C, Castellani MR, Balistreri WF, et al. Scintigraphic documentation of an improvement in hepatobiliary excretory function after treatment with ursodeoxycholic acid in patients with cystic fibrosis and associated liver disease. Hepatology. 1992;15(4):677–84.

    Article  CAS  PubMed  Google Scholar 

  51. Lindblad A, Glaumann H, Strandvik B. A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease. Hepatology. 1998;27(1):166–74.

    Article  CAS  PubMed  Google Scholar 

  52. Van der Feen C, van der Doef HPJ, van der Ent CK, Houwen RHJ. Ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients. J Cyst Fibros. 2016;15(6):834–8.

    Article  PubMed  CAS  Google Scholar 

  53. Cheng K, Ashby D, Smyth R. Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Syst Rev. 2017;9:CD000222.

    PubMed  Google Scholar 

  54. Turck D, Braegger CP, Colombo C, et al. ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin Nutr. 2016;35(3):557–77.

    Article  PubMed  Google Scholar 

  55. Pozler O, Krajina A, Vanicek H, et al. Transjugular intrahepatic portosystemic shunt in five children with cystic fibrosis: long-term results. Hepato-Gastroenterology. 2003;50(52):1111–4.

    PubMed  Google Scholar 

  56. Ledder O, Haller W, Couper RTL, Lewindon P, Oliver M. Cystic fibrosis: an update for clinicians. Part 2: Hepatobiliary and pancreatic manifestations. J Gastroenterol Hepatol. 2014;29:1954–62.

    Article  PubMed  Google Scholar 

  57. Debray D, Lykavieris P, Gauthier F, Dousset B, Sardet A, Munck A, Laselve H, Bernard O. Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension. J Hepatol. 1999;31(1):77–83.

    Article  CAS  PubMed  Google Scholar 

  58. Lupi A, Barbiero G, Battistel M, Ferrarese A, Loy M, Feltracco P, Stramare R, Burra P, Senzolo M. Transjugular intrahepatic portosystemic shunt in non-cirrhotic portal hypertension related to cystic fibrosis in a lung transplant patient. J Cyst Fibros. 2020;

    Google Scholar 

  59. Linnane B, Oliver MR, Robinson PJ. Does splenectomy in cystic fibrosis related liver disease improve lung function and nutritional status? A case series. Arch Dis Child. 2006;91(9):771–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Louis D, Duc ML, Reix P, Chazalette JP, Durieu I, Feigelson J, Bellon G. Partial splenectomy for portal hypertension in cystic fibrosis related liver disease. Pediatr Pulmonol. 2007;42(12):1173–80.

    Article  PubMed  Google Scholar 

  61. Morrell MR, Kiel SC, Pilewski JM. Organ transplantation for cystic fibrosis. Semin Respir Crit Care Med. 2019;40(6):842–56.

    Article  PubMed  Google Scholar 

  62. Freeman AJ, Sellers ZM, Mazariegos G, et al. A multidisciplinary approach to pretransplant and posttransplant management of cystic fibrosis-associated liver disease. Liver Transpl. 2019;25(4):640–57.

    Article  PubMed  Google Scholar 

  63. Colombo C, Costantini D, Rocchi A, et al. Effects of liver transplantation on the nutritional status of patients with cystic fibrosis. Transpl Int. 2005;18(2):246–55.

    Article  PubMed  Google Scholar 

  64. Nash KL, Collier JD, French J, et al. Cystic fibrosis liver disease: to transplant or not to transplant? Am J Transplant. 2008;8(1):162–9.

    CAS  PubMed  Google Scholar 

  65. Molmenti EP, Squires RH, Nagata D, et al. Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population. Pediatr Transplant. 2003;7(2):93–7.

    Article  PubMed  Google Scholar 

  66. Nash EF, Volling C, Gutierrez CA, Tullis E, et al. Outcomes of patients with cystic fibrosis undergoing lung transplantation with and without cystic fibrosis-associated liver cirrhosis. Clin Transpl. 2012;26:34–41.

    Article  CAS  Google Scholar 

  67. Dowman JK, Watson D, Loganathan S, et al. Long-term impact of liver transplantation on respiratory function and nutritional status in children and adults with cystic fibrosis. Am J Transplant. 2012;12(4):954–64.

    Article  CAS  PubMed  Google Scholar 

  68. Black SM, Woodley FW, Tumin D, Mumtaz K, Whitson BA, Tobias JD, Hayes D Jr. Cystic fibrosis associated with worse survival after liver transplantation. Dig Dis Sci. 2016;61(4):1178–85.

    Article  CAS  PubMed  Google Scholar 

  69. Desai CS, Gruessner A, Habib S, Gruessner R, Khan KM. Survival of cystic fibrosis patients undergoing liver and liver-lung transplantations. Transplant Proc. 2013;45(1):290–2.

    Article  CAS  PubMed  Google Scholar 

  70. Usatin DJ, Perito ER, Posselt AM, Rosenthal P. Under utilization of pancreas transplants in cystic fibrosis recipients in the United Network Organ Sharing (UNOS) data 1987-2014. Am J Transplant. 2016;16(5):1620–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Colombo C. Mutation-targeted personalised medicine for cystic fibrosis. Lancet Respir Med. 2014;2(11):863–5.

    Article  PubMed  Google Scholar 

  72. Burgel PR, Munck A, Durieu I, Chiron R, Mely L, Prevotat A, Murris-Espin M, Porzio M, Abely M, Reix P, Marguet C, Macey J, Sermet-Gaudelus I, Corvol H, Bui S, Lemonnier L, Dehillotte C, Da Silva J, Paillasseur JL, Hubert D, French Cystic Fibrosis Reference Network Study Group. Real-life safety and effectiveness of lumacaftor-ivacaftor in patients with cystic fibrosis. Am J Respir Crit Care Med. 2020;201(2):188–97.

    Article  CAS  PubMed  Google Scholar 

  73. Debray D, Narkewicz MR, Bodewes FAJA, Colombo C, Housset C, de Jonge HR, Jonker JW, Kelly DA, Ling SC, Poynard T, Sogni P, Trauner M, Witters P, Baumann U, Wilschanski M, Verkade HJ. Cystic fibrosis-related liver disease: research challenges and future perspectives. J Pediatr Gastroenterol Nutr. 2017;65(4):443–8.

    Article  PubMed  Google Scholar 

  74. Witters P, Libbrecht L, Roskams T, Boeck KD, Dupont L, Proesmans M, Vermeulen F, Strandvik B, Lindblad A, Stéphenne X, Sokal E, Gosseye S, Heye S, Maleux G, Aerts R, Monbaliu D, Pirenne J, Hoffman I, Nevens F, Cassiman D. Noncirrhotic presinusoidal portal hypertension is common in cystic fibrosis-associated liver disease. Hepatology. 2011;53(3):1064–5.

    Google Scholar 

  75. Wu H, Vu M, Dhingra S, Ackah R, Goss JA, Rana A, Quintanilla N, Patel K, Leung DH. Obliterative portal venopathy without cirrhosis is prevalent in pediatric cystic fibrosis liver disease with portal hypertension. Clin Gastroenterol Hepatol. 2019;17(10):2134–6.

    Google Scholar 

  76. Scott-Jupp R, Lama M, Tanner MS. Prevalence of liver disease in cystic fibrosis. Arch Dis Child. 1991;66(6):698–701.

    Google Scholar 

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Authors and Affiliations

  1. Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

    Carla Colombo, Laura Zazzeron, Chiara Lanfranchi & Valeria Daccò

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  1. Carla Colombo
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  2. Laura Zazzeron
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  4. Valeria Daccò
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Correspondence to Carla Colombo .

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  1. Scientific Consultant, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Negrar, Verona, Italy

    Annarosa Floreani

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Colombo, C., Zazzeron, L., Lanfranchi, C., Daccò, V. (2021). Liver Disease in Cystic Fibrosis. In: Floreani, A. (eds) Diseases of the Liver and Biliary Tree. Springer, Cham. https://doi.org/10.1007/978-3-030-65908-0_6

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