Advertisement

Pre-transplant diabetes predicts atherosclerotic vascular events and cardiovascular mortality in liver transplant recipients: a long-term follow-up study

      Highlights

      • Liver transplant recipients show a high cardiovascular risk.
      • No validated guidelines are available for cardiovascular prevention.
      • Available studies display clear methodological limits.
      • The present study shows a very long follow-up period.
      • Pre-transplant diabetes is a strong predictor of cardiovascular events.

      Abstract

      Background Early after surgery, liver transplant (LT) recipients often develop weight gain. Metabolic disorders and cardiovascular disease represent main drivers of morbidity and mortality. Our aim was to identify predictors of atherosclerotic vascular events (AVE) and to assess the impact of AVE on the long-term outcome.
      Methods We retrospectively analyzed data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics. Cox Regression analysis was performed to identify predictors of AVE, global mortality, and cardiovascular mortality. Survival analysis was performed using the Kaplan-Meier method.
      Results We analyzed data from 367 subjects during a median follow-up of 14 years. Thirty-seven post-LT AVE were registered. Patients with AVE more frequently showed pre-LT diabetes mellitus (DM) (48.6 vs 13.9%, p=0.000). In the post-LT period, patients with AVE satisfied criteria of metabolic syndrome in 83.8% vs. 36.7% of subjects without AVE (p=0.000). At multivariate analysis, pre-LT DM independently predicted AVE (HR 2.250, CI 4.848-10.440, p=0.038). Moreover, both pre-LT DM and AVE strongly predicted cardiovascular mortality (HR 5.418, CI 1.060–29.183, p=0.049, and HR 86.097, CI 9.510–779.480, p=0.000, respectively).
      Conclusions Pre-LT DM is the main risk factor for post-LT AVE. Pre-LT DM and post-LT AVE are strong, long-term predictors of cardiovascular mortality. Patients with pre-LT DM should obtain a personalized follow-up for prevention or early diagnosis of AVE.

      Keywords

      Abbreviations:

      AVE (atherosclerotic vascular event), BMI (body mass index), CI (confidence interval), CNIs (calcineurin inhibitors), CSA (cyclosporine), CV (cardiovascular), DM (diabetes mellitus), EVE (everolimus), HCC (hepatocellular carcinoma), IR (insulin resistance), LT (liver transplant), mTOR (mammalian target of rapamycin), MELD (model for end-stage liver disease), MetS (metabolic syndrome), MMF (mycophenolate mofetile), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), SD (standard deviation), SIR (sirolimus), TAC (tacrolimus)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Jadlowiec C.C.
        • Taner T.
        Liver transplantation: current status and challenges.
        World J Gastroenterol. 2016; 22: 4438-4445https://doi.org/10.3748/wjg.v22.i18.4438
        • De Carvalho L.
        • Parise E.R.
        • Samuel D.
        Factors associated with nutritional status in liver transplant patients who survived the first year after transplantation.
        J Gastroenterol Hepatol. 2010; 25: 391-396
      1. Merli M., Giusto M., Riggio O., Gentili F., Molinaro A., Attili A.F., et al. Improvement of nutritional status in malnourished cirrhotic patients one year after liver transplantation. e-SPEN2011;6:e142-7.

        • Richardson R.A.
        • Garden O.J.
        • Davidson H.I.
        Reduction in energy expenditure after liver transplantation.
        Nutrition. 2001; 17: 585-589
        • Richards J.
        • Gunson B.
        • Johnson J.
        • Neuberger J.
        Weight gain and obesity after liver transplantation.
        Transpl Int. 2005; 18: 461-466
        • Jiménez-Pérez M.
        • González-Grande R.
        • Omonte Guzmán E.
        • Amo Trillo V.
        • Rodrigo López J.M.
        Metabolic complications in liver transplant recipients.
        World J Gastroenterol. 2016; 22: 6416-6423
        • Watt K.D.
        • Charlton M.R.
        Metabolic syndrome and liver transplantation: a review and guide to management.
        J Hepatol. 2010; 53: 199-206
        • Lucey M.R.
        • Terrault N.
        • Ojo L.
        • Hay J.E.
        • Neuberger J.
        • Blumberg E.
        • et al.
        Long term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
        Liver Transpl. 2013; 19: 3-26
        • Madhwal S.
        • Atreja A.
        • Albeldawi M.
        • Lopez R.
        • Post A.
        • Costa M.A.
        Is liver transplantation a risk factor for cardiovascular disease? A meta-analysis of observational studies.
        Liver Transpl. 2012; 18: 1140-1146
        • Desai S.
        • Hong J.C.
        • Saab S.
        Cardiovascular risk factors following orthotopic liver transplantation: predisposing factors, incidence and management.
        Liver Int. 2010; 30: 948-957
      2. U.S. Department of Health and Human Services. Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. 2012. https://optn.transplant.hrsa.gov/data/view-data-reports/annual-report/. Published June 2014].

        • Watt K.D.
        • Pedersen R.A.
        • Kremers W.K.
        • Heimbach J.K.
        • Sanchez W.
        • Gores G.J.
        Long-term probability of and mortality from de novo malignancy after liver transplantation.
        Gastroenterology. 2009; 137: 2010-2017
        • Martin P.
        • DiMartini A.
        • Feng S.
        • Brown Jr., R.
        • Fallon M.
        Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
        Hepatology. 2014; 59: 1144-1165
        • Konerman M.A.
        • Fritze D.
        • Weinberg R.L.
        • Sonnenday C.J.
        • Sharma P.
        Incidence of and risk assessment for adverse cardiovascular outcomes after liver transplantation: a systematic review.
        Transplantation. 2017; 101: 1645-1657https://doi.org/10.1097/TP.0000000000001710
        • Grundy S.M.
        • Cleeman J.I.
        • Daniels S.R.
        • Donato K.A.
        • Eckel R.H.
        • Franklin B.A.
        • et al.
        Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.
        Circulation. 2005; 112: 2735-2752
        • Dureja P.
        • Mellinger J.
        • Agni R.
        • Chang F.
        • Avey G.
        • Lucey M.
        • et al.
        NAFLD recurrence in liver transplant recipients.
        Transplantation. 2011; 91: 684-689
        • Stone N.J.
        • Robinson J.G.
        • Lichtenstein A.H.
        • Bairey Merz C.N.
        • Blum C.B.
        • et al.
        ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
        J Am Coll Cardiol. 2013; 63 (2014): 2889-2934
        • Rabkin J.M.
        • De La Melena V.
        • Orloff S.L.
        • Corless C.L.
        • Rosen H.R.
        • Olyaei A.J.
        Late mortality after orthotopic liver transplantation.
        Am J Surg. 2001; 18: 475-479
        • VanWagner L.B.
        • Serper M.
        • Kang R.
        • Levitsky J.
        • Hohmann S.
        • Abecassis M.
        • et al.
        Factors associated with major adverse cardiovascular events after liver transplantation among a national sample.
        Am J Transplant. 2016; 16: 2684-2694
        • Watt K.D.
        • Fan C.
        • Therneau T.
        • Heimbach J.K.
        • Seaberg E.C.
        • Charlton M.R.
        Serum adipokine and inflammatory markers before and after liver transplantation in recipients with major cardiovascular events.
        Liver Transpl. 2014; 20: 791-797
        • Weick A.
        • Chacra W.
        • Kuchipudi A.
        • Elbatta M.
        • Divine G.
        • Burmeister C.
        • et al.
        Incidence of cardiovascular and cerebrovascular events associated with sirolimus use after liver transplantation.
        Transplant Proc. 2015; 47: 460-464
        • Guckelberger O.
        • Mutzke F.
        • Glanemann M.
        • Neumann U.P.
        • Jonas S.
        • Neuhaus R.
        • et al.
        Validation of cardiovascular risk scores in a liver transplant population.
        Liver Transpl. 2006; 12: 394-401
        • Albeldawi M.
        • Aggarwal A.
        • Madhwal S.
        • Cywinski J.
        • Lopez R.
        • Eghtesad B.
        • et al.
        Cumulative risk of cardiovascular events after orthotopic liver transplantation.
        Liver Transpl. 2012; 18: 370-375
        • Kong Y.G.
        • Kang J.W.
        • Kim Y.K.
        • Seo H.
        • Lim T.H.
        • Hwang S.
        • et al.
        Preoperative coronary calcium score is predictive of early postoperative cardiovascular complications in liver transplant recipients.
        Br J Anaesth. 2015; 114: 437-443https://doi.org/10.1093/bja/aeu384
        • European Association for the Study of the Liver
        EASL clinical practice guidelines: liver transplantation.
        J Hepatol. 2016; 64: 433-485
        • Coss E.
        • Watt K.D.
        • Pedersen R.
        • Dierkhising R.
        • Heimbach J.K.
        • Charlton M.R.
        Predictors of cardiovascular events after liver transplantation: a role for pretransplant serum troponin levels.
        Liver Transpl. 2011; 17: 23-31
        • Aravinthan A.D.
        • Fateen W.
        • Doyle A.C.
        • Venkatachalapathy S.V.
        • Issachar A.
        • Galvin Z.
        • et al.
        The impact of preexisting and post-transplant diabetes mellitus on outcomes following liver transplantation.
        Transplantation. 2019; 103: 2523-2530
        • Fussner L.A.
        • Heimbach J.K.
        • Fan C.
        • Dierkhising R.
        • Coss E.
        • Leise M.D.
        • et al.
        Cardiovascular disease after liver transplantation: when, what, and who is at risk.
        Liver Transpl. 2015; 21: 889-896
        • Thoefner L.B.
        • Rostved A.A.
        • Pommergaard H.C.
        • Rasmussen A.
        Risk factors for metabolic syndrome after liver transplantation: a systematic review and meta analysis.
        Transplant Rev (Orlando). 2018; 32: 69-77https://doi.org/10.1016/j.trre.2017.03.004
        • Adinolfi L.E.
        • Petta S.
        • Fracanzani A.L.
        • Coppola C.
        • Narciso V.
        • Nevola R.
        • et al.
        Impact of hepatitis C virus clearance by direct-acting antiviral treatment on the incidence of major cardiovascular events: a prospective multicentre study.
        Atherosclerosis. 2020; 296: 40-47
        • Burra P.
        • Senzolo M.
        • Adam R.
        • Delvart V.
        • Karam V.
        • Germani G.
        • et al.
        Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry).
        Am J Transplant. 2010; 10: 138-148
        • Kodali S.
        • Kaif M.
        • Tariq R.
        • Singal A.K.
        Alcohol relapse after liver transplantation for alcoholic cirrhosis-impact on liver graft and patient survival: a meta-analysis.
        Alcohol Alcohol. 2018; 53: 166-172
        • McKenna G.J.
        • Trotter J.F.
        • Klintmalm E.
        • Ruiz R.
        • Onaca N.
        • Testa G.
        • et al.
        Sirolimus and cardiovascular disease risk in liver transplantation.
        Transplantation. 2013; 95: 215-221
        • Saliba F.
        • Fischer L.
        • de Simone P.
        • Bernhardt P.
        • Bader G.
        • Fung J.
        Association between renal dysfunction and major adverse cardiac events after liver transplantation: evidence from an international randomized trial of everolimus-based immunosuppression.
        Ann Transplant. 2018; 23: 751-757