Liver transplantation and nonalcoholic steatohepatitis: the state of the art

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents one of the most diffuse liver diseases worldwide. It is a condition ranging from liver steatosis to non-alcoholic steatohepatitis (NASH) and NASH-related cirrhosis. Recently, the term metabolic dysfunction-associated fatty liver disease has been proposed in place of NAFLD, accenting the metabolic and cardiovascular risks that accompany hepatic disease. In the last decades, NASH and NASH-related cirrhosis have been the fastest growing indications for liver transplantation (LT), and they will probably overcome the other indications in next future. After LT, recipients show an important increase in body weight due to a greater caloric intake, partially because of the metabolic influence of immunosuppressant drugs, favoring the development of diabetes mellitus, dyslipidemias, and arterial hypertension. These metabolic complications will, in turn, elevate cardiovascular risk in this population. In this review, we analyze the main metabolic challenges of both pre-and post-LT periods.

Keywords

Non-alcoholic steatohepatitis / liver transplantation / diabetes / metabolic syndrome / cardiovascular risk / graft survival

References

[1] Association for the Study of the Liver. Electronic address: [e-mail]. EASL clinical practice guidelines: liver transplantation.J Hepatol2016;64:433-85

[2] Philips CA,Abduljaleel JK,Augustine P.Critical updates on chronic hepatitis B virus infection in 2021.Cureus2021;13:e19152 PMCID:PMC8557099

[3] Yousafzai MT,Alavi M,Dore GJ.Global cascade of care for chronic hepatitis C virus infection: a systematic review and meta-analysis.J Viral Hepat2021;28:1340-54

[4] Burra P,Germani G.NAFLD and liver transplantation: disease burden, current management and future challenges.JHEP Rep2020;2:100192 PMCID:PMC7607500

[5] Younossi ZM,Abdelatif D,Henry L.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology2016;64:73-84

[6] Kim CH.Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome.Cleve Clin J Med2008;75:721-8

[7] Eslam M,Sarin SK.A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement.J Hepatol2020;73:202-9

[8] Singh S,Wang Z,Murad MH.Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.Clin Gastroenterol Hepatol2015;13:643-54.e1 PMCID:PMC4208976

[9] Younossi ZM,Afendy M.Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008.Clin Gastroenterol Hepatol2011;9:524-530.e1; quiz e60

[10] Cotter TG.Nonalcoholic steatohepatitis after liver transplantation.Liver Transpl2020;26:141-59

[11] Adam R,Cailliez V.all the other 126 contributing centers (wwweltr.org) and the European Liver and Intestine Transplant Association (ELITA). 2018 annual report of the European liver transplant registry (ELTR)-50-year evolution of liver transplantation.Transpl Int2018;31:1293-317

[12] Kolly P.Surveillance for hepatocellular carcinoma in patients with NASH.Diagnostics (Basel)2016;6:22 PMCID:PMC4931417

[13] Younossi Z,Ong JP.Global nonalcoholic steatohepatitis councilnonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.Clin Gastroenterol Hepatol2019;17:748-755.e3

[14] Haldar D,Hodson J.European Liver and Intestine Transplant Association (ELITA)Outcomes of liver transplantation for non-alcoholic steatohepatitis: a european liver transplant registry study.J Hepatol2019;71:313-22 PMCID:PMC6656693

[15] Wong RJ,Ahmed A.Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.Hepatology2014;59:2188-95

[16] Axley P,Arora S.NASH is the most rapidly growing etiology for acute-on-chronic liver failure-related hospitalization and disease burden in the united states: a population-based study.Liver Transpl2019;25:695-705

[17] Angulo P.Nonalcoholic fatty liver disease.N Engl J Med2002;346:1221-31

[18] Parikh ND,Wang J.Projected increase in obesity and non-alcoholic-steatohepatitis-related liver transplantation waitlist additions in the United States.Hepatology2019;70:487-95

[19] Watt KD,Kremers WK,Charlton MR.Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study.Am J Transplant2010;10:1420-7 PMCID:PMC2891375

[20] Ferreira SC,Cardoso ASR.Eating behaviour patterns are associated with excessive weight gain after liver transplantation.J Hum Nutr Diet2019;32:693-701

[21] Charco R,Vargas V.Serum cholesterol changes in long-term survivors of liver transplantation: a comparison between cyclosporine and tacrolimus therapy.Liver Transpl Surg1999;5:204-8

[22] Bhagat V,Nudo CG,Tzakis A.Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease.Liver Transpl2009;15:1814-20

[23] Nair S,Thuluvath PJ.Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States.Hepatology2002;35:105-9

[24] Leonard J,Malinchoc M,Charlton M.The impact of obesity on long-term outcomes in liver transplant recipients-results of the NIDDK liver transplant database.Am J Transplant2008;8:667-72

[25] Hakeem AR,Raza SS.Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom.Liver Transpl2013;19:551-62

[26] Singhal A,Wima K.Impact of recipient morbid obesity on outcomes after liver transplantation.Transpl Int2015;28:148-55

[27] Segev DL,Locke JE.Prolonged waiting times for liver transplantation in obese patients.Ann Surg2008;248:863-70

[28] Conzen KD,Collins KM.Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis.HPB (Oxford)2015;17:251-7 PMCID:PMC4333787

[29] Tsochatzis E,Nadalin S.International liver transplantation consensus statement on end-stage liver disease due to nonalcoholic steatohepatitis and liver transplantation.Transplantation2019;103:45-56

[30] van Son J,Gomes-Neto AW.Post-transplant obesity impacts long-term survival after liver transplantation.Metabolism2020;106:154204

[31] Beckmann S,Ruppar T,De Geest S.Body weight parameters are related to morbidity and mortality after liver transplantation: a systematic review and meta-analysis.Transplantation2019;103:2287-303

[32] Dare AJ,Phillips AR.Additive effect of pretransplant obesity, diabetes, and cardiovascular risk factors on outcomes after liver transplantation.Liver Transpl2014;20:281-90

[33] Lieber SR,Jiang Y.The impact of post-transplant diabetes mellitus on liver transplant outcomes.Clin Transplant2019;33:e13554 PMCID:PMC6995642

[34] Barone M,Losurdo G,Leandro G.Systematic review with meta-analysis: post-operative complications and mortality risk in liver transplant candidates with obesity.Aliment Pharmacol Ther2017;46:236-45

[35] Wong RJ,Cheung R.Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.Gastroenterology2015;148:547-55

[36] O’Leary JG,Jennings L,Davis GL.Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants.Clin Gastroenterol Hepatol2011;9:700-704.e1 PMCID:PMC4408909

[37] Trail KC,Larsen JL.Results of liver transplantation in diabetic recipients.Surgery1993;114:650-6; discussion 656

[38] Gitto S,Marzi L.other members of MEDITRA research groupPre-transplant diabetes predicts atherosclerotic vascular events and cardiovascular mortality in liver transplant recipients: a long-term follow-up study.Eur J Intern Med2020;79:70-5

[39] Eshraghian A,Kazemi K.Portal vein thrombosis in patients with liver cirrhosis and its impact on early and long-term outcomes after liver transplantation.Int J Clin Pract2018;e13309

[40] Molinari M,Tsung A.Prediction of perioperative mortality of cadaveric liver transplant recipients during their evaluations.Transplantation2019;103:e297-307 PMCID:PMC6756253

[41] Saliba F,Pageaux GP.Diapason Study GroupRisk factors for new-onset diabetes mellitus following liver transplantation and impact of hepatitis C infection : an observational multicenter study.Liver Transpl2007;13:136-44

[42] Kuo HT,Ye X,Martin P.Risk factors for new-onset diabetes mellitus in adult liver transplant recipients, an analysis of the organ procurement and transplant network/united network for organ sharing database.Transplantation2010;89:1134-40

[43] Park CW,Wong LL.Implications of worse renal dysfunction and medical comorbidities in patients with NASH undergoing liver transplant evaluation: impact on MELD and more.Clin Transplant2011;25:E606-11

[44] Targher G,Byrne CD.CKD and nonalcoholic fatty liver disease.Am J Kidney Dis2014;64:638-52

[45] Musso G,Tabibian JH.Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.PLoS Med2014;11:e1001680 PMCID:PMC4106719

[46] Chinnadurai R,Kalra PA.Increased risk for cardiovascular events in patients with diabetic kidney disease and non-alcoholic fatty liver disease.Nephron2019;141:24-30

[47] Paik J,Younoszai Z,Trimble G.Chronic kidney disease is independently associated with increased mortality in patients with nonalcoholic fatty liver disease.Liver Int2019;39:342-52

[48] Fussner LA,Heimbach JK.The impact of gender and NASH on chronic kidney disease before and after liver transplantation.Liver Int2014;34:1259-66

[49] Ramachandran J,John L.Chronic kidney disease following liver transplantation: a South Australian experience.Transplant Proc2010;42:3644-6

[50] VanWagner LB,Skaro AI,Rinella ME.Impact of renal impairment on cardiovascular disease mortality after liver transplantation for nonalcoholic steatohepatitis cirrhosis.Liver Int2015;35:2575-83 PMCID:PMC5204362

[51] Agopian VG,Hong JC.Liver transplantation for nonalcoholic steatohepatitis: the new epidemic.Ann Surg2012;256:624-33

[52] Molnar MZ,Jiang Y.Global NAFLD ConsortiumAssociation of pretransplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.Liver Transpl2019;25:399-410 PMCID:PMC6709989

[53] Houlihan DD,Davidov Y.Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: time to reconsider immunosuppression regimens?.Liver Transpl2011;17:1292-8

[54] Sharma S,Verbeek T.Management of patients with non-alcoholic steatohepatitis undergoing liver transplantation: considerations for the anesthesiologist.J Cardiothorac Vasc Anesth2021:S1053-0770(21)00601

[55] Malik SM,Fontes P,Ahmad J.Outcome after liver transplantation for NASH cirrhosis.Am J Transplant2009;9:782-93

[56] Pastori D,Perri L.Relation of nonalcoholic fatty liver disease and Framingham Risk Score to flow-mediated dilation in patients with cardiometabolic risk factors.Am J Cardiol2015;115:1402-6

[57] Kim BJ,Kim BS.The association between nonalcoholic fatty liver disease, metabolic syndrome and arterial stiffness in nondiabetic, nonhypertensive individuals.Cardiology2012;123:54-61

[58] Patel SS,Guzman L.Coronary artery disease in decompensated patients undergoing liver transplantation evaluation.Liver Transpl2018;24:333-42

[59] van Kuijk JP,Schouten O.Timing of noncardiac surgery after coronary artery stenting with bare metal or drug-eluting stents. Am J Cardiol 2009;104:1229-34.

[60] Liu H,Traboulsi M.Cirrhotic cardiomyopathy: Implications for liver transplantation.Liver Transpl2017;23:826-35

[61] Laryea M,Molinari M.Metabolic syndrome in liver transplant recipients: prevalence and association with major vascular events.Liver Transpl2007;13:1109-14

[62] Rubín A,Aguilera V.Long-term outcome of “long-term liver transplant survivors”.Transpl Int2013;26:740-50

[63] Stepanova M.Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.Clin Gastroenterol Hepatol2012;10:646-50

[64] Lu H,Hu F,Luo S.Independent association between nonalcoholic fatty liver disease and cardiovascular disease: a systematic review and meta-analysis.Int J Endocrinol2013;2013:124958 PMCID:PMC3639649

[65] Wang X,Riaz DR,Liu C.Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis.Clin Gastroenterol Hepatol2014;12:394-402.e1

[66] Nagai S,Chau LC.Increased risk of death in first year after liver transplantation among patients with nonalcoholic steatohepatitis vs liver disease of other etiologies.Clin Gastroenterol Hepatol2019;17:2759-2768.e5

[67] Fussner LA,Fan C.Cardiovascular disease after liver transplantation: when, what, and who is at risk.Liver Transpl2015;21:889-96

[68] Sprinzl MF,Lohse N.Metabolic syndrome and its association with fatty liver disease after orthotopic liver transplantation.Transpl Int2013;26:67-74

[69] Sgourakis G.Corticosteroid-free immunosuppression in liver transplantation: an evidence-based review.World J Gastroenterol2014;20:10703-14 PMCID:PMC4138451

[70] Gilad O,Levy S.Metabolic and renal effects of mammalian target of rapamycin inhibitors treatment after liver transplantation: real-life single-center experience.Transplant Proc2021;53:221-7

[71] Bianchi G,Marzocchi R,Zoli M.Metabolic syndrome in liver transplantation: relation to etiology and immunosuppression.Liver Transpl2008;14:1648-54

[72] O’grady J,Hardy P,Truesdale A.Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial.The Lancet2002;360:1119-25

[73] Hüsing A,Schmidt HH.Lipids in liver transplant recipients.World J Gastroenterol2016;22:3315-24 PMCID:PMC4806189

[74] Losurdo G,Rendina M,Leandro G.Systematic review with meta-analysis: de novo non-alcoholic fatty liver disease in liver-transplanted patients.Aliment Pharmacol Ther2018;47:704-14

[75] Burra P.Orthotopic liver transplantation in non-alcoholic fatty liver disease patients.Rev Recent Clin Trials2014;9:210-6

[76] Tokodai K,Kjaernet F,Ericzon BG.Characteristics and risk factors for recurrence of nonalcoholic steatohepatitis following liver transplantation.Scand J Gastroenterol2019;54:233-9

[77] Ong J,Reddy V.Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease.Liver Transpl2001;7:797-801

[78] El Atrache MM,Divine G.Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome.Clin Transplant2012;26:E505-12

[79] Dumortier J,Belbouab S.Non-alcoholic fatty liver disease in liver transplant recipients: another story of “seed and soil”.Am J Gastroenterol2010;105:613-20

[80] Burke A.Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and orthotopic liver transplantation.Am J Transplant2004;4:686-93

[81] Hübscher SG.Transplantation pathology.Semin Liver Dis2009;29:74-90

[82] Yalamanchili K,Klintmalm GB,Davis GL.Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease.Liver Transpl2010;16:431-9

[83] Vallin M,Boillot O,Scoazec JY.Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis.Liver Transpl2014;20:1064-71

[84] Narayanan P,Izzy M.Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation.Transplantation2019;103:e14-21

[85] Moura Neto A,Righetto CM.Clinical profile of patients with diabetes mellitus and liver transplantation: results after a multidisciplinary team intervention.Transplant Proc2018;50:784-7