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2004; Elsevier BV; Volume: 126; Issue: 4 Linguagem: Inglês

10.1053/j.gastro.2004.02.043

1528-0012

Michael Trauner, Peter Fickert, Frank Lammert, Hanns‐Ulrich Marschall,

Pediatric Hepatobiliary Diseases and Treatments

We greatly appreciate the letter by Rosmorduc et al. and would like to thank them for their thoughtful comments and for further exploring one of the hypotheses brought forward in our recent paper by Fickert et al.1Fickert P. Zollner G. Fuchsbichler A. Stumptner C. Weiglein A.H. Lammert F. Marschall H.U. Tsybrovskyy O. Zatloukal K. Denk H. Trauner M. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles.Gastroenterology. 2002; 123: 1238-1251Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Their findings in 34 unselected patients with primary sclerosing cholangitis (PSC) dismiss a major role for genetic variations of ABCB4 (previously referred to as MDR3, the human homologue of rodent Mdr2) in the pathogenesis of PSC. Although the authors analyzed single polymorphisms and did not define ABCB4 “haplotypes,” i.e., unique combinations of genetic markers present in a chromosome that better cover the overall variation at a gene locus,2Cardon L.R. Abecasis G.R. Using haplotype blocks to map human complex trait loci.Trends Genet. 2003; 19: 135-140Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar this observation is in line with a report by Pauli-Magnus et al. in 46 PSC patients.3Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 2004;(in press).Google Scholar Furthermore, this is consistent with a normal biliary phospholipid/bile salt ratio (indicative of a normal MDR3 function) previously reported in 45 PSC patients.4De Vree J.M.L. Defects in hepatobiliary transport. Genetics and therapy of progressive familial intrahepatic cholestasis type 3.in: University of Amsterdam, 1999: 32Google ScholarGiven the fact that PSC might represent a “mixed bag” of diseases with variable pathogenetic background in individual subgroups, a general role of ABCB4 mutations in “unselected PSC patients” would have been very surprising to us. Considering the toxicity of the human bile salt pool, we would expect such mutations in younger, female patients with PSC having gallstones. Such “unusual PSC patients” could have been missed in these studies since, depending on the definition of PSC, patients with cholelithiasis may have been excluded despite the fact that this phenotype can be part of the spectrum of PSC.5Pokorny C.S. McCaughan G.W. Gallagher N.D. Selby W.S. Sclerosing cholangitis and biliary tract calculi-primary or secondary?.Gut. 1992; 33: 1376-1380Crossref PubMed Scopus (29) Google Scholar Interestingly, Mdr2−/− mice develop cholesterol cholecystolithiasis and at later time points also choledocholithiasis (following the development of sclerosing cholangitis) with a female predominance.6Lammert F. Wang D.Q.H. Hillebrandt S. Geier A. Fickert P. Trauner M. Paigen B. Carey M.C. Spontaneous cholecysto- and hepatolithiasis in Mdr2-knockout mice a model of low-phospholipid-associated cholelithiasis.Hepatology. 2004; 39: 117-128Crossref PubMed Scopus (132) Google Scholar Patients with obviously dilated bile ducts on cholangiograms had certainly been excluded in studies of patients with progressive familial intrahepatic cholestasis subytype 3 (PFIC3), a generally accepted pediatric manifestation of ABCB4 mutations.7Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease one gene for three diseases.Semin Liver Dis. 2001; 21: 551-562Crossref PubMed Scopus (150) Google Scholar Our findings in Mdr2−/− mice therefore appear to call for a reconsideration of the phenotypic appearance of PFIC3, which could also include large bile duct disease. Moreover, ABCB4 defects might be expected in pediatric PSC patients. However, a key role for immune mechanisms, at least at young age, is suggested from pediatric PSC that frequently overlaps with autoimmune hepatitis and responds well to immunosuppressive therapy.8Gregorio G.V. Portmann B. Karani J. Harrison P. Donaldson P.T. Vergani D. Mieli-Vergani G. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood a 16-year prospective study.Hepatology. 2001; 33: 544-553Crossref PubMed Scopus (531) Google Scholar, 9Feldstein A.E. Perrault J. El-Youssif M. Lindor K.D. Freese D.K. Angulo P. Primary sclerosing cholangitis in children a long-term follow-up study.Hepatology. 2003; 38: 210-217Crossref PubMed Scopus (193) Google ScholarWe would suggest that ABCB4 might be a modifier gene10Nadeau J.H. Modifier genes in mice and humans.Nat Rev Genet. 2001; 2: 165-174Crossref PubMed Scopus (455) Google Scholar for cholestatic liver diseases that can potentially aggravate immune-mediated or vascular bile duct injury (e.g., increased susceptibility of injured ducts to non-micellar bile salts as a result of decreased biliary phospholipid secretion). The only manifestation of cholestasis so far linked to an abnormally low biliary phospholipid/bile salt ratio, indicative of impaired phosphatidylcholine transport via MDR3, is total-parenteral nutrition-induced cholestasis.11De Vree J.M. Romijn J.A. Mok K.S. Mathus-Vliegen L.M. Stoutenbeek C.P. Ostrow J.D. Tytgat G.N. Sauerwein H.P. Oude Elferink R.P. Groen A.K. Lack of enteral nutrition during critical illness is associated with profound decrements in biliary lipid concentrations.Am J Clin Nutr. 1999; 70: 70-77Crossref PubMed Scopus (33) Google Scholar Of note, rapidly progressive sclerosing cholangitis has been reported in patients recovering from sepsis or severe burns.12Engler S. Elsing C. Flechtenmacher C. Theilmann L. Stremmel W. Stiehl A. Progressive sclerosing cholangitis after septic shock a new variant of vanishing bile duct disorders.Gut. 2003; 52: 688-693Crossref PubMed Scopus (84) Google Scholar These findings may imply a possible role for endotoxin-induced proinflammatory cytokines interfering with biliary phospholipid excretion. In this context it is attractive to speculate that increased bacterial translocation due to inflammatory bowel disease (IBD) could be related to or even interfere with phospholipid secretion in patients with IBD and concomitant PSC. Thus, although one might expect an increased susceptibility in individuals with ABCB4 defects, other genetic mechanisms (e.g., polymorphisms in cytokine genes responsible for ABCB4 suppression and also linked to the pathogenesis of PSC13Mitchell S.A. Grove J. Spurkland A. Boberg K.M. Fleming K.A. Day C.P. Schrumpf E. Chapman R.W. European Study Group of Primary Sclerosing CholangitisAssociation of the tumour necrosis factor alpha-308 but not the interleukin 10–627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis.Gut. 2001; 49: 288-294Crossref PubMed Scopus (95) Google Scholar might be equally or even more important.Lessons from CFTR (ABCC7) in PSC have shown that “negative” reports14Girodon E. Sternberg D. Chazouilleres O. Cazeneuve C. Huot D. Calmus Y. Poupon R. Goossens M. Housset C. Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis.J Hepatol. 2002; 37: 192-197Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar may be followed by “positive” reports15Sheth S. Shea J.C. Bishop M.D. Chopra S. Regan M.M. Malmberg E. Walker C. Ricci R. Tsui L.C. Durie P.R. Zielenski J. Freedman S.D. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis.Hum Genet. 2003; 113: 286-292Crossref PubMed Scopus (93) Google Scholar from other patient populations. Similarly, the contribution of ABCB4 mutations/polymorphisms in intrahepatic cholestasis of pregnancy may be variable depending on the geographic and ethnic background, as well as clinical characteristics of the study population with both “positive”16Jacquemin E. Cresteil D. Manouvrier S. Boute O. Hadchouel M. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy.Lancet. 1999; 353: 210-211Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, 17Dixon P.H. Weerasekera N. Linton K.J. Donaldson O. Chambers J. Egginton E. Weaver J. Nelson-Piercy C. de Swiet M. Warnes G. Elias E. Higgins C.F. Johnston D.G. McCarthy M.I. Williamson C. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy evidence for a defect in protein trafficking.Hum Mol Genet. 2000; 9: 1209-1217Crossref PubMed Scopus (264) Google Scholar, 18Lucena J.F. Herrero J.I. Quiroga J. Sangro B. Garcia-Foncillas J. Zabalegui N. Sola J. Herraiz M. Medina J.F. Prieto J. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis.Gastroenterology. 2003; 124: 1037-1042Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar and “negative“19Eloranta M.L. Heiskanen J.T. Hiltunen M.J. Mannermaa A.J. Punnonen K.R. Heinonen S.T. Multidrug resistance 3 gene mutation 1712delT and estrogen receptor alpha gene polymorphisms in Finnish women with obstetric cholestasis.Eur J Obstet Gynecol Reprod Biol. 2002; 105: 132-135Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 20Savander M. Ropponen A. Avela K. Weerasekera N. Cormand B. Hirvioja M.L. Riikonen S. Ylikorkala O. Lehesjoki A.E. Williamson C. Aittomaki K. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy.Gut. 2003; 52: 1025-1029Crossref PubMed Scopus (115) Google Scholar associations being reported. Therefore, a positive association of genetic ABCB4 variations with PSC still remains a possibility in other populations, in particular in subpopulations with more “unusual” features outlined above.In summary, the concept of “toxic bile” contributing to sclerosing cholangitis as a result of hereditary and/or acquired ABCB4 (MDR3) defects should not be generally dismissed, since this pathogenetic principle may still apply to a specific, yet to be defined subpopulation of patients with sclerosing cholangitis (including PSC). In addition, this pathogenetic concept also implies novel therapeutic strategies, since recent reports have identified ABCB4 as a target of ligand-activated nuclear receptors including PPAR-α and FXR.21Huang L, Zhao A, Lew JL, Zhang T, Hrywna Y, Thompson JR, Pedro Nd N, Royo I, Blevins RA, Pelaez F, Wright SD, Cui J. Farnesoid X-receptor activates transcription of the phospholipid pump MDR3. J Biol Chem 2003 [Epub ahead of print]Google Scholar Specific therapies aimed at stimulating (reduced or remnant) ABCB4 expression and function via their regulating nuclear receptors are already available22Liu Y. Binz J. Numerick M.J. Dennis S. Luo G. Desai B. MacKenzie K.I. Mansfield T.A. Kliewer S.A. Goodwin B. Jones S.A. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.J Clin Invest. 2003; 112: 1678-1687Crossref PubMed Scopus (346) Google Scholar and may readily be applied clinically in the future. We greatly appreciate the letter by Rosmorduc et al. and would like to thank them for their thoughtful comments and for further exploring one of the hypotheses brought forward in our recent paper by Fickert et al.1Fickert P. Zollner G. Fuchsbichler A. Stumptner C. Weiglein A.H. Lammert F. Marschall H.U. Tsybrovskyy O. Zatloukal K. Denk H. Trauner M. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles.Gastroenterology. 2002; 123: 1238-1251Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Their findings in 34 unselected patients with primary sclerosing cholangitis (PSC) dismiss a major role for genetic variations of ABCB4 (previously referred to as MDR3, the human homologue of rodent Mdr2) in the pathogenesis of PSC. Although the authors analyzed single polymorphisms and did not define ABCB4 “haplotypes,” i.e., unique combinations of genetic markers present in a chromosome that better cover the overall variation at a gene locus,2Cardon L.R. Abecasis G.R. Using haplotype blocks to map human complex trait loci.Trends Genet. 2003; 19: 135-140Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar this observation is in line with a report by Pauli-Magnus et al. in 46 PSC patients.3Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 2004;(in press).Google Scholar Furthermore, this is consistent with a normal biliary phospholipid/bile salt ratio (indicative of a normal MDR3 function) previously reported in 45 PSC patients.4De Vree J.M.L. Defects in hepatobiliary transport. Genetics and therapy of progressive familial intrahepatic cholestasis type 3.in: University of Amsterdam, 1999: 32Google Scholar Given the fact that PSC might represent a “mixed bag” of diseases with variable pathogenetic background in individual subgroups, a general role of ABCB4 mutations in “unselected PSC patients” would have been very surprising to us. Considering the toxicity of the human bile salt pool, we would expect such mutations in younger, female patients with PSC having gallstones. Such “unusual PSC patients” could have been missed in these studies since, depending on the definition of PSC, patients with cholelithiasis may have been excluded despite the fact that this phenotype can be part of the spectrum of PSC.5Pokorny C.S. McCaughan G.W. Gallagher N.D. Selby W.S. Sclerosing cholangitis and biliary tract calculi-primary or secondary?.Gut. 1992; 33: 1376-1380Crossref PubMed Scopus (29) Google Scholar Interestingly, Mdr2−/− mice develop cholesterol cholecystolithiasis and at later time points also choledocholithiasis (following the development of sclerosing cholangitis) with a female predominance.6Lammert F. Wang D.Q.H. Hillebrandt S. Geier A. Fickert P. Trauner M. Paigen B. Carey M.C. Spontaneous cholecysto- and hepatolithiasis in Mdr2-knockout mice a model of low-phospholipid-associated cholelithiasis.Hepatology. 2004; 39: 117-128Crossref PubMed Scopus (132) Google Scholar Patients with obviously dilated bile ducts on cholangiograms had certainly been excluded in studies of patients with progressive familial intrahepatic cholestasis subytype 3 (PFIC3), a generally accepted pediatric manifestation of ABCB4 mutations.7Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease one gene for three diseases.Semin Liver Dis. 2001; 21: 551-562Crossref PubMed Scopus (150) Google Scholar Our findings in Mdr2−/− mice therefore appear to call for a reconsideration of the phenotypic appearance of PFIC3, which could also include large bile duct disease. Moreover, ABCB4 defects might be expected in pediatric PSC patients. However, a key role for immune mechanisms, at least at young age, is suggested from pediatric PSC that frequently overlaps with autoimmune hepatitis and responds well to immunosuppressive therapy.8Gregorio G.V. Portmann B. Karani J. Harrison P. Donaldson P.T. Vergani D. Mieli-Vergani G. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood a 16-year prospective study.Hepatology. 2001; 33: 544-553Crossref PubMed Scopus (531) Google Scholar, 9Feldstein A.E. Perrault J. El-Youssif M. Lindor K.D. Freese D.K. Angulo P. Primary sclerosing cholangitis in children a long-term follow-up study.Hepatology. 2003; 38: 210-217Crossref PubMed Scopus (193) Google Scholar We would suggest that ABCB4 might be a modifier gene10Nadeau J.H. Modifier genes in mice and humans.Nat Rev Genet. 2001; 2: 165-174Crossref PubMed Scopus (455) Google Scholar for cholestatic liver diseases that can potentially aggravate immune-mediated or vascular bile duct injury (e.g., increased susceptibility of injured ducts to non-micellar bile salts as a result of decreased biliary phospholipid secretion). The only manifestation of cholestasis so far linked to an abnormally low biliary phospholipid/bile salt ratio, indicative of impaired phosphatidylcholine transport via MDR3, is total-parenteral nutrition-induced cholestasis.11De Vree J.M. Romijn J.A. Mok K.S. Mathus-Vliegen L.M. Stoutenbeek C.P. Ostrow J.D. Tytgat G.N. Sauerwein H.P. Oude Elferink R.P. Groen A.K. Lack of enteral nutrition during critical illness is associated with profound decrements in biliary lipid concentrations.Am J Clin Nutr. 1999; 70: 70-77Crossref PubMed Scopus (33) Google Scholar Of note, rapidly progressive sclerosing cholangitis has been reported in patients recovering from sepsis or severe burns.12Engler S. Elsing C. Flechtenmacher C. Theilmann L. Stremmel W. Stiehl A. Progressive sclerosing cholangitis after septic shock a new variant of vanishing bile duct disorders.Gut. 2003; 52: 688-693Crossref PubMed Scopus (84) Google Scholar These findings may imply a possible role for endotoxin-induced proinflammatory cytokines interfering with biliary phospholipid excretion. In this context it is attractive to speculate that increased bacterial translocation due to inflammatory bowel disease (IBD) could be related to or even interfere with phospholipid secretion in patients with IBD and concomitant PSC. Thus, although one might expect an increased susceptibility in individuals with ABCB4 defects, other genetic mechanisms (e.g., polymorphisms in cytokine genes responsible for ABCB4 suppression and also linked to the pathogenesis of PSC13Mitchell S.A. Grove J. Spurkland A. Boberg K.M. Fleming K.A. Day C.P. Schrumpf E. Chapman R.W. European Study Group of Primary Sclerosing CholangitisAssociation of the tumour necrosis factor alpha-308 but not the interleukin 10–627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis.Gut. 2001; 49: 288-294Crossref PubMed Scopus (95) Google Scholar might be equally or even more important. Lessons from CFTR (ABCC7) in PSC have shown that “negative” reports14Girodon E. Sternberg D. Chazouilleres O. Cazeneuve C. Huot D. Calmus Y. Poupon R. Goossens M. Housset C. Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis.J Hepatol. 2002; 37: 192-197Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar may be followed by “positive” reports15Sheth S. Shea J.C. Bishop M.D. Chopra S. Regan M.M. Malmberg E. Walker C. Ricci R. Tsui L.C. Durie P.R. Zielenski J. Freedman S.D. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis.Hum Genet. 2003; 113: 286-292Crossref PubMed Scopus (93) Google Scholar from other patient populations. Similarly, the contribution of ABCB4 mutations/polymorphisms in intrahepatic cholestasis of pregnancy may be variable depending on the geographic and ethnic background, as well as clinical characteristics of the study population with both “positive”16Jacquemin E. Cresteil D. Manouvrier S. Boute O. Hadchouel M. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy.Lancet. 1999; 353: 210-211Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, 17Dixon P.H. Weerasekera N. Linton K.J. Donaldson O. Chambers J. Egginton E. Weaver J. Nelson-Piercy C. de Swiet M. Warnes G. Elias E. Higgins C.F. Johnston D.G. McCarthy M.I. Williamson C. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy evidence for a defect in protein trafficking.Hum Mol Genet. 2000; 9: 1209-1217Crossref PubMed Scopus (264) Google Scholar, 18Lucena J.F. Herrero J.I. Quiroga J. Sangro B. Garcia-Foncillas J. Zabalegui N. Sola J. Herraiz M. Medina J.F. Prieto J. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis.Gastroenterology. 2003; 124: 1037-1042Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar and “negative“19Eloranta M.L. Heiskanen J.T. Hiltunen M.J. Mannermaa A.J. Punnonen K.R. Heinonen S.T. Multidrug resistance 3 gene mutation 1712delT and estrogen receptor alpha gene polymorphisms in Finnish women with obstetric cholestasis.Eur J Obstet Gynecol Reprod Biol. 2002; 105: 132-135Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 20Savander M. Ropponen A. Avela K. Weerasekera N. Cormand B. Hirvioja M.L. Riikonen S. Ylikorkala O. Lehesjoki A.E. Williamson C. Aittomaki K. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy.Gut. 2003; 52: 1025-1029Crossref PubMed Scopus (115) Google Scholar associations being reported. Therefore, a positive association of genetic ABCB4 variations with PSC still remains a possibility in other populations, in particular in subpopulations with more “unusual” features outlined above. In summary, the concept of “toxic bile” contributing to sclerosing cholangitis as a result of hereditary and/or acquired ABCB4 (MDR3) defects should not be generally dismissed, since this pathogenetic principle may still apply to a specific, yet to be defined subpopulation of patients with sclerosing cholangitis (including PSC). In addition, this pathogenetic concept also implies novel therapeutic strategies, since recent reports have identified ABCB4 as a target of ligand-activated nuclear receptors including PPAR-α and FXR.21Huang L, Zhao A, Lew JL, Zhang T, Hrywna Y, Thompson JR, Pedro Nd N, Royo I, Blevins RA, Pelaez F, Wright SD, Cui J. Farnesoid X-receptor activates transcription of the phospholipid pump MDR3. J Biol Chem 2003 [Epub ahead of print]Google Scholar Specific therapies aimed at stimulating (reduced or remnant) ABCB4 expression and function via their regulating nuclear receptors are already available22Liu Y. Binz J. Numerick M.J. Dennis S. Luo G. Desai B. MacKenzie K.I. Mansfield T.A. Kliewer S.A. Goodwin B. Jones S.A. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.J Clin Invest. 2003; 112: 1678-1687Crossref PubMed Scopus (346) Google Scholar and may readily be applied clinically in the future.