Skip to main content

Advertisement

SpringerLink
Log in

Sex-related influence of angiotensin-converting enzyme polymorphisms on fibrosis progression due to recurrent hepatitis C after liver transplantation

  • Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Experimental evidence and clinical studies suggest that the renin–angiotensin system and its inhibitors may play a role in regulating the mechanisms of liver fibrosis development. The present study aimed to verify whether carriage of specific angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) allelic variants, modulating angiotensin II generation, could affect the outcome of recurrent hepatitis C after liver transplantation, via several metabolic pathways.

Methods

Forty-five (29 men) recipients, with a median histological follow-up of 60 months after orthotopic liver transplantation (OLT), were studied. ACE gene I/D polymorphism was assessed by means of a polymerase chain reaction procedure. Fibrosis progression was evaluated annually during the follow-up.

Results

Weight gain 1 year post-OLT (defined as an increase in body mass index, BMI, of >0.5 kg/m2) was significantly more common among D/* carriers (22/22 vs. 16/23, P < 0.005); patients who 1 year after OLT had an increase in their BMI value of >0.5 kg/m2 more frequently had a triglycerides/cholesterol ratio of ≤ 0.7 (16/22 vs. 8/23, χ-squared test P < 0.02). This association was stronger in men. Female D/D homozygotes had the highest probability of showing significant liver fibrosis (7/10) in comparison with men (11/29) and I/* women (1/6) (P < 0.01).

Conclusions

In patients with recurrent hepatitis C, carriers of the D allele appeared to gain more weight after liver transplantation, and in male liver recipients, the D allele was associated with a peculiar lipid profile that was associated with a slower rate of allograft fibrosis progression. Among female recipients, carriage of the D allele may favor more severe allograft fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. M Berenguer FX Lopez-Labrador TL Wright (2001) ArticleTitleHepatitis C and liver transplantation J Hepatol 35 666–78 Occurrence Handle11690716 Occurrence Handle10.1016/S0168-8278(01)00179-9 Occurrence Handle1:STN:280:DC%2BD3MnktVyguw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  2. M Berenguer (2002) ArticleTitleNatural history of recurrent hepatitis C Liver Transpl 8 S14–8 Occurrence Handle12362293 Occurrence Handle10.1053/jlts.2002.35781

    Article  PubMed  Google Scholar 

  3. M Berenguer (2002) ArticleTitleOutcome of posttransplantation hepatitis C virus disease—is it the host, the virus, or how we modify the host and/or the virus? Liver Transpl 8 889–91 Occurrence Handle12360429 Occurrence Handle10.1053/jlts.2002.35841

    Article  PubMed  Google Scholar 

  4. M Wali RF Harrison PJ Gow D Mutimer (2002) ArticleTitleAdvancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C Gut 51 248–52 Occurrence Handle12117889 Occurrence Handle10.1136/gut.51.2.248 Occurrence Handle1:STN:280:DC%2BD38zpslSlug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  5. VI Machicao H Bonatti M Krishna BA Aqel FJ Lukens JH Nguyen et al. (2004) ArticleTitleDonor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C Transplantation 77 84–92 Occurrence Handle14724440 Occurrence Handle10.1097/01.TP.0000095896.07048.BB

    Article  PubMed  Google Scholar 

  6. LM Forman JD Lewis JA Berlin HI Feldman MR Lucey (2002) ArticleTitleThe association between hepatitis C infection and survival after orthotopic liver transplantation Gastroenterology 122 889–96 Occurrence Handle11910340 Occurrence Handle10.1053/gast.2002.32418

    Article  PubMed  Google Scholar 

  7. P Toniutto C Fabris C Avellini R Minisini D Bitetto E Rossi et al. (2005) ArticleTitleExcess body weight, liver steatosis, and early fibrosis progression due to hepatitis C recurrence after liver transplantation World J Gastroenterol 11 5944–50 Occurrence Handle16273604

    PubMed  Google Scholar 

  8. C Fabris P Toniutto D Bitetto R Minisini C Smirne M Caldato et al. (2005) ArticleTitleLow fibrosis progression of recurrent hepatitis C in apolipoprotein E epsilon4 carriers: relationship with the blood lipid profile Liver Int 25 1128–35 Occurrence Handle16343062 Occurrence Handle10.1111/j.1478-3231.2005.01156.x Occurrence Handle1:CAS:528:DC%2BD28XkslSkug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  9. P Strazzullo R Iacone L Iacoviello O Russo G Barba P Russo et al. (2003) ArticleTitleGenetic variation in the renin–angiotensin system and abdominal adiposity in men: the Olivetti Prospective Heart Study Ann Intern Med 138 17–23 Occurrence Handle12513040 Occurrence Handle1:CAS:528:DC%2BD3sXhslOgsrc%3D

    PubMed  CAS  Google Scholar 

  10. P Toniutto C Fabris R Minisini L Apollonio E Fumo M Caldato et al. (2005) ArticleTitleWeight gain after liver transplantation and the insertion/deletion polymorphism of the angiotensin-converting enzyme gene Transplantation 79 1338–43 Occurrence Handle15912101 Occurrence Handle10.1097/01.TP.0000158712.42875.51 Occurrence Handle1:CAS:528:DC%2BD2MXksVajsL0%3D

    Article  PubMed  CAS  Google Scholar 

  11. H Yoshiji S Kuriyama J Yoshii Y Ikenaka R Noguchi T Nakatani et al. (2001) ArticleTitleAngiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats Hepatology 34 745–50 Occurrence Handle11584371 Occurrence Handle1:CAS:528:DC%2BD3MXns1Kisrs%3D

    PubMed  CAS  Google Scholar 

  12. JR Jonsson AD Clouston Y Ando LI Kelemen MJ Horn MD Adamson et al. (2001) ArticleTitleAngiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis Gastroenterology 121 148–55 Occurrence Handle11438504 Occurrence Handle10.1053/gast.2001.25480 Occurrence Handle1:CAS:528:DC%2BD3MXlt1yktL4%3D

    Article  PubMed  CAS  Google Scholar 

  13. G Paizis ME Cooper JM Schembri C Tikellis LM Burrell PW Angus (2002) ArticleTitleUp-regulation of components of the renin–angiotensin system in the bile duct-ligated rat liver Gastroenterology 123 1667–76 Occurrence Handle12404241 Occurrence Handle10.1053/gast.2002.36561 Occurrence Handle1:CAS:528:DC%2BD38XptVGjt7g%3D

    Article  PubMed  CAS  Google Scholar 

  14. PS Leung PM Suen SP Ip CK Yip G Chen PB Lai (2003) ArticleTitleExpression and localization of AT1 receptors in hepatic Kupffer cells: its potential role in regulating a fibrogenic response Regul Pept 116 61–9 Occurrence Handle14599716 Occurrence Handle10.1016/S0167-0115(03)00192-7 Occurrence Handle1:CAS:528:DC%2BD3sXos1Kmsrg%3D

    Article  PubMed  CAS  Google Scholar 

  15. K Kanno S Tazuma K Chayama (2003) ArticleTitleAT1A-deficient mice show less severe progression of liver fibrosis induced by CCl(4) Biochem Biophys Res Commun 308 177–83 Occurrence Handle12890498 Occurrence Handle10.1016/S0006-291X(03)01357-3 Occurrence Handle1:CAS:528:DC%2BD3sXlvVCkurw%3D

    Article  PubMed  CAS  Google Scholar 

  16. R Bataller P Sancho-Bru P Gines JM Lora A Al-Garawi M Sole et al. (2003) ArticleTitleActivated human hepatic stellate cells express the renin–angiotensin system and synthesize angiotensin II Gastroenterology 125 117–25 Occurrence Handle12851877 Occurrence Handle10.1016/S0016-5085(03)00695-4 Occurrence Handle1:CAS:528:DC%2BD3sXmtVWqur4%3D

    Article  PubMed  CAS  Google Scholar 

  17. F Cambien O Poirier L Lecerf A Evans JP Cambou D Arveiler et al. (1992) ArticleTitleDeletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction Nature 359 641–4 Occurrence Handle1328889 Occurrence Handle10.1038/359641a0 Occurrence Handle1:CAS:528:DyaK38XmtlWgu7Y%3D

    Article  PubMed  CAS  Google Scholar 

  18. B Rigat C Hubert P Corvol F Soubrier (1992) ArticleTitlePCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1) Nucleic Acids Res 20 1433 Occurrence Handle1313972 Occurrence Handle10.1093/nar/20.6.1433-a Occurrence Handle1:CAS:528:DyaK38XksVWltLk%3D

    Article  PubMed  CAS  Google Scholar 

  19. K Ishak A Baptista L Bianchi F Callea J De Groote F Gudat et al. (1995) ArticleTitleHistological grading and staging of chronic hepatitis J Hepatol 22 696–9 Occurrence Handle7560864 Occurrence Handle10.1016/0168-8278(95)80226-6 Occurrence Handle1:STN:280:BymD3srhsVE%3D

    Article  PubMed  CAS  Google Scholar 

  20. EG Erdos RA Skidgel (1987) ArticleTitleThe angiotensin I-converting enzyme Lab Invest 56 345–8 Occurrence Handle3031365 Occurrence Handle1:STN:280:BiiC2s7hsVc%3D

    PubMed  CAS  Google Scholar 

  21. B Rigat C Hubert F Alhenc-Gelas F Cambien P Corvol F Soubrier (1990) ArticleTitleAn insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels J Clin Invest 86 1343–6 Occurrence Handle1976655 Occurrence Handle1:CAS:528:DyaK3cXmt1Gmt7s%3D Occurrence Handle10.1172/JCI114844

    Article  PubMed  CAS  Google Scholar 

  22. L Tiret B Rigat S Visvikis C Breda P Corvol F Cambien et al. (1992) ArticleTitleEvidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels Am J Hum Genet 51 197–205 Occurrence Handle1319114 Occurrence Handle1:CAS:528:DyaK38Xlt1yksbw%3D

    PubMed  CAS  Google Scholar 

  23. AH Danser MA Schalekamp WA Bax AM van den Brink PR Saxena GA Riegger et al. (1995) ArticleTitleAngiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism Circulation 92 1387–8 Occurrence Handle7664416 Occurrence Handle1:CAS:528:DyaK2MXot1yitrw%3D

    PubMed  CAS  Google Scholar 

  24. L Tiret F Kee O Poirier V Nicaud L Lecerf A Evans et al. (1993) ArticleTitleDeletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction Lancet 341 991–2 Occurrence Handle8096947 Occurrence Handle10.1016/0140-6736(93)91075-W Occurrence Handle1:STN:280:ByyB38rmvF0%3D

    Article  PubMed  CAS  Google Scholar 

  25. DK Nagi CA Foy V Mohamed-Ali JS Yudkin PJ Grant WC Knowler (1998) ArticleTitleAngiotensin-1-converting enzyme (ACE) gene polymorphism, plasma ACE levels, and their association with the metabolic syndrome and electrocardiographic coronary artery disease in Pima Indians Metabolism 47 622–6 Occurrence Handle9591757 Occurrence Handle10.1016/S0026-0495(98)90250-5 Occurrence Handle1:CAS:528:DyaK1cXjtFertbs%3D

    Article  PubMed  CAS  Google Scholar 

  26. K Uemura J Nakura K Kohara T Miki (2000) ArticleTitleAssociation of ACE I/D polymorphism with cardiovascular risk factors Hum Genet 107 239–42 Occurrence Handle11071385 Occurrence Handle10.1007/s004390000358 Occurrence Handle1:CAS:528:DC%2BD3cXotFShs7k%3D

    Article  PubMed  CAS  Google Scholar 

  27. T Wilsgaard E Arnesen (2004) ArticleTitleChange in serum lipids and body mass index by age, sex, and smoking status: the Tromso study 1986–1995 Ann Epidemiol 14 265–73 Occurrence Handle15066606 Occurrence Handle10.1016/j.annepidem.2003.08.004

    Article  PubMed  Google Scholar 

  28. UP Neumann T Berg M Bahra D Seehofer JM Langrehr R Neuhaus et al. (2004) ArticleTitleFibrosis progression after liver transplantation in patients with recurrent hepatitis C J Hepatol 41 830–6 Occurrence Handle15519657 Occurrence Handle10.1016/j.jhep.2004.06.029 Occurrence Handle1:CAS:528:DC%2BD2cXptFKrsrY%3D

    Article  PubMed  CAS  Google Scholar 

  29. V Agnello G Abel M Elfahal GB Knight QX Zhang (1999) ArticleTitleHepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor Proc Natl Acad Sci U S A 96 12766–71 Occurrence Handle10535997 Occurrence Handle10.1073/pnas.96.22.12766 Occurrence Handle1:CAS:528:DyaK1MXnt1yqsbY%3D

    Article  PubMed  CAS  Google Scholar 

  30. M Monazahian I Bohme S Bonk A Koch C Scholz S Grethe et al. (1999) ArticleTitleLow density lipoprotein receptor as a candidate receptor for hepatitis C virus J Med Virol 57 223–9 Occurrence Handle10022791 Occurrence Handle10.1002/(SICI)1096-9071(199903)57:3<223::AID-JMV2>3.0.CO;2-4 Occurrence Handle1:CAS:528:DyaK1MXhtlShsLs%3D

    Article  PubMed  CAS  Google Scholar 

  31. S Yokohama M Yoneda M Haneda S Okamoto M Okada K Aso et al. (2004) ArticleTitleTherapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis Hepatology 40 1222–5 Occurrence Handle15382153 Occurrence Handle10.1002/hep.20420 Occurrence Handle1:CAS:528:DC%2BD2cXhtVCgt7jK

    Article  PubMed  CAS  Google Scholar 

  32. Y Terui T Saito H Watanabe H Togashi S Kawata Y Kamada et al. (2002) ArticleTitleEffect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C Hepatology 36 1022 Occurrence Handle12297856 Occurrence Handle10.1053/jhep.2002.32679

    Article  PubMed  Google Scholar 

  33. A Rimola MC Londono G Guevara M Bruguera M Navasa X Forns et al. (2004) ArticleTitleBeneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation Transplantation 78 686–91 Occurrence Handle15371669 Occurrence Handle10.1097/01.TP.0000128913.09774.CE Occurrence Handle1:CAS:528:DC%2BD2cXnsFGqsrY%3D

    Article  PubMed  CAS  Google Scholar 

  34. EH Forrest D Thorburn E Spence KA Oien G Inglis CA Smith et al. (2005) ArticleTitlePolymorphisms of the renin–angiotensin system and the severity of fibrosis in chronic hepatitis C virus infection J Viral Hepat 12 519–24 Occurrence Handle16108768 Occurrence Handle10.1111/j.1365-2893.2005.00630.x Occurrence Handle1:STN:280:DC%2BD2MvktlSmsA%3D%3D

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Medicine Experimental and Clinical, Internal Medicine, Medical Liver Transplant Unit, University of Udine, P. zale S.M. della Misericordia 1, 33100, Udine, Italy

    Carlo Fabris, Pierluigi Toniutto, Davide Bitetto & Ezio Fornasiere

  2. Department of Clinical and Experimental Medicine, University of Eastern Piedmont “A. Avogadro”, Novara, Italy

    Rosalba Minisini, Carlo Smirne & Mario Pirisi

Authors
  1. Carlo Fabris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierluigi Toniutto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Davide Bitetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rosalba Minisini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ezio Fornasiere
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlo Smirne
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mario Pirisi
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fabris, C., Toniutto, P., Bitetto, D. et al. Sex-related influence of angiotensin-converting enzyme polymorphisms on fibrosis progression due to recurrent hepatitis C after liver transplantation. J Gastroenterol 42, 543–549 (2007). https://doi.org/10.1007/s00535-007-2040-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-007-2040-1

Key words

Search

Navigation