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Hepatobiliary complications of cystic fibrosis

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Abstract

Cystic fibrosis (CF) is the most common potentially lethal genetic disease in the Caucasian population. The disease results from mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMPactivated Cl-channel in the apical membrane of most secretory epithelia. In the liver, CFTR is located in biliary epithelial cells or cholangiocytes and gallbladder epithelia, where it appears to play a role in normal bile formation. However, how a defective CFTR protein leads to associated liver and biliary disease in a subset of patients with CF is unknown. Improvements in life expectancy have led to an increasing recognition of hepatobiliary complications from CF. Whereas the biliary tract disease is usually clinically evident, the liver involvement may progress silently, only manifesting as end-stage liver disease and portal hypertension. Unlike the pancreatic involvement in CF, a genotype-phenotype correlation is not apparent in the expression of liver disease, suggesting the presence of as yet unidentifiable "genetic modifiers" influencing disease expression. This review focuses on the pathogenesis, clinical manifestations, screening, diagnosis, and treatment of CF hepatobiliary disease.

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References and Recommended Reading

  1. Dodge JA, Morison S, Lewis PA, et al.: Incidence, population, and survival of cystic fibrosis in the UK, 1968–95. UK Cystic Fibrosis Survey Management Committee. Arch Dis Child 1997, 77:493–496.

    PubMed  CAS  Google Scholar 

  2. Gabriel SE, Brigman KN, Koller BH, et al.: Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 1994, 266:107–109.

    Article  PubMed  CAS  Google Scholar 

  3. Riordan JR, Rommens JM, Kerem B-S, et al.: Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989, 245:1066–1073. This study identified the gene defect in CF. The gene, located on chromosome 7, codes for a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR). A mutation at position 508 in the first nucleotide binding fold accounts for the most common mutation in CF. Identification of the gene defect in CF provided critical breakthroughs in our understanding of the pathogenesis of this disease.

    Article  PubMed  CAS  Google Scholar 

  4. Cohn JA, Strong TA, Picciotto MA, et al.: Localization of CFTR in human bile duct epithelial cells. Gastroenterology 1993, 105:1857–1864. This study demonstrated that, in liver, CFTR is localized to the apical membrane of bile duct epithelial cells, or cholangiocytes. It is not found in hepatic parenchymal cells (hepatocytes) or other cells of the liver. The role of CFTR in biliary epithelium provided insight into the mechanisms of normal bile formation.

    PubMed  CAS  Google Scholar 

  5. Fitz JG, Basavappa S, McGill J, et al.: Regulation of membrane chloride currents in rat bile duct epithelial cells. J Clin Invest 1993, 91:319–328. This paper described the regulatory mechanisms involved in Cl− secretion in the apical membrane of biliary epithelial cells. Distinct Cl− conductances were described, including both Ca2+-and cAMP-activated channels. The study demonstrated that cAMP-regulated Cl− secretion is associated with endogenous expression of CFTR.

    PubMed  CAS  Google Scholar 

  6. Feranchak AP, Sokol RJ: Cholangiocyte biology and cystic fibrosis liver disease. Semin Liver Dis 2001, 21:471–488.

    Article  PubMed  CAS  Google Scholar 

  7. McGill J, Gettys TW, Basavappa S, Fitz JG: GTP-binding proteins regulate high conductance anion channels in rat bile duct epithelial cells. J Membr Biol 1993, 133:253–261.

    PubMed  CAS  Google Scholar 

  8. Roman RM, Wang Y, Fitz JG: Regulation of cell volume in a human biliary cell line: calcium-dependent activation of K+ and Cl-currents. Am J Physiol 1996, 271:G239-G248.

    PubMed  CAS  Google Scholar 

  9. Roman RM, Feranchak AP, Salter KD, et al.: Endogenous ATP regulates Cl-secretion in cultured human and rat biliary epithelial cells. Am J Physiol 1999, 276:G1391-G400.

    PubMed  CAS  Google Scholar 

  10. Feranchak AP, Roman RM, Doctor RB, et al.: The lipid products of phosphoinositide 3-kinase contribute to regulation of cholangiocyte ATP and chloride transport. J Biol Chem 1999, 274:30979–30986.

    Article  PubMed  CAS  Google Scholar 

  11. Feranchak A, Goodwin S, Troetsch, M, et al.: Regulation of secretion in biliary epithelial cells: role of basolateral K+ channels [abstract]. Pediatr Res 2003, 53:175A.

    Google Scholar 

  12. Chari RS, Schutz SM, Haebig JA, et al.: Adenosine nucleotides in bile. Am J Physiol 1996, 270:G246-G252.

    PubMed  CAS  Google Scholar 

  13. Feranchak AP, Fitz JG: Adenosine triphosphate release and purinergic regulation of cholangiocyte transport. Semin Liver Dis 2002, 22:251–262.

    Article  PubMed  CAS  Google Scholar 

  14. Feranchak AP, Fitz JG, Roman RM: Volume-sensitive purinergic signaling in human hepatocytes. J Hepatol 2000, 33:174–182.

    Article  PubMed  CAS  Google Scholar 

  15. Knowles MR, Clarke LL, Boucher RC: Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis. N Engl J Med 1991, 325:533–538.

    Article  PubMed  CAS  Google Scholar 

  16. Parr CE, Sullivan DM, Paradiso AM, et al.: Cloning and expression of a human P2u nucleotide receptor, a target for cystic fibrosis pharmacotherapy. Proc Natl Acad Sci U S A 1994, 91:3275–3279.

    Article  PubMed  CAS  Google Scholar 

  17. Sokol RJ, Durie PR: Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr 1999, 28(Suppl 1):S1-S13. This paper is derived from the Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group recommendations for the management of liver and biliary tract disease. Information regarding pathogenesis, prevalence, and diagnosis is provided. Included are guidelines for the screening and treatment of CF liver and biliary disease.

    Article  PubMed  Google Scholar 

  18. Colombo C, Apostolo MG, Ferrari M, et al.: Analysis of risk factors for the development of liver disease associated with cystic fibrosis. J Pediatr 1994, 124:393–399.

    Article  PubMed  CAS  Google Scholar 

  19. Zielenski J, Corey M, Rozmahel R, et al.: Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13.Nat Genet 1999, 22:128–129.

    Article  PubMed  CAS  Google Scholar 

  20. Duthie A, Doherty DG, Donaldson PT, et al.: The major histocompatibility complex influences the development of chronic liver disease in male children and young adults with cystic fibrosis. J Hepatol 1995, 23:532–537.

    Article  PubMed  CAS  Google Scholar 

  21. Henrion-Caude A, Flamant C, Roussey M, et al.: Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism. Hepatology 2002, 36:913–917.

    PubMed  CAS  Google Scholar 

  22. Clarke LL, Grubb BR, Yankaskas J, et al.: Relationship of a noncystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in cftr (-/-) mice. Proc Natl Acad Sci U S A 1994, 91:479–483.

    Article  PubMed  CAS  Google Scholar 

  23. Rozmahel R, Wilschanski M, Matin A, et al.: Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet 1996, 12:280–287.

    Article  PubMed  CAS  Google Scholar 

  24. Rohlfs EM, Shaheen NJ, Silverman LM: Is the hemochromatosis gene a modifier locus for cystic fibrosis? Genet Test 1998, 2:85–88.

    PubMed  CAS  Google Scholar 

  25. Friedman K, Ling S, Macek M, et al.: Complex multigenic inheritence influences the development of severe liver disease in CF [A]. Presented at the 15th North American Cystic Fibrosis Conference, Orlando, FL, 2001.

  26. Lindblad A, Glaumann H, Strandvik B: Natural history of liver disease in cystic fibrosis. Hepatology 1999, 30:1151–1158.

    Article  PubMed  CAS  Google Scholar 

  27. Colombo C, Apostolo MG, Ferrari M, et al.: Analysis of risk factors for the development of liver disease associated with cystic fibrosis. J Pediatr 1994, 124:393–399.

    Article  PubMed  CAS  Google Scholar 

  28. Gaskin KJ, Waters DLM, Howman-Giles R, et al.: Liver disease and common bile duct stenosis in cystic fibrosis. N Engl J Med 1988, 318:340–346.

    Article  PubMed  CAS  Google Scholar 

  29. Colombo C, Battezzati PM, Crosignani A, et al.: Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome. Hepatology 2002, 36:1374–1382.

    PubMed  Google Scholar 

  30. Roy CC, Weber AM, Morin CL, et al.: Hepatobiliary disease in cystic fibrosis: a survey of current issues and concepts. J Pediatr Gastroenterol Nutr 1982, 1:469–478.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. Colombo C, Bertolini E, Assaisso ML, et al.: Failure of ursodeoxycholic acid to dissolve radiolucent gallstones in patients with cystic fibrosis. Acta Paediatr 1993, 82:562–565.

    PubMed  CAS  Google Scholar 

  33. Sheth S, Shea JC, Bishop MD, et al.: Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 2003, 113:286–292.

    Article  PubMed  Google Scholar 

  34. Williams SG, Evanson JE, Barrett N, et al.: An ultrasound scoring system for the diagnosis of liver disease in cystic fibrosis. J Hepatol 1995, 22:513–521.

    Article  PubMed  CAS  Google Scholar 

  35. Lenaerts C, Lapierre C, Patriquin H, et al.: Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors. J Pediatr 2003, 143:343–350.

    Article  PubMed  Google Scholar 

  36. Williams SM, Goodman R, Thomson A, et al.: Ultrasound evaluation of liver disease in cystic fibrosis as part of an annual assessment clinic: a 9-year review. Clin Radiol 2002, 57:365–370.

    Article  PubMed  Google Scholar 

  37. Rattenbury JM, Taylor CJ, Heath PK, et al.: Serum glutathione S-transferase B1 activity as an index of liver function in cystic fibrosis. J Clin Pathol 1995, 48:771–774.

    PubMed  CAS  Google Scholar 

  38. Schoenau E, Boeswald W, Wanner R, et al.: High-molecularmass (’biliary’) isoenzyme of alkaline phosphatase and the diagnosis of liver dysfunction in cystic fibrosis. Clin Chem 1989, 35:1888–1890.

    PubMed  CAS  Google Scholar 

  39. Wyatt HA, Dhawan A, Cheeseman P, et al.: Serum hyaluronic acid concentrations are increased in cystic fibrosis patients with liver disease. Arch Dis Child 2002, 86:190–193.

    Article  PubMed  CAS  Google Scholar 

  40. Schwarz KB, Rosensweig J, Sharma S, et al.: Plasma markers of platelet activation in cystic fibrosis liver and lung disease. J Pediatr Gastroenterol Nutr 2003, 37:187–191.

    Article  PubMed  CAS  Google Scholar 

  41. Augarten A, Berman H, Aviram M, et al.: Serum CA 19-9 levels as a diagnostic marker in cystic fibrosis patients with borderline sweat tests. Clin Exp Med 2003, 3:119–123.

    Article  PubMed  CAS  Google Scholar 

  42. Gerling B, Becker M, Staab D, Schuppan D: Prediction of liver fibrosis according to serum collagen VI level in children with cystic fibrosis. N Engl J Med 1997, 336:1611–1612.

    Article  PubMed  CAS  Google Scholar 

  43. Leonardi S, Giambusso F, Sciuto C, et al.: Are serum type III procollagen and prolyl hydroxylase useful as noninvasive markers of liver disease in patients with cystic fibrosis? J Pediatr Gastroenterol Nutr 1998, 27:603–605.

    Article  PubMed  CAS  Google Scholar 

  44. Colombo C, Battezzati PM, Podda M, et al.: Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a doubleblind multicenter trial. Hepatology 1996, 23:1484–1490.

    Article  PubMed  CAS  Google Scholar 

  45. Colombo C, Setchell KD, Podda M, et al.: Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis. J Pediatr 1990, 117:482–489.

    Article  PubMed  CAS  Google Scholar 

  46. Colombo C, Setchell KD, Podda M, et al.: Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis. J Pediatr 1990, 117:482–489.

    Article  PubMed  CAS  Google Scholar 

  47. van de Meeberg PC, Houwen RH, Sinaasappel M, et al.: Lowdose versus high-dose ursodeoxycholic acid in cystic fibrosisrelated cholestatic liver disease: results of a randomized study with 1-year follow-up. Scand J Gastroenterol 1997, 32:369–373.

    Article  PubMed  Google Scholar 

  48. 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, 27:166–174.

    Article  PubMed  CAS  Google Scholar 

  49. Nousia-Arvanitakis S, Fotoulaki M, Economou H, et al.: Longterm prospective study of the effect of ursodeoxycholic acid on cystic fibrosis-related liver disease. J Clin Gastroenterol 2001, 32:324–328.

    Article  PubMed  CAS  Google Scholar 

  50. Efrati O, Barak A, Modan-Moses D, et al.: Liver cirrhosis and portal hypertension in cystic fibrosis. Eur J Gastroenterol Hepatol 2003, 15:1073–1078.

    Article  PubMed  Google Scholar 

  51. Fridell JA, Bond GJ, Mazariegos GV, et al.: Liver transplantation in children with cystic fibrosis: a long-term longitudinal review of a single center’s experience. J Pediatr Surg 2003, 38:1152–1156.

    Article  PubMed  Google Scholar 

  52. Molmenti EP, Squires RH, Nagata D, et al.: Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population. Pediatr Transplant 2003, 7:93–97.

    Article  PubMed  Google Scholar 

  53. Molmenti EP, Squires RH, Nagata D, et al.: Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population. Pediatr Transplant 2003, 7:93–97.

    Article  PubMed  Google Scholar 

  54. Noble-Jamieson G, Valente J, Barnes ND, et al.: Liver transplantation for hepatic cirrhosis in cystic fibrosis. Arch Dis Child 1994, 71:349–352.

    Article  PubMed  CAS  Google Scholar 

  55. Couetil JP, Houssin DP, Soubrane O, et al.: Combined lung and liver transplantation in patients with cystic fibrosis: a 4 1/2-year experience. J Thorac Cardiovasc Surg 1995, 110:1415–1422.

    Article  PubMed  CAS  Google Scholar 

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  1. Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children’s Hospital and the University of Colorado Health Sciences Center, 1056 East 19th Avenue, #B290, 80218, Denver, CO, USA

    Andrew P. Feranchak MD

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Feranchak, A.P. Hepatobiliary complications of cystic fibrosis. Curr Gastroenterol Rep 6, 231–239 (2004). https://doi.org/10.1007/s11894-004-0013-6

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  • DOI: https://doi.org/10.1007/s11894-004-0013-6

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