Liver Disease in Cystic Fibrosis

  • Dominique DebrayEmail author


Cystic fibrosis-associated liver disease (CFLD) is characterized histologically by biliary obstruction, inflammation, and focal biliary cirrhosis which may progress to multilobular cirrhosis and portal hypertension in approximately 5–10% of patients. Knowledge of the underlying pathological aspects and optimal therapeutic management to prevent progression of the liver disease to cirrhosis are sorely lacking. CFLD is frequently asymptomatic leading to challenges in early diagnosis. If they develop, cirrhosis and portal hypertension are early events occurring mainly in the pediatric age, while end-stage liver disease with liver failure is a late event. Annual screening for liver involvement (hepatomegaly, splenomegaly at physical examination, persistent abnormalities of liver enzymes, and pathological ultrasonography of the liver) is recommended to detect pre-symptomatic signs of liver disease. A liver biopsy may be indicated if there is diagnostic doubt, to exclude other causes of liver disease. Several noninvasive tools to measure liver stiffness as an indirect measure of fibrosis are being evaluated among the pediatric CF population in order to identify patients at risk of cirrhosis and to document disease progression. There is no evidence that ursodeoxycholic acid halts the progression of liver disease. Management should focus on nutrition, prevention of bleeding, and variceal decompression. Ideal candidates for liver transplantation are CF patients who have clear evidence of end-stage liver disease with liver failure rather than severe portal hypertension, but adequate consideration should be given to the severity of other organ involvement. Early liver transplantation may be considered for children with deteriorating nutritional status and lung function as there is evidence that liver transplantation may prevent further decline.


Cystic fibrosis CFTR Liver disease Cirrhosis Portal hypertension Liver transplantation Therapy 


  1. 1.
    Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992–2001.PubMedCrossRefGoogle Scholar
  2. 2.
    Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066–73.PubMedCrossRefGoogle Scholar
  3. 3.
    McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003;361:1671–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Amaral MD. Novel personalized therapies for cystic fibrosis: treating the basic defect in all patients. J Intern Med. 2015;277:155–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Colombo C, Battezzati PM, Crosignani A, Morabito A, Costantini D, Padoan R, Giunta A. Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome. Hepatology. 2002;36:1374–82.PubMedCrossRefGoogle Scholar
  6. 6.
    Lindblad A, Glaumann H, Strandvik B. Natural history of liver disease in cystic fibrosis. Hepatology. 1999;30:1151–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Lamireau T, Monnereau S, Martin S, Marcotte JE, Winnock M, Alvarez F. Epidemiology of liver disease in cystic fibrosis: a longitudinal study. J Hepatol. 2004;41:920–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Cystic Fibrosis Foundation Patient Registry ADRttCD, Bethesda. p. 73.
  9. 9.
    Debray D, Narkewicz MR, Bodewes F, Colombo C, Housset C, de Jonge HR, Jonker JW, et al. Cystic fibrosis-related liver disease: research challenges and future perspectives. J Pediatr Gastroenterol Nutr. 2017;65:443–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Oppenheimer EH, Esterly JR. Hepatic changes in young infants with cystic fibrosis: possible relation to focal biliary cirrhosis. J Pediatr. 1975;86:683–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Vawter GF, Shwachman H. Cystic fibrosis in adults: an autopsy study. Pathol Annu. 1979;14(Pt 2):357–82.PubMedGoogle Scholar
  12. 12.
    Leung DH, Narkewicz MR. Cystic fibrosis-related cirrhosis. J Cyst Fibros. 2017;16(Suppl 2):S50–61.PubMedCrossRefGoogle Scholar
  13. 13.
    Colombo C, Battezzati PM. Liver involvement in cystic fibrosis: primary organ damage or innocent bystander? J Hepatol. 2004;41:1041–4.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    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;14:1207–1215.e3.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B, Castaldo G, et al. Genetic modifiers of liver disease in cystic fibrosis. JAMA. 2009;302:1076–83.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Lewindon PJ, Pereira TN, Hoskins AC, Bridle KR, Williamson RM, Shepherd RW, Ramm GA. The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. Am J Pathol. 2002;160:1705–15.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Mueller-Abt PR, Frawley KJ, Greer RM, Lewindon PJ. Comparison of ultrasound and biopsy findings in children with cystic fibrosis related liver disease. J Cyst Fibros. 2008;7:215–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Pereira TN, Lewindon PJ, Greer RM, Hoskins AC, Williamson RM, Shepherd RW, Ramm GA. Transcriptional basis for hepatic fibrosis in cystic fibrosis-associated liver disease. J Pediatr Gastroenterol Nutr. 2012;54:328–35.PubMedCrossRefGoogle Scholar
  20. 20.
    Witters P, Libbrecht L, Roskams T, De Boeck K, Dupont L, Proesmans M, Vermeulen F, et al. Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension. J Cyst Fibros. 2017;16:e11–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Hillaire S, Cazals-Hatem D, Bruno O, de Miranda S, Grenet D, Pote N, Soubrane O, et al. Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy. Liver Transpl. 2017;23:1342–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Assis DN, Debray D. Gallbladder and bile duct disease in cystic fibrosis. J Cyst Fibros. 2017;16(Suppl 2):S62–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Santamaria F, Vajro P, Oggero V, Greco L, Angelillo M, Carrillo F, De Ritis G. Volume and emptying of the gallbladder in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 1990;10:303–6.PubMedCrossRefGoogle Scholar
  24. 24.
    O’Connor PJ, Southern KW, Bowler IM, Irving HC, Robinson PJ, Littlewood JM. The role of hepatobiliary scintigraphy in cystic fibrosis. Hepatology. 1996;23:281–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Stern RC, Rothstein FC, Doershuk CF. Treatment and prognosis of symptomatic gallbladder disease in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 1986;5:35–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Angelico M, Gandin C, Canuzzi P, Bertasi S, Cantafora A, De Santis A, Quattrucci S, et al. Gallstones in cystic fibrosis: a critical reappraisal. Hepatology. 1991;14:768–75.PubMedCrossRefGoogle Scholar
  27. 27.
    Colombo C, Bertolini E, Assaisso ML, Bettinardi N, Giunta A, Podda M. Failure of ursodeoxycholic acid to dissolve radiolucent gallstones in patients with cystic fibrosis. Acta Paediatr. 1993;82:562–5.PubMedCrossRefGoogle Scholar
  28. 28.
    O’Brien S, Keogan M, Casey M, Duffy G, McErlean D, Fitzgerald MX, Hegarty JE. Biliary complications of cystic fibrosis. Gut. 1992;33:387–91.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Nagel RA, Westaby D, Javaid A, Kavani J, Meire HB, Lombard MG, Wise A, et al. Liver disease and bile duct abnormalities in adults with cystic fibrosis. Lancet. 1989;2:1422–5.PubMedCrossRefGoogle Scholar
  30. 30.
    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;30:1052–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Waters DL, Dorney SF, Gruca MA, Martin HC, Howman-Giles R, Kan AE, De Silva M, et al. Hepatobiliary disease in cystic fibrosis patients with pancreatic sufficiency. Hepatology. 1995;21:963–9.PubMedGoogle Scholar
  32. 32.
    Strandvik B, Hjelte L, Gabrielsson N, Glaumann H. Sclerosing cholangitis in cystic fibrosis. Scand J Gastroenterol Suppl. 1988;143:121–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Gaskin KJ, Waters DL, Howman-Giles R, de Silva M, Earl JW, Martin HC, Kan AE, et al. Liver disease and common-bile-duct stenosis in cystic fibrosis. N Engl J Med. 1988;318:340–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Abdul-Karim FW, King TA, Dahms BB, Gauderer MW, Boat TF. Carcinoma of extrahepatic biliary system in an adult with cystic fibrosis. Gastroenterology. 1982;82:758–62.PubMedCrossRefGoogle Scholar
  35. 35.
    Tesluk H, McCauley K, Kurland G, Ruebner BH. Cholangiocarcinoma in an adult with cystic fibrosis. J Clin Gastroenterol. 1991;13:485–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Perdue DG, Cass OW, Milla C, Dunitz J, Jessurun J, Sharp HL, Schwarzenberg SJ. Hepatolithiasis and cholangiocarcinoma in cystic fibrosis: a case series and review of the literature. Dig Dis Sci. 2007;52:2638–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Naderi AS, Farsian FN, Lee WM. Cholangiocarcinoma after lung transplantation in a patient with cystic fibrosis. Eur J Gastroenterol Hepatol. 2008;20:1115–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Maisonneuve P, Marshall BC, Knapp EA, Lowenfels AB. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J Natl Cancer Inst. 2013;105:122–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Potter CJ, 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;25:32–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Lewindon PJ, Shepherd RW, Walsh MJ, Greer RM, Williamson R, Pereira TN, Frawley K, et al. Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy. Hepatology. 2011;53:193–201.PubMedCrossRefGoogle Scholar
  41. 41.
    Chen AH, Innis SM, Davidson AG, James SJ. Phosphatidylcholine and lysophosphatidylcholine excretion is increased in children with cystic fibrosis and is associated with plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine. Am J Clin Nutr. 2005;81:686–91.PubMedCrossRefGoogle Scholar
  42. 42.
    Feranchak AP, Sokol RJ. Cholangiocyte biology and cystic fibrosis liver disease. Semin Liver Dis. 2001;21:471–88.PubMedCrossRefGoogle Scholar
  43. 43.
    Lindblad A, Hultcrantz R, Strandvik B. Bile-duct destruction and collagen deposition: a prominent ultrastructural feature of the liver in cystic fibrosis. Hepatology. 1992;16:372–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Cohn JA, Strong TV, Picciotto MR, Nairn AC, Collins FS, Fitz JG. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology. 1993;105:1857–64.PubMedCrossRefGoogle Scholar
  45. 45.
    Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Elferink RP. The biliary HCO(3)(−) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology. 2010;52:1489–96.PubMedCrossRefGoogle Scholar
  46. 46.
    Hultcrantz R, Mengarelli S, Strandvik B. Morphological findings in the liver of children with cystic fibrosis: a light and electron microscopical study. Hepatology. 1986;6:881–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Kinnman N, Lindblad A, Housset C, Buentke E, Scheynius A, Strandvik B, Hultcrantz R. Expression of cystic fibrosis transmembrane conductance regulator in liver tissue from patients with cystic fibrosis. Hepatology. 2000;32:334–40.PubMedCrossRefGoogle Scholar
  48. 48.
    Goodchild MC, Murphy GM, Howell AM, Nutter SA, Anderson CM. Aspects of bile acid metabolism in cystic fibrosis. Arch Dis Child. 1975;50:769–78.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Watkins JB, Tercyak AM, Szczepanik P, Klein PD. Bile salt kinetics in cystic fibrosis: influence of pancreatic enzyme replacement. Gastroenterology. 1977;73:1023–8.PubMedCrossRefGoogle Scholar
  50. 50.
    O’Brien S, Mulcahy H, Fenlon H, O’Broin A, Casey M, Burke A, FitzGerald MX, et al. Intestinal bile acid malabsorption in cystic fibrosis. Gut. 1993;34:1137–41.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Bijvelds MJ, Jorna H, Verkade HJ, Bot AG, Hofmann F, Agellon LB, Sinaasappel M, et al. Activation of CFTR by ASBT-mediated bile salt absorption. Am J Physiol Gastrointest Liver Physiol. 2005;289:G870–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Bodewes FA, van der Wulp MY, Beharry S, Doktorova M, Havinga R, Boverhof R, James Phillips M, et al. Altered intestinal bile salt biotransformation in a cystic fibrosis (Cftr−/−) mouse model with hepato-biliary pathology. J Cyst Fibros. 2015;14:440–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Bijvelds MJ, de Jonge HR, Verkade HJ. Bile acid handling in cystic fibrosis: marked phenotypic differences between mouse models. Gastroenterology. 2012;143:e19–20; author reply e20.PubMedCrossRefGoogle Scholar
  54. 54.
    Bodewes FA, Wouthuyzen-Bakker M, Bijvelds MJ, Havinga R, de Jonge HR, Verkade HJ. Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1035–42.PubMedCrossRefGoogle Scholar
  55. 55.
    Strandvik B, Einarsson K, Lindblad A, Angelin B. Bile acid kinetics and biliary lipid composition in cystic fibrosis. J Hepatol. 1996;25:43–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Debray D, Rainteau D, Barbu V, Rouahi M, El Mourabit H, Lerondel S, Rey C, et al. Defects in gallbladder emptying and bile acid homeostasis in mice with cystic fibrosis transmembrane conductance regulator deficiencies. Gastroenterology. 2012;142:1581–1591.e6.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-kappaB-mediated inflammatory response in mice. Gastroenterology. 2011;141:1498–508, 1508 e1491–1495.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Fiorotto R, Villani A, Kourtidis A, Scirpo R, Amenduni M, Geibel PJ, Cadamuro M, et al. The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity. Hepatology. 2016;64:2118–34.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Blanco PG, Zaman MM, Junaidi O, Sheth S, Yantiss RK, Nasser IA, Freedman SD. Induction of colitis in cftr−/− mice results in bile duct injury. Am J Physiol Gastrointest Liver Physiol. 2004;287:G491–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759–63.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Scirpo R, Fiorotto R, Villani A, Amenduni M, Spirli C, Strazzabosco M. Stimulation of nuclear receptor peroxisome proliferator-activated receptor-gamma limits NF-kappaB-dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology. 2015;62:1551–62.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Harmon GS, Dumlao DS, Ng DT, Barrett KE, Dennis EA, Dong H, Glass CK. Pharmacological correction of a defect in PPAR-gamma signaling ameliorates disease severity in Cftr-deficient mice. Nat Med. 2010;16:313–8.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Flass T, Tong S, Frank DN, Wagner BD, Robertson CE, Kotter CV, Sokol RJ, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Debray D, Lykavieris P, Gauthier F, Dousset B, Sardet A, Munck A, Laselve H, et al. Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension. J Hepatol. 1999;31:77–83.PubMedCrossRefGoogle Scholar
  65. 65.
    Leeuwen L, Magoffin AK, Fitzgerald DA, Cipolli M, Gaskin KJ. Cholestasis and meconium ileus in infants with cystic fibrosis and their clinical outcomes. Arch Dis Child. 2014;99:443–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Maurage C, Lenaerts C, Weber A, Brochu P, Yousef I, Roy CC. Meconium ileus and its equivalent as a risk factor for the development of cirrhosis: an autopsy study in cystic fibrosis. J Pediatr Gastroenterol Nutr. 1989;9:17–20.PubMedCrossRefGoogle Scholar
  67. 67.
    Chryssostalis A, Hubert D, Coste J, Kanaan R, Burgel PR, Desmazes-Dufeu N, Soubrane O, 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;55:1377–82.PubMedCrossRefGoogle Scholar
  68. 68.
    Lykavieris P, Bernard O, Hadchouel M. Neonatal cholestasis as the presenting feature in cystic fibrosis. Arch Dis Child. 1996;75:67–70.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Buxbaum J, Nguyen N, Kulkarni S, Palmer S, Rao A, Selby R. Multidisciplinary treatment of cystic fibrosis-related recurrent pyogenic cholangitis (CF-RPC). Dig Dis Sci. 2015;60:1801–4.PubMedCrossRefGoogle Scholar
  70. 70.
    Woodruff SA, Sontag MK, Accurso FJ, Sokol RJ, Narkewicz MR. Prevalence of elevated liver enzymes in children with cystic fibrosis diagnosed by newborn screen. J Cyst Fibros. 2017;16:139–45.PubMedCrossRefGoogle Scholar
  71. 71.
    Mayer-Hamblett N, Kloster M, Ramsey BW, Narkewicz MR, Saiman L, Goss CH. Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials. Contemp Clin Trials. 2013;34:232–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Bodewes FA, van der Doef HP, Houwen RH, Verkade HJ. Increase of serum gamma-Glutamyltransferase associated with development of cirrhotic cystic fibrosis liver disease. J Pediatr Gastroenterol Nutr. 2015;61:113–8.PubMedGoogle Scholar
  73. 73.
    Lenaerts C, Lapierre C, Patriquin H, Bureau N, Lepage G, Harel F, Marcotte J, et al. Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors. J Pediatr. 2003;143:343–50.PubMedCrossRefGoogle Scholar
  74. 74.
    Williams SM, Goodman R, Thomson A, McHugh K, Lindsell DR. Ultrasound evaluation of liver disease in cystic fibrosis as part of an annual assessment clinic: a 9-year review. Clin Radiol. 2002;57:365–70.PubMedCrossRefGoogle Scholar
  75. 75.
    Leung DH, Ye W, Molleston JP, Weymann A, Ling S, Paranjape SM, Romero R, et al. Baseline ultrasound and clinical correlates in children with cystic fibrosis. J Pediatr. 2015;167:862–868.e2.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Colombo C, Castellani MR, Balistreri WF, Seregni E, Assaisso ML, Giunta A. 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;15:677–84.PubMedCrossRefGoogle Scholar
  77. 77.
    Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging. 2011;34:729–49.PubMedCrossRefGoogle Scholar
  78. 78.
    Leung DH, Khan M, Minard CG, Guffey D, Ramm LE, Clouston AD, Miller G, et al. Aspartate aminotransferase to platelet ratio and fibrosis-4 as biomarkers in biopsy-validated pediatric cystic fibrosis liver disease. Hepatology. 2015;62:1576–83.PubMedCrossRefGoogle Scholar
  79. 79.
    Cook NL, Pereira TN, Lewindon PJ, Shepherd RW, Ramm GA. Circulating microRNAs as noninvasive diagnostic biomarkers of liver disease in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2015;60:247–54.PubMedCrossRefGoogle Scholar
  80. 80.
    Karlas T, Neuschulz M, Oltmanns A, Guttler A, Petroff D, Wirtz H, Mainz JG, et al. Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores. PLoS One. 2012;7:e42139.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Manco M, Zupone CL, Alghisi F, D’Andrea ML, Lucidi V, Monti L. Pilot study on the use of acoustic radiation force impulse imaging in the staging of cystic fibrosis associated liver disease. J Cyst Fibros. 2012;11:427–32.PubMedCrossRefGoogle Scholar
  82. 82.
    Gominon AL, Frison E, Hiriart JB, Vergniol J, Clouzeau H, Enaud R, Bui S, et al. Assessment of liver disease progression in cystic fibrosis using transient elastography. J Pediatr Gastroenterol Nutr. 2018;66:455–60.PubMedCrossRefGoogle Scholar
  83. 83.
    Franchi-Abella S, Corno L, Gonzales E, Antoni G, Fabre M, Ducot B, Pariente D, et al. Feasibility and diagnostic accuracy of supersonic shear-wave elastography for the assessment of liver stiffness and liver fibrosis in children: a pilot study of 96 patients. Radiology. 2016;278:554–62.PubMedCrossRefGoogle Scholar
  84. 84.
    Witters P, De Boeck K, Dupont L, Proesmans M, Vermeulen F, Servaes R, Verslype C, et al. Non-invasive liver elastography (Fibroscan) for detection of cystic fibrosis-associated liver disease. J Cyst Fibros. 2009;8:392–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Menten R, Leonard A, Clapuyt P, Vincke P, Nicolae AC, Lebecque P. Transient elastography in patients with cystic fibrosis. Pediatr Radiol. 2010;40:1231–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Aqul A, Jonas MM, Harney S, Raza R, Sawicki GS, Mitchell PD, Fawaz R. Correlation of transient elastography with severity of cystic fibrosis-related liver disease. J Pediatr Gastroenterol Nutr. 2017;64:505–11.PubMedCrossRefGoogle Scholar
  87. 87.
    Tang A, Cloutier G, Szeverenyi NM, Sirlin CB. Ultrasound elastography and MR elastography for assessing liver fibrosis: part 2, diagnostic performance, confounders, and future directions. AJR Am J Roentgenol. 2015;205:33–40.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Burgel PR, Bellis G, Olesen HV, Viviani L, Zolin A, Blasi F, Elborn JS. Future trends in cystic fibrosis demography in 34 European countries. Eur Respir J. 2015;46:133–41.PubMedCrossRefGoogle Scholar
  89. 89.
    Ye W, Narkewicz MR, Leung DH, Karnsakul W, Murray KF, Alonso EM, Magee JC, et al. Variceal hemorrhage and adverse liver outcomes in patients with cystic fibrosis cirrhosis. J Pediatr Gastroenterol Nutr. 2018;66:122–7.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Slieker MG, van der Doef HP, Deckers-Kocken JM, van der Ent CK, Houwen RH. Pulmonary prognosis in cystic fibrosis patients with liver disease. J Pediatr. 2006;149:144; author reply 144–145.PubMedCrossRefGoogle Scholar
  91. 91.
    Pencharz PB, Durie PR. Pathogenesis of malnutrition in cystic fibrosis, and its treatment. Clin Nutr. 2000;19:387–94.PubMedCrossRefGoogle Scholar
  92. 92.
    Sacher-Huvelin S, Cales P, Bureau C, Valla D, Vinel JP, Duburque C, Attar A, et al. Screening of esophageal varices by esophageal capsule endoscopy: results of a French multicenter prospective study. Endoscopy. 2015;47:486–92.PubMedCrossRefGoogle Scholar
  93. 93.
    McCarty TR, Afinogenova Y, Njei B. Use of wireless capsule endoscopy for the diagnosis and grading of esophageal varices in patients with portal hypertension: a systematic review and meta-analysis. J Clin Gastroenterol. 2017;51:174–82.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Goldschmidt I, Brauch C, Poynard T, Baumann U. Spleen stiffness measurement by transient elastography to diagnose portal hypertension in children. J Pediatr Gastroenterol Nutr. 2014;59:197–203.PubMedCrossRefGoogle Scholar
  95. 95.
    Gana JC, Turner D, Mieli-Vergani G, Davenport M, Miloh T, Avitzur Y, Yap J, et al. A clinical prediction rule and platelet count predict esophageal varices in children. Gastroenterology. 2011;141:2009–16.PubMedCrossRefGoogle Scholar
  96. 96.
    Isted A, Grammatikopoulos T, Davenport M. Prediction of esophageal varices in biliary atresia: derivation of the “varices prediction rule”, a novel noninvasive predictor. J Pediatr Surg. 2015;50:1734–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Kelleher T, Staunton M, O’Mahony S, McCormick PA. Advanced hepatocellular carcinoma associated with cystic fibrosis. Eur J Gastroenterol Hepatol. 2005;17:1123–4.PubMedCrossRefGoogle Scholar
  98. 98.
    McKeon D, Day A, Parmar J, Alexander G, Bilton D. Hepatocellular carcinoma in association with cirrhosis in a patient with cystic fibrosis. J Cyst Fibros. 2004;3:193–5.PubMedCrossRefGoogle Scholar
  99. 99.
    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;23:1484–90.PubMedCrossRefGoogle Scholar
  100. 100.
    Cheng K, Ashby D, Smyth RL. Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Syst Rev. 2017;9:CD000222.PubMedGoogle Scholar
  101. 101.
    Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology. 2013;145:521–36.PubMedCrossRefGoogle Scholar
  102. 102.
    Colombo C, Crosignani A, Alicandro G, Zhang W, Biffi A, Motta V, Corti F, et al. Long-term ursodeoxycholic acid therapy does not alter lithocholic acid levels in patients with cystic fibrosis with associated liver disease. J Pediatr. 2016;177:59–65.e51.PubMedCrossRefGoogle Scholar
  103. 103.
    Dodge JA, Turck D. Cystic fibrosis: nutritional consequences and management. Best Pract Res Clin Gastroenterol. 2006;20:531–46.PubMedCrossRefGoogle Scholar
  104. 104.
    Cogliandolo A, Patania M, Curro G, Chille G, Magazzu G, Navarra G. Postoperative outcomes and quality of life in patients with cystic fibrosis undergoing laparoscopic cholecystectomy: a retrospective study. Surg Laparosc Endosc Percutan Tech. 2011;21:179–83.PubMedCrossRefGoogle Scholar
  105. 105.
    Gooding I, Dondos V, Gyi KM, Hodson M, Westaby D. Variceal hemorrhage and cystic fibrosis: outcomes and implications for liver transplantation. Liver Transpl. 2005;11:1522–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Pozler O, Krajina A, Vanicek H, Hulek P, Zizka J, Michl A, Elias P. Transjugular intrahepatic portosystemic shunt in five children with cystic fibrosis: long-term results. Hepatogastroenterology. 2003;50:1111–4.PubMedGoogle Scholar
  107. 107.
    Arnon R, Annunziato RA, Miloh T, Padilla M, Sogawa H, Batemarco L, Willis A, et al. Liver and combined lung and liver transplantation for cystic fibrosis: analysis of the UNOS database. Pediatr Transplant. 2011;15:254–64.PubMedCrossRefGoogle Scholar
  108. 108.
    Desai CS, Gruessner A, Habib S, Gruessner R, Khan KM. Survival of cystic fibrosis patients undergoing liver and liver-lung transplantations. Transplant Proc. 2013;45:290–2.PubMedCrossRefGoogle Scholar
  109. 109.
    Dowman JK, Watson D, Loganathan S, Gunson BK, Hodson J, Mirza DF, Clarke J, 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;12:954–64.PubMedCrossRefGoogle Scholar
  110. 110.
    Fridell JA, Bond GJ, Mazariegos GV, Orenstein DM, Jain A, Sindhi R, Finder JD, et al. Liver transplantation in children with cystic fibrosis: a long-term longitudinal review of a single center’s experience. J Pediatr Surg. 2003;38:1152–6.PubMedCrossRefGoogle Scholar
  111. 111.
    Milkiewicz P, Skiba G, Kelly D, Weller P, Bonser R, Gur U, Mirza D, et al. Transplantation for cystic fibrosis: outcome following early liver transplantation. J Gastroenterol Hepatol. 2002;17:208–13.PubMedCrossRefGoogle Scholar
  112. 112.
    Melzi ML, Kelly DA, Colombo C, Jara P, Manzanares J, Colledan M, Strazzabosco M, et al. Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry. Transpl Int. 2006;19:726–31.PubMedCrossRefGoogle Scholar
  113. 113.
    Mendizabal M, Reddy KR, Cassuto J, Olthoff KM, Faust TW, Makar GA, Rand EB, et al. Liver transplantation in patients with cystic fibrosis: analysis of united network for organ sharing data. Liver Transpl. 2011;17:243–50.PubMedCrossRefGoogle Scholar
  114. 114.
    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;16:1620–5.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Bandsma RH, Bozic MA, Fridell JA, Crull MH, Molleston J, Avitzur Y, Mozer-Glassberg Y, et al. Simultaneous liver-pancreas transplantation for cystic fibrosis-related liver disease: a multicenter experience. J Cyst Fibros. 2014;13:471–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Hayes D Jr, Warren PS, McCoy KS, Sheikh SI. Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy. J Pediatr Gastroenterol Nutr. 2015;60:578–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Colombo C. Mutation-targeted personalised medicine for cystic fibrosis. Lancet Respir Med. 2014;2:863–5.PubMedCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Pediatric Liver UnitReference Center for Biliary Atresia and Genetic Cholestatic Diseases, Hôpital Necker-Enfants MaladesParisFrance

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