The Journal of Pediatrics
Volume 151, Issue 3 , Pages 230-232, September 2007

What is the Role of Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Primary Sclerosing Cholangitis?

  • Dennis D. Black

      Affiliations

    • Corresponding Author InformationReprint requests: Dennis D. Black, Department of Pediatrics, University of Tennessee Health Science Center, Children’s Foundation Research Center of Memphis, Le Bonheur Children’s Medical Center, Room 401, West Tower, 50 North Dunlap, Memphis, TN 38103.

Department of Pediatrics, University of Tennessee Health Science Center, Children’s Foundation Research Center of Memphis, Le Bonheur Children’s Medical Center, Memphis, Tennessee

Article Outline

Abbreviations: CF, Cystic fibrosis, CFTR, Cystic fibrosis transmembrane conductance regulator, DHA, Docosahexaenoic acid, IBD, Inflammatory bowel disease, NTPD, Nasal transmembrane potential difference, PPAR-α, Peroxisome proliferator-activated receptor-α, PSC, Primary sclerosing cholangitis, STOPSC, Studies of Primary Sclerosing Cholangitis

 

Primary sclerosing cholangitis (PSC) is a devastating and insidiously progressive cholestatic liver disease resulting from progressive inflammation, fibrosis, and obliteration of the intrahepatic and extrahepatic bile ducts.1 It is a relatively uncommon disorder, with an approximate annual incidence of 1 per 100,000. Most adult patients (>70%) have or will develop inflammatory bowel disease (IBD), usually ulcerative colitis, and approximately 5% of patients with IBD may develop PSC. Ultimately, PSC leads to cirrhosis and end-stage liver disease necessitating transplantation. Cholangiocarcinoma is a dreaded and often fatal complication.

See related article, p 255

Although predominantly an adult disease, PSC affects children as well.2 The prognosis may be somewhat better in children than in adults, because dominant strictures, recurrent cholangitis, and cholangiocarcinoma are uncommon in children. However, approximately 1/3 of pediatric patients require transplantation by adulthood.

There is no satisfactory treatment for PSC. Although high-dose oral ursodeoxycholic acid therapy improves biochemical measures, it does not appear to alter clinical outcome.3 PSC is associated with autoantibodies, occurs in the setting of IBD, and may occasionally present as an overlap syndrome with autoimmune hepatitis. However, PSC does not behave as a typical autoimmune disease and generally responds poorly to immunosuppressive therapy, although a subset of pediatric patients may demonstrate a response.4

The etiology of PSC remains a mystery but is probably multifactorial. Several lines of evidence from animal models and in vitro studies suggest a process of immune dysregulation in the setting of genetic predisposition. The process is initiated by an acute or chronic insult (eg, portal bacteremia in IBD), which triggers an immune response within the liver targeting the cholangiocytes, with resultant chronic inflammation.1 Although hepatic immune cells, such as Kupffer cells, may be major players in this process, it is now clear that the cholangiocyte itself is susceptible to activation. This “reactive” cholangiocyte phenotype acquires the ability to secrete proinflammatory cytokines and chemotactic molecules and is an active participant in the inflammatory process.5 Cholangiocytes generate nitric oxide in response to proinflammatory cytokines, which in turn inhibits cAMP-dependent secretion, including that mediated by cystic fibrosis (CF) transmembrane conductance regulator (CFTR), further contributing to decreased bile flow.6

Of recent interest are genes that may predispose to PSC, participate in the disease process, modulate disease severity, and/or influence the response to therapy and prognosis. Candidate genes include HLA haplotypes, biliary transporter genes (eg, mdr3), genes that modulate host–bacteria interactions (eg, nod2), liver disease–modifying genes (eg, alpha-1-antitrypsin), and inflammatory mediator genes (eg, tumor necrosis factor-α gene-promoter polymorphisms). However, the association of CFTR dysfunction and mutations in the CFTR gene with PSC is of particular interest. The CFTR gene product is a cAMP-regulated chloride channel expressed in diverse tissues, including respiratory tract, intestine, pancreas, sweat glands, male reproductive tract, and the hepatic canalicular and cholangiocyte membranes. Depending on their location and zygosity, CFTR gene mutations may have a clinical spectrum ranging from asymptomatic to severe illness, as well as a differing predilection for specific organs.

There is compelling clinical and experimental evidence linking CFTR dysfunction to PSC. There are similarities between liver disease seen in patients with CF and PSC, including chronic inflammation, bile duct injury, and progressive fibrosis. Presumably, thickened, inspissated bile in CF causes obstruction and inflammation, with resultant injury of bile duct epithelium. In cftr−/− mice with experimentally induced acute colitis, elevated serum alkaline phosphatase levels and histological bile duct injury developed.7 Interestingly, although both cftr−/− and wild-type mice exhibited suppressed peroxisome proliferator-activated receptor-α (PPAR-α) expression in liver with colitis induction, mRNA levels later increased in the wild-type but not in the cftr−/− animals, concomitant with development of bile duct injury. PPAR-α recently has been recognized as an important anti-inflammatory immunomodulator. Treatment with the long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) restored PPAR-α expression in the cftr−/− mice and prevented bile duct injury.8 The protective effects of DHA may be related to its role as a PPAR-α agonist, as well as to other anti-inflammatory properties. In a study of a cftr−/− mouse model that develops CF-like disease of all organs, including liver, DHA treatment specifically and significantly reduced hepatic periportal inflammation without effect on other organs.9 A human pilot study to assess the impact of DHA treatment in adults with CFTR mutations and PSC is currently underway.

The association of CFTR mutations and PSC has been studied in adults with conflicting results.10, 11, 12, 13 However, the negative studies tended to use a small sample size or to screen for only a limited number of mutations. The article by Pall et al14 in this issue of The Journal is the first report in a pediatric population of patients with PSC. Their data demonstrate that CFTR function in these patients with PSC, as assessed by sweat chloride analysis and nasal transmembrane potential difference (NTPD), is intermediate between non-PSC IBD disease control and classic CF values.

A major strength of this study is the evaluation of CFTR function by 2 methods, the classic sweat chloride test and the more sensitive (and technically challenging) NTPD measurement. Few gene products are this accessible in living humans for in vivo functional analysis, but NTPD testing cannot be performed easily in young children. The comprehensive genetic analysis is another strength, although the results were not conclusive despite identification of various mutations (CF-causing), variants (associated with decreased CFTR function and/or non-CF CFTR-defective diseases), and polymorphisms (not linked to specific diseases) in a high percentage of both PSC and disease control patients. This finding differs from that of an adult study by this same group showing significantly higher frequencies of mutations and variants in PSC patients.12

There are several possible explanations for the discrepancy. First, it is possible that some of the IBD controls may have early, clinically silent PSC or may be predisposed to develop PSC later. Hopefully, this cohort will be followed into adulthood. Second, other genes undoubtedly contribute to the CFTR-deficient PSC phenotype, including those that modulate the inflammatory response as well as liver disease modifiers. Expanded genetic analysis to include these genes in the future may help clarify this issue. Finally, the present study involves a relatively small sample; a much larger number of subjects is needed to provide a more definitive answer.

Another intriguing relationship is that between CFTR function and IBD, given the strong association of IBD with PSC. Such factors as mucosal permeability and bacterial flora are thought to be important for the portal access of bacteria and their products, such as LPS and CpG DNA, to possibly contribute to PSC pathogenesis. In the intestine, CFTR is a modulator of permeability, mucus production, and interactions with bacteria. Therefore, CFTR dysfunction in colonic mucosa, as well as biliary epithelium, may contribute to development of PSC. A recent study from Europe demonstrated an association of heterozygosity of the CFTR ΔF508 mutation with a reduced incidence of Crohn’s disease, especially right-sided colitis.15 Therefore, studies of CFTR gene mutations and PSC should include non-IBD controls, as well as both normal and non-PSC liver disease controls.

A recent PSC conference jointly sponsored by NIDDK, the Office of Rare Diseases, and the Morgan Foundation stressed the need for genetic studies in PSC to increase our understanding of the pathogenesis, disease course and prognosis, and response to potential new therapies.1 Both pediatric and adult studies are crucial, because there may be age-related differences in factors such as the relative role of autoimmunity, clinical course, prognosis, and response to treatment, especially immunomodulatory therapy. Larger-scale genetic studies are needed to identify other relevant genetic markers and clinical associations. A newly launched North American PSC registry and DNA repository, Studies of Primary Sclerosing Cholangitis (STOPSC) (www.STOPSC.org), comprises 19 pediatric and adult hepatology programs in 12 major medical centers. Hopefully, STOPSC will provide the number of subjects needed to power studies of this uncommon, but clinically important, disease. The report by Pall et al14 in this issue of The Journal is a groundbreaking beginning, but much more remains to be done.

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References 

  1. LaRusso NF, Shneider BL, Black D, Gores GJ, James SP, Doo E, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology. 2006;44:746–764
  2. Feldstein AE, Perrault J, El-Youssif M, Lindor KD, Freese DK, Angulo P. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology. 2003;38:210–217
  3. Olsson R, Boberg KM, de Muckadell OS, Lindgren S, Hultcrantz R, Folvik G, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 2005;129:1464–1472
  4. Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33:544–553
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  7. Blanco PG, Zaman MM, Junaidi O, Sheth S, Yantiss RK, Nasser IA, et al. Induction of colitis in cftr−/− mice results in bile duct injury. Am J Physiol Gastrointest Liver Physiol. 2004;287:G491–G496
  8. Pall H, Zaman MM, Andersson C, Freedman SD. Decreased peroxisome proliferator activated receptor alpha is associated with bile duct injury in cystic fibrosis transmembrane conductance regulator−/− mice. J Pediatr Gastroenterol Nutr. 2006;42:275–281
  9. Beharry S, Ackerley C, Corey M, Kent G, Heng YM, Christensen H, et al. Long-term docosahexaenoic acid therapy in a congenic murine model of cystic fibrosis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G839–G848
  10. McGill JM, Williams DM, Hunt CM. Survey of cystic fibrosis transmembrane conductance regulator genotypes in primary sclerosing cholangitis. Dig Dis Sci. 1996;41:540–542
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  12. Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, et al. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet. 2003;113:286–292
  13. Gallegos-Orozco JF, C EY, Wang N, Rakela J, Charlton MR, Cutting GR, et al. Lack of association of common cystic fibrosis transmembrane conductance regulator gene mutations with primary sclerosing cholangitis. Am J Gastroenterol. 2005;100:874–878
  14. Pall H, Zielenski J, Jonas MM, Dasilva DA, Potvin KM, Yuan X-W, et al. Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function. J Pediatr. 2007;151:255–259
  15. Bresso F, Askling J, Astegiano M, Demarchi B, Sapone N, Rizzetto M, et al. Potential role for the common cystic fibrosis deltaF508 mutation in Crohn’s disease. Inflamm Bowel Dis. 2007;13:531–536

PII: S0022-3476(07)00486-6

doi:10.1016/j.jpeds.2007.05.025

Refers to article:

  • Primary Sclerosing Cholangitis in Childhood is Associated with Abnormalities in Cystic Fibrosis–Mediated Chloride Channel Function , 28 July 2007

    Harpreet Pall, Julian Zielenski, Maureen M. Jonas, Deborah A. DaSilva, Kimberly M. Potvin, Xiao-Wei Yuan, Qiuju Huang, Steven D. Freedman
    The Journal of Pediatrics September 2007 (Vol. 151, Issue 3, Pages 255-259)

The Journal of Pediatrics
Volume 151, Issue 3 , Pages 230-232, September 2007

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