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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
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
M Berenguer (2002) ArticleTitleNatural history of recurrent hepatitis C Liver Transpl 8 S14–8 Occurrence Handle12362293 Occurrence Handle10.1053/jlts.2002.35781
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
EG Erdos RA Skidgel (1987) ArticleTitleThe angiotensin I-converting enzyme Lab Invest 56 345–8 Occurrence Handle3031365 Occurrence Handle1:STN:280:BiiC2s7hsVc%3D
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Author information
Authors and Affiliations
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00535-007-2040-1