Skip to main content

Advertisement

SpringerLink
Log in

Nonalcoholic Fatty Liver Disease: Key Considerations Before and After Liver Transplantation

  • Review
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in developed countries and is on trajectory to become the leading indication for liver transplantation in the USA and much of the world. Patients with NAFLD cirrhosis awaiting liver transplant face unique challenges and increased risk for waiting list stagnation and dropout due to burdensome comorbidities including obesity, diabetes, cardiovascular disease, and kidney disease. Thus far, patients transplanted for NAFLD cirrhosis have excellent mid- and long-term patient and graft survival, but concerns regarding short-term morbidity and mortality continue to exist. Post-liver transplantation, NAFLD occurs as both a recurrent and de novo manifestation, each with unique outcomes. NAFLD in the donor population is of concern given the growing demand for liver transplantation and mounting pressure to expand the donor pool. This review addresses key issues surrounding NAFLD as an indication for transplantation, including its increasing prevalence, unique patient demographics, outcomes related to liver transplantation, development of post-liver transplantation NAFLD, and NAFLD in the liver donor population. It also highlights exciting areas where further research is needed, such as the role of bariatric surgery and preconditioning of marginal donor grafts.

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

Fig. 1

Similar content being viewed by others

References

  1. Charlton M, Kasparova P, Weston S, et al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl. 2001;7:608–614.

    Article  CAS  PubMed  Google Scholar 

  2. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141:1249–1253.

    Article  PubMed  Google Scholar 

  3. Taniguchi M. Liver transplantation in the MELD era—analysis of the OPTN/UNOS registry. Clin Transpl. 2012:41–65.

  4. Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology (Baltimore, Md.). 2014;59:2188–2195.

    Article  Google Scholar 

  5. Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148:547–555.

    Article  PubMed  Google Scholar 

  6. Kemmer N, Neff GW, Franco E, et al. Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation. Transplantation. 2013;96:860–862.

    CAS  PubMed  Google Scholar 

  7. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology (Baltimore, Md.). 1999;29:664–669.

    Article  CAS  Google Scholar 

  8. Liou I, Kowdley KV. Natural history of nonalcoholic steatohepatitis. J Clin Gastroenterol. 2006;40:S11–S16.

    PubMed  Google Scholar 

  9. Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States. Liver Transpl. 2012;18:29–37.

    Article  PubMed  Google Scholar 

  10. Park CW, Tsai NT, Wong LL. Implications of worse renal dysfunction and medical comorbidities in patients with NASH undergoing liver transplant evaluation: impact on MELD and more. Clin Transpl. 2011;25:E606–E611.

    Article  Google Scholar 

  11. Vanwagner LB, Bhave M, Te HS, Feinglass J, Alvarez L, Rinella ME. Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events. Hepatology (Baltimore, Md.). 2012;56:1741–1750.

    Article  Google Scholar 

  12. LaMattina JC, Foley DP, Fernandez LA, et al. Complications associated with liver transplantation in the obese recipient. Clin Transpl. 2012;26:910–918.

    Article  Google Scholar 

  13. Hakeem AR, Cockbain AJ, Raza SS, et al. Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom. Liver Transpl. 2013;19:551–562.

    Article  PubMed  Google Scholar 

  14. Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology (Baltimore, Md.). 2002;35:105–109.

    Article  Google Scholar 

  15. Perez-Protto SE, Quintini C, Reynolds LF, et al. Comparable graft and patient survival in lean and obese liver transplant recipients. Liver Transpl. 2013;19:907–915.

    Article  PubMed  Google Scholar 

  16. Segev DL, Thompson RE, Locke JE, et al. Prolonged waiting times for liver transplantation in obese patients. Ann Surg. 2008;248:863–870.

    Article  PubMed  Google Scholar 

  17. Ayloo S, Armstrong J, Hurton S, Molinari M. Obesity and liver transplantation. World J Transpl. 2015;5:95–101.

    Article  Google Scholar 

  18. Hafeez S, Ahmed MH. Bariatric surgery as potential treatment for nonalcoholic fatty liver disease: a future treatment by choice or by chance? J Obes. 2013;2013:839275.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lazzati A, Iannelli A, Schneck AS, et al. Bariatric surgery and liver transplantation: a systematic review a new frontier for bariatric surgery. Obes Surg. 2015;25:134–142.

    Article  PubMed  Google Scholar 

  20. Lin MY, Tavakol MM, Sarin A, et al. Laparoscopic sleeve gastrectomy is safe and efficacious for pretransplant candidates. Surg Obes Relat Dis. 2013;9:653–658.

    Article  PubMed  Google Scholar 

  21. Lonardo A, Sookoian S, Pirola CJ, Targher G. Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism. 2015. doi:10.1016/j.metabol.2015.09.017.

    PubMed  Google Scholar 

  22. Patel S, Kiefer TL, Ahmed A, et al. Comparison of the frequency of coronary artery disease in alcohol-related versus non-alcohol-related endstage liver disease. Am J Cardiol. 2011;108:1552–1555.

    Article  PubMed  Google Scholar 

  23. Ripoll C, Yotti R, Bermejo J, Banares R. The heart in liver transplantation. J Hepatol. 2011;54:810–822.

    Article  PubMed  Google Scholar 

  24. Carey EJ, Aqel BA, Byrne TJ, et al. Pretransplant fasting glucose predicts new-onset diabetes after liver transplantation. J Transpl. 2012;2012:614781.

    Google Scholar 

  25. Park C, Hsu C, Neelakanta G, et al. Severe intraoperative hyperglycemia is independently associated with surgical site infection after liver transplantation. Transplantation. 2009;87:1031–1036.

    Article  PubMed  Google Scholar 

  26. Lai JC, Feng S, Terrault NA, Lizaola B, Hayssen H, Covinsky K. Frailty predicts waitlist mortality in liver transplant candidates. Am J Transpl. 2014;14:1870–1879.

    Article  CAS  Google Scholar 

  27. Athyros VG, Tziomalos K, Daskalopoulos GN, Karagiannis A, Mikhailidis DP. Statin-based treatment for cardiovascular risk and non-alcoholic fatty liver disease. Killing two birds with one stone? Ann Med. 2011;43:167–171.

    Article  CAS  PubMed  Google Scholar 

  28. Kwong AJ, Lai JC, Dodge JL, Roberts JP. Outcomes for liver transplant candidates listed with low model for end-stage liver disease score. Liver Transpl. 2015;21:1403–1409.

    Article  PubMed  Google Scholar 

  29. O’Leary JG, Landaverde C, Jennings L, Goldstein RM, Davis GL. Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants. Clin Gastroenterol Hepatol. 2011;9:700–704.e701.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wong RJ, Chou C, Bonham CA, Concepcion W, Esquivel CO, Ahmed A. Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data. Clin Transpl. 2014;28:713–721.

    Article  Google Scholar 

  31. Malik SM, deVera ME, Fontes P, Shaikh O, Ahmad J. Outcome after liver transplantation for NASH cirrhosis. Am J Transpl. 2009;9:782–793.

    Article  CAS  Google Scholar 

  32. Barritt AS, Dellon ES, Kozlowski T, Gerber DA, Hayashi PH. The influence of nonalcoholic fatty liver disease and its associated comorbidities on liver transplant outcomes. J Clin Gastroenterol. 2011;45:372–378.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Agopian VG, Kaldas FM, Hong JC, et al. Liver transplantation for nonalcoholic steatohepatitis: the new epidemic. Ann Surg. 2012;256:624–633.

    Article  PubMed  Google Scholar 

  34. Bhagat V, Mindikoglu AL, Nudo CG, Schiff ER, Tzakis A, Regev A. Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease. Liver Transpl. 2009;15:1814–1820.

    Article  PubMed  Google Scholar 

  35. Kennedy C, Redden D, Gray S, et al. Equivalent survival following liver transplantation in patients with non-alcoholic steatohepatitis compared with patients with other liver diseases. HPB. 2012;14:625–634.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wang X, Li J, Riaz DR, Shi G, Liu C, Dai Y. Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12:394–402.e391.

    Article  PubMed  Google Scholar 

  37. Musso G, Gambino R, Tabibian JH, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med. 2014;11:e1001680.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Houlihan DD, Armstrong MJ, Davidov Y, et al. Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: time to reconsider immunosuppression regimens? Liver Transpl. 2011;17:1292–1298.

    Article  PubMed  Google Scholar 

  39. Singal AK, Salameh H, Kuo YF, Wiesner RH. Evolving frequency and outcomes of simultaneous liver kidney transplants based on liver disease etiology. Transplantation. 2014;98:216–221.

    Article  CAS  PubMed  Google Scholar 

  40. Reddy SK, Steel JL, Chen HW, et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology (Baltimore, Md.). 2012;55:1809–1819.

    Article  Google Scholar 

  41. Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology (Baltimore, Md.). 2015;62:1723–1730.

    Article  CAS  Google Scholar 

  42. Therapondos G, Flapan AD, Plevris JN, Hayes PC. Cardiac morbidity and mortality related to orthotopic liver transplantation. Liver Transpl. 2004;10:1441–1453.

    Article  PubMed  Google Scholar 

  43. VanWagner LB, Lapin B, Skaro AI, Lloyd-Jones DM, et al. Impact of renal impairment on cardiovascular disease mortality after liver transplantation for nonalcoholic steatohepatitis cirrhosis. Liver Int. 2015;35:2575–2583.

    Article  CAS  PubMed  Google Scholar 

  44. Patil DT, Yerian LM. Evolution of nonalcoholic fatty liver disease recurrence after liver transplantation. Liver Transpl. 2012;18:1147–1153.

    Article  PubMed  Google Scholar 

  45. Burke A, Lucey MR. Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and orthotopic liver transplantation. Am J Transpl. 2004;4:686–693.

    Article  Google Scholar 

  46. Laish I, Braun M, Mor E, Sulkes J, Harif Y, Ben Ari Z. Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. Liver Transpl. 2011;17:15–22.

    Article  PubMed  Google Scholar 

  47. McAlister VC, Haddad E, Renouf E, Malthaner RA, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis. Am J Transpl. 2006;6:1578–1585.

    Article  CAS  Google Scholar 

  48. Dumortier J, Giostra E, Belbouab S, et al. Non-alcoholic fatty liver disease in liver transplant recipients: another story of “seed and soil”. Am J Gastroenterol. 2010;105:613–620.

    Article  PubMed  Google Scholar 

  49. Yalamanchili K, Saadeh S, Klintmalm GB, Jennings LW, Davis GL. Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease. Liver Transpl. 2010;16:431–439.

    PubMed  Google Scholar 

  50. Dureja P, Mellinger J, Agni R, et al. NAFLD recurrence in liver transplant recipients. Transplantation. 2011;91:684–689.

    Article  PubMed  Google Scholar 

  51. Contos MJ, Cales W, Sterling RK, et al. Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl. 2001;7:363–373.

    Article  CAS  PubMed  Google Scholar 

  52. Seo S, Maganti K, Khehra M, et al. De novo nonalcoholic fatty liver disease after liver transplantation. Liver Transpl. 2007;13:844–847.

    Article  PubMed  Google Scholar 

  53. Vallin M, Guillaud O, Boillot O, Hervieu V, Scoazec JY, Dumortier J. Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis. Liver Transpl. 2014;20:1064–1071.

    Article  PubMed  Google Scholar 

  54. Finkenstedt A, Auer C, Glodny B, et al. Patatin-like phospholipase domain-containing protein 3 rs738409-G in recipients of liver transplants is a risk factor for graft steatosis. Clin Gastroenterol Hepatol. 2013;11:1667–1672.

    Article  CAS  PubMed  Google Scholar 

  55. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology (Baltimore, Md.). 2010;51:121–129.

    Article  CAS  Google Scholar 

  56. McCormack L, Dutkowski P, El-Badry AM, Clavien PA. Liver transplantation using fatty livers: always feasible? J Hepatol. 2011;54:1055–1062.

    Article  PubMed  Google Scholar 

  57. Nocito A, El-Badry AM, Clavien PA. When is steatosis too much for transplantation? J Hepatol. 2006;45:494–499.

    Article  PubMed  Google Scholar 

  58. Durand F, Renz JF, Alkofer B, et al. Report of the Paris consensus meeting on expanded criteria donors in liver transplantation. Liver Transpl. 2008;14:1694–1707.

    Article  PubMed  Google Scholar 

  59. Perkins JD. Saying “yes” to obese living liver donors: short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation. Liver Transpl. 2006;12:1012–1013.

    Article  PubMed  Google Scholar 

  60. Selzner N, Selzner M, Jochum W, Amann-Vesti B, Graf R, Clavien PA. Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis. J Hepatol. 2006;44:694–701.

    Article  PubMed  Google Scholar 

  61. Spitzer AL, Lao OB, Dick AA, et al. The biopsied donor liver: incorporating macrosteatosis into high-risk donor assessment. Liver Transpl. 2010;16:874–884.

    Article  PubMed  Google Scholar 

  62. Zezos P, Renner EL. Liver transplantation and non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20:15532–15538.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ahn JS, Sinn DH, Gwak GY, et al. Steatosis among living liver donors without evidence of fatty liver on ultrasonography: potential implications for preoperative liver biopsy. Transplantation. 2013;95:1404–1409.

    Article  PubMed  Google Scholar 

  64. Nakamuta M, Morizono S, Soejima Y, et al. Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation. Transplantation. 2005;80:608–612.

    Article  CAS  PubMed  Google Scholar 

  65. Chu MJ, Vather R, Hickey AJ, Phillips AR, Bartlett AS. Impact of ischaemic preconditioning on experimental steatotic livers following hepatic ischaemia-reperfusion injury: a systematic review. HPB. 2015;17:1–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Clavien PA, Yadav S, Sindram D, Bentley RC. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg. 2000;232:155–162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gurusamy KS, Kumar Y, Sharma D, Davidson BR. Ischaemic preconditioning for liver transplantation. The Cochrane Database of Systematic Reviews. 2008:Cd006315.

  68. Franchello A, Gilbo N, David E, et al. Ischemic preconditioning (IP) of the liver as a safe and protective technique against ischemia/reperfusion injury (IRI). Am J Transpl. 2009;9:1629–1639.

    Article  CAS  Google Scholar 

  69. Degli Esposti D, Sebagh M, Pham P, et al. Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes. Cell Death Dis. 2011;2:e111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Beck-Schimmer B, Breitenstein S, Urech S, et al. A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Ann Surg. 2008;248:909–918.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Duke University Medical Center, 905 South LaSalle Street, DUMC 3256, GSRB1, Durham, NC, 27710, USA

    Yuval A. Patel, Carl L. Berg & Cynthia A. Moylan

  2. Division of Gastroenterology, Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC, 27705, USA

    Cynthia A. Moylan

Authors
  1. Yuval A. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carl L. Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cynthia A. Moylan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cynthia A. Moylan.

Ethics declarations

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, Y.A., Berg, C.L. & Moylan, C.A. Nonalcoholic Fatty Liver Disease: Key Considerations Before and After Liver Transplantation. Dig Dis Sci 61, 1406–1416 (2016). https://doi.org/10.1007/s10620-016-4035-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-016-4035-3

Keywords

Search

Navigation