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Metabolic mechanisms for and treatment of NAFLD or NASH occurring after liver transplantation

Abstract

The rising tide of non-alcoholic fatty liver disease (NAFLD) associated with the obesity epidemic is a major health concern worldwide. NAFLD — specifically its more advanced form, non-alcoholic steatohepatitis (NASH)-related cirrhosis — is now the fastest growing indication for liver transplantation in the USA and Europe. Although the short-term and mid-term overall survival rates of patients who receive a liver transplant for NASH-related cirrhosis are essentially similar to those of patients who receive a transplant for other liver indications, recipients with NASH-related cirrhosis have an increased risk of waiting-list mortality and of developing recurrent liver disease and cardiometabolic complications in the longer term after liver transplantation. This Review provides a brief overview of the epidemiology of NAFLD and NASH and the occurrence of NAFLD or NASH in patients after liver transplantation for NASH and other liver indications. It also discusses the putative metabolic mechanisms underlying the emergence of NAFLD or NASH after liver transplantation as well as optimal therapeutic approaches for recipients of liver transplants, including the management of cardiometabolic comorbidities, tailored immunosuppression, lifestyle changes and pharmacotherapy for NAFLD.

Key points

  • Non-alcoholic fatty liver disease (NAFLD) — specifically its more advanced form, non-alcoholic steatohepatitis (NASH)-related cirrhosis — is the fastest growing indication for liver transplantation in western countries.

  • After liver transplantation, recurrent and de novo NAFLD frequently occur.

  • Overall survival rates of patients who receive a liver transplant for NASH-related cirrhosis are similar to those of patients who receive a transplant for other liver-related disease indications.

  • However, patients who receive a liver transplant for NASH-related cirrhosis are at greater risk of developing recurrent NAFLD and cardiometabolic complications after liver transplantation than patients who receive a transplant for other liver-related disease indications.

  • The increased risk of cardiometabolic complications following transplantation is exacerbated by immunosuppressant treatment.

  • Lifestyle modification, management of immunosuppressant drugs and specific medical treatment of coexisting cardiometabolic complications are the cornerstone of treatment following liver transplantation.

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Fig. 1: Trends in liver transplantation and risk of occurrence of NAFLD and NASH after transplantation.
Fig. 2: Putative mechanisms implicated in the development of recurrent NAFLD or NASH in patients who have undergone transplantation for NASH-related cirrhosis.
Fig. 3: Putative mechanisms implicated in the development of de novo NAFLD or NASH in patients who have undergone transplantation for other causes of chronic liver disease (not NASH-related cirrhosis).
Fig. 4: Proposed therapeutic approach to patients with NAFLD after transplantation to reduce the risk of cardiovascular disease.

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Acknowledgements

C.D.B. is supported in part by grants from the Southampton National Institute for Health Research Biomedical Research Centre, and G.T. is supported in part by grants from the University School of Medicine of Verona, Verona, Italy, both outside of the submitted work.

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G.T., A.L., A.M., S.P. and C.D.B. researched data for the article, contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission. A.C. researched data for the article, contributed substantially to discussion of the content, and reviewed and/or edited the manuscript before submission.

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Lonardo, A., Mantovani, A., Petta, S. et al. Metabolic mechanisms for and treatment of NAFLD or NASH occurring after liver transplantation. Nat Rev Endocrinol 18, 638–650 (2022). https://doi.org/10.1038/s41574-022-00711-5

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