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.
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.
This is a preview of subscription content, access via your institution
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).
Mantovani, A. et al. Complications, morbidity and mortality of nonalcoholic fatty liver disease. Metabolism 111S, 154170 (2020).
Younossi, Z. M. et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64, 1577–1586 (2016).
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) & European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 64, 1388–1402 (2016).
Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of liver diseases. Hepatology 67, 328–357 (2018).
Younossi, Z. M. et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J. Hepatol. 71, 793–801 (2019).
Le, M. H. et al. 2019 global NAFLD prevalence: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2021.12.002 (2021).
Eslam, M. et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J. Hepatol. 73, 202–209 (2020).
Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 6, 903–913 (2021).
Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut 70, 962–969 (2021).
Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis. Gut 71, 156–162 (2020).
Mantovani, A. et al. Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies. Gut 71, 778–788 (2022).
Byrne, C. D. & Targher, G. NAFLD: a multisystem disease. J. Hepatol. 62, S47–S64 (2015).
Burra, P., Becchetti, C. & Germani, G. NAFLD and liver transplantation: disease burden, current management and future challenges. JHEP Rep. 2, 100192 (2020).
Wong, R. J. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 148, 547–555 (2015).
Shirazi, F., Wang, J. & Wong, R. J. Nonalcoholic steatohepatitis becomes the leading indication for liver transplant registrants among US adults born between 1945 and 1965. J. Clin. Exp. Hepatol. 10, 30–36 (2020).
Younossi, Z. et al. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin. Gastroenterol. Hepatol. 17, 748–755.e3 (2019).
Younossi, Z. M. et al. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States. Clin. Gastroenterol. Hepatol. 19, 580–589.e5 (2021).
Belli, L. S. et al. Impact of DAAs on liver transplantation: major effects on the evolution of indications and results. An ELITA study based on the ELTR registry. J. Hepatol. 69, 810–817 (2018).
Haldar, D. et al. Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European liver transplant registry study. J. Hepatol. 71, 313–322 (2019).
Holmer, M. et al. Nonalcoholic fatty liver disease is an increasing indication for liver transplantation in the Nordic countries. Liver Int. 38, 2082–2090 (2018).
Williams, R. et al. Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on liver disease in the UK. Lancet 391, 1097–1107 (2018).
Kern, B. et al. High incidence of hepatocellular carcinoma and postoperative complications in patients with nonalcoholic steatohepatitis as a primary indication for deceased liver transplantation. Eur. J. Gastroenterol. Hepatol. 31, 205–210 (2019).
Nagai, S. et al. Disease-specific waitlist outcomes in liver transplantation - a retrospective study. Transpl. Int. 34, 499–513 (2021).
Pais, R. et al. NAFLD and liver transplantation: current burden and expected challenges. J. Hepatol. 65, 1245–1257 (2016).
Wang, X. et al. Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 12, 394–402.e1 (2014).
Saeed, N. et al. Incidence and risks for nonalcoholic fatty liver disease and steatohepatitis post-liver transplant: systematic review and meta-analysis. Transplantation 103, e345–e354 (2019).
Vallin, M. et al. Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis. Liver Transpl. 20, 1064–1071 (2014).
Hejlova, I. et al. Prevalence and risk factors of steatosis after liver transplantation and patient outcomes. Liver Transpl. 22, 644–655 (2016).
Narayanan, P. et al. Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation. Transplantation 103, e14–e21 (2019).
Cotter, T. G. & Charlton, M. Nonalcoholic steatohepatitis after liver transplantation. Liver Transpl. 26, 141–159 (2020).
Tsochatzis, E. et al. International liver transplantation consensus statement on end-stage liver disease due to nonalcoholic steatohepatitis and liver transplantation. Transplantation 103, 45–56 (2019).
Seo, S. et al. De novo nonalcoholic fatty liver disease after liver transplantation. Liver Transpl. 13, 844–847 (2007).
Dumortier, J. et al. Non-alcoholic fatty liver disease in liver transplant recipients: another story of “seed and soil”. Am. J. Gastroenterol. 105, 613–620 (2010).
Gitto, S. et al. De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients. Eur. J. Gastroenterol. Hepatol. 30, 766–773 (2018).
Golabi, P. et al. Liver transplantation (LT) for cryptogenic cirrhosis (CC) and nonalcoholic steatohepatitis (NASH) cirrhosis: data from the scientific registry of transplant recipients (SRTR): 1994 to 2016. Medicine 97, e11518 (2018).
Finelli, C. & Tarantino, G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J. Gastroenterol. 19, 802–812 (2013).
Manne, V., Handa, P. & Kowdley, K. V. Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Clin. Liver Dis. 22, 23–37 (2018).
du Plessis, J. et al. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology 149, 635–648.e14 (2015).
du Plessis, J. et al. Pro-inflammatory cytokines but not endotoxin-related parameters associate with disease severity in patients with NAFLD. PLoS One 11, e0166048 (2016).
Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).
Lonardo, A. et al. A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue? Acta Diabetol. 56, 385–396 (2019).
Bedi, O., Aggarwal, S., Trehanpati, N., Ramakrishna, G. & Krishan, P. Molecular and pathological events involved in the pathogenesis of diabetes-associated nonalcoholic fatty liver disease. J. Clin. Exp. Hepatol. 9, 607–618 (2019).
Ertunc, M. E. & Hotamisligil, G. S. Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J. Lipid Res. 57, 2099–2114 (2016).
Marra, F. & Svegliati-Baroni, G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J. Hepatol. 68, 280–295 (2018).
Schwabe, R. F., Tabas, I. & Pajvani, U. B. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology 158, 1913–1928 (2020).
Richards, J., Gunson, B., Johnson, J. & Neuberger, J. Weight gain and obesity after liver transplantation. Transpl. Int. 18, 461–466 (2005).
Hong, H. C. et al. Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean sarcopenic obesity study. Hepatology 59, 1772–1778 (2014).
Bianchi, G., Marchesini, G., Marzocchi, R., Pinna, A. D. & Zoli, M. Metabolic syndrome in liver transplantation: relation to etiology and immunosuppression. Liver Transpl. 14, 1648–1654 (2008).
Heisel, O., Heisel, R., Balshaw, R. & Keown, P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am. J. Transpl. 4, 583–595 (2004).
Lieber, S. R. et al. The impact of post-transplant diabetes mellitus on liver transplant outcomes. Clin. Transpl. 33, e13554 (2019).
Charlton, M. et al. International liver transplantation society consensus statement on immunosuppression in liver transplant recipients. Transplantation 102, 727–743 (2018).
Pagadala, M., Dasarathy, S., Eghtesad, B. & McCullough, A. J. Posttransplant metabolic syndrome: an epidemic waiting to happen. Liver Transpl. 15, 1662–1670 (2009).
Germani, G. et al. Management of recurrent and de novo NAFLD/NASH after liver transplantation. Transplantation 103, 57–67 (2019).
Muduma, G., Saunders, R., Odeyemi, I. & Pollock, R. F. Systematic review and meta-analysis of tacrolimus versus ciclosporin as primary immunosuppression after liver transplant. PLoS One 11, e0160421 (2016).
Galvin, Z. et al. Predictors of de novo nonalcoholic fatty liver disease after liver transplantation and associated fibrosis. Liver Transpl. 25, 56–67 (2019).
Dureja, P. et al. NAFLD recurrence in liver transplant recipients. Transplantation 91, 684–689 (2011).
Brodosi, L., Petta, S., Petroni, M. L., Marchesini, G. & Morelli, M. C. Management of diabetes in candidates for liver transplantation and in transplant recipients. Transplantation 106, 462–478 (2022).
Derfler, K. et al. Decreased postheparin lipolytic activity in renal transplant recipients with cyclosporin A. Kidney Int. 40, 720–727 (1991).
Zhang, C. et al. The circFASN/miR-33a pathway participates in tacrolimus-induced dysregulation of hepatic triglyceride homeostasis. Signal. Transduct. Target. Ther. 5, 23 (2020).
Mizuta, K. et al. Influence of tacrolimus on bile acid and lipid composition in continuously drained bile using a rat model. Comparative study with cyclosporine. Transpl. Int. 12, 316–322 (1999).
Ventura-Aguiar, P., Campistol, J. M. & Diekmann, F. Safety of mTOR inhibitors in adult solid organ transplantation. Expert. Opin. Drug Saf. 15, 303–319 (2016).
Zimmermann, A. et al. Changes in lipid and carbohydrate metabolism under mTOR- and calcineurin-based immunosuppressive regimen in adult patients after liver transplantation. Eur. J. Intern. Med. 29, 104–109 (2016).
Bhat, M., Sonenberg, N. & Gores, G. J. The mTOR pathway in hepatic malignancies. Hepatology 58, 810–818 (2013).
Syed, N. A. & Khandelwal, R. L. Reciprocal regulation of glycogen phosphorylase and glycogen synthase by insulin involving phosphatidylinositol-3 kinase and protein phosphatase-1 in HepG2 cells. Mol. Cell Biochem. 211, 123–136 (2000).
Bussiere, C. T., Lakey, J. R., Shapiro, A. M. & Korbutt, G. S. The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia 49, 2341–2349 (2006).
Hao, L., Chan, S. M. & Lafferty, K. J. Mycophenolate mofetil can prevent the development of diabetes in BB rats. Ann. N. Y. Acad. Sci. 696, 328–332 (1993).
Lombardi, R., Iuculano, F., Pallini, G., Fargion, S. & Fracanzani, A. L. Nutrients, genetic factors, and their interaction in non-alcoholic fatty liver disease and cardiovascular disease. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21228761 (2020).
Roske, A. E. & Plauth, M. Liver transplantation, body composition, and substrate utilization: does organ transplantation normalize the metabolic situation of the patient? Nutrition 15, 504–505 (1999).
Jensen, M. D. et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the obesity society. J. Am. Coll. Cardiol. 63, 2985–3023 (2014).
Ou, H., Fu, Y., Liao, W., Zheng, C. & Wu, X. Association between smoking and liver fibrosis among patients with nonalcoholic fatty liver disease. Can. J. Gastroenterol. Hepatol. 2019, 6028952 (2019).
Li, Y., Liu, L., Wang, B., Wang, J. & Chen, D. Hematocrit is associated with fibrosis in patients with nonalcoholic steatohepatitis. Eur. J. Gastroenterol. Hepatol. 26, 332–338 (2014).
Dev, A., Patel, K., Conrad, A., Blatt, L. M. & McHutchison, J. G. Relationship of smoking and fibrosis in patients with chronic hepatitis C. Clin. Gastroenterol. Hepatol. 4, 797–801 (2006).
Trepo, E. & Valenti, L. Update on NAFLD genetics: from new variants to the clinic. J. Hepatol. 72, 1196–1209 (2020).
Finkenstedt, A. 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. 11, 1667–1672 (2013).
Kim, H. et al. Effect of PNPLA3 I148M polymorphism on histologically proven non-alcoholic fatty liver disease in liver transplant recipients. Hepatol. Res. 48, E162–E171 (2018).
Mikova, I. et al. Donor PNPLA3 and TM6SF2 variant alleles confer additive risks for graft steatosis after liver transplantation. Transplantation 104, 526–534 (2020).
Satapathy, S. K. et al. Clinical and genetic risk factors of recurrent nonalcoholic fatty liver disease after liver transplantation. Clin. Transl. Gastroenterol. 12, e00302 (2021).
Liu, Z. T. et al. PNPLA3 I148M variant affects non-alcoholic fatty liver disease in liver transplant recipients. World J. Gastroenterol. 21, 10054–10056 (2015).
John, B. V. et al. Recipient but not donor adiponectin polymorphisms are associated with early posttransplant hepatic steatosis in patients transplanted for non-nonalcoholic fatty liver disease indications. Exp. Clin. Transpl. 16, 439–445 (2018).
Stender, S. et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat. Genet. 49, 842–847 (2017).
Pennisi, G. et al. PNPLA3 rs738409 C>G variant predicts fibrosis progression by noninvasive tools in nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 19, 1979–1981 (2021).
Grimaudo, S. et al. Association between PNPLA3 rs738409 C>G variant and liver-related outcomes in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 18, 935–944.e3 (2020).
Dunn, W. et al. Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C. Hepatology 59, 453–460 (2014).
do O, N. T. et al. The common I148 M variant of PNPLA3 does not predict fibrosis progression after liver transplantation for hepatitis C. Hepatology 54, 1483–1484 (2011).
Liu, C. H. et al. miRNAs in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. J. Hepatol. 69, 1335–1348 (2018).
Mas, V. R., Bardhi, E. & Berenguer, M. Circulating microRNAs: dynamic markers of liver transplant injury. Transplantation 106, 705–706 (2022).
Erhartova, D. et al. Serum miR-33a is associated with steatosis and inflammation in patients with non-alcoholic fatty liver disease after liver transplantation. PLoS One 14, e0224820 (2019).
Najafi-Shoushtari, S. H. et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328, 1566–1569 (2010).
Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).
Gan, L., Chitturi, S. & Farrell, G. C. Mechanisms and implications of age-related changes in the liver: nonalcoholic fatty liver disease in the elderly. Curr. Gerontol. Geriatr. Res. 2011, 831536 (2011).
Ebmeier, K. P. et al. Clinical features predicting dementia in idiopathic Parkinson’s disease: a follow-up study. Neurology 40, 1222–1224 (1990).
DiStefano, J. K. NAFLD and NASH in postmenopausal women: implications for diagnosis and treatment. Endocrinology https://doi.org/10.1210/endocr/bqaa134 (2020).
Balakrishnan, M. et al. Women have a lower risk of nonalcoholic fatty liver disease but a higher risk of progression vs men: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 19, 61–71.e15 (2021).
Lonardo, A. et al. Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps. Hepatology 70, 1457–1469 (2019).
Goossens, G. H., Jocken, J. W. E. & Blaak, E. E. Sexual dimorphism in cardiometabolic health: the role of adipose tissue, muscle and liver. Nat. Rev. Endocrinol. 17, 47–66 (2021).
Burra, P. et al. Clinical impact of sexual dimorphism in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Liver Int. 41, 1713–1733 (2021).
Sarkar, M., Watt, K. D., Terrault, N. & Berenguer, M. Outcomes in liver transplantation: does sex matter? J. Hepatol. 62, 946–955 (2015).
Mouzaki, M. et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58, 120–127 (2013).
Grabherr, F., Grander, C., Effenberger, M., Adolph, T. E. & Tilg, H. Gut dysfunction and non-alcoholic fatty liver disease. Front. Endocrinol. 10, 611 (2019).
Brandl, K. & Schnabl, B. Intestinal microbiota and nonalcoholic steatohepatitis. Curr. Opin. Gastroenterol. 33, 128–133 (2017).
Nighot, M. et al. Lipopolysaccharide-induced increase in intestinal permeability is mediated by TAK-1 activation of IKK and MLCK/MYLK gene. Am. J. Pathol. 189, 797–812 (2019).
Gabarre, P. et al. Immunosuppressive therapy after solid organ transplantation and the gut microbiota: bidirectional interactions with clinical consequences. Am. J. Transpl. 22, 1014–1030 (2022).
Kim, H. K. & Kim, C. H. Quality matters as much as quantity of skeletal muscle: clinical implications of myosteatosis in cardiometabolic health. Endocrinol. Metab. 36, 1161–1174 (2021).
Armandi, A., Rosso, C., Caviglia, G. P., Ribaldone, D. G. & Bugianesi, E. The impact of dysmetabolic sarcopenia among insulin sensitive tissues: a narrative review. Front. Endocrinol. 12, 716533 (2021).
Camporez, J. P. et al. Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc. Natl Acad. Sci. USA 113, 2212–2217 (2016).
Delogu, W. et al. Myostatin regulates the fibrogenic phenotype of hepatic stellate cells via c-jun N-terminal kinase activation. Dig. Liver Dis. 51, 1400–1408 (2019).
Bot, D. et al. Both muscle quantity and quality are predictors of waiting list mortality in patients with end-stage liver disease. Clin. Nutr. ESPEN 42, 272–279 (2021).
van Vugt, J. L. A. et al. A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: a competing risk analysis in a national cohort. J. Hepatol. 68, 707–714 (2018).
van Vugt, J. L. et al. Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation. Am. J. Transpl. 16, 2277–2292 (2016).
Nachit, M. & Leclercq, I. A. Emerging awareness on the importance of skeletal muscle in liver diseases: time to dig deeper into mechanisms! Clin. Sci. 133, 465–481 (2019).
Nachit, M. et al. Muscle fat content is strongly associated with NASH: a longitudinal study in patients with morbid obesity. J. Hepatol. 75, 292–301 (2021).
Kim, H. et al. Histologically proven non-alcoholic fatty liver disease and clinically related factors in recipients after liver transplantation. Clin. Transpl. 28, 521–529 (2014).
Miyaaki, H. et al. Risk factors and clinical course for liver steatosis or nonalcoholic steatohepatitis after living donor liver transplantation. Transplantation 103, 109–112 (2019).
Posner, A. D. et al. Resolution of donor non-alcoholic fatty liver disease following liver transplantation. Clin. Transpl. https://doi.org/10.1111/ctr.13032 (2017).
Finer, N. Weight loss interventions and nonalcoholic fatty liver disease: optimizing liver outcomes. Diabetes Obes. Metab. 24 (Suppl. 2), 44–54 (2022).
Koutoukidis, D. A. et al. The effect of the magnitude of weight loss on non-alcoholic fatty liver disease: a systematic review and meta-analysis. Metabolism 115, 154455 (2021).
Berzigotti, A., Saran, U. & Dufour, J. F. Physical activity and liver diseases. Hepatology 63, 1026–1040 (2016).
Babu, A. F. et al. Positive effects of exercise intervention without weight loss and dietary changes in NAFLD-related clinical parameters: a systematic review and meta-analysis. Nutrients https://doi.org/10.3390/nu13093135 (2021).
Houttu, V., Csader, S., Nieuwdorp, M., Holleboom, A. G. & Schwab, U. Dietary interventions in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. Front. Nutr. 8, 716783 (2021).
Mosca, A. et al. Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents. J. Hepatol. 66, 1031–1036 (2017).
Guasch-Ferré, M. & Willett, W. C. The Mediterranean diet and health: a comprehensive overview. J. Intern. Med. 290, 549–566 (2021).
Yki-Järvinen, H., Luukkonen, P. K., Hodson, L. & Moore, J. B. Dietary carbohydrates and fats in nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 18, 770–786 (2021).
Anastacio, L. R. & Davisson Correia, M. I. Nutrition therapy: integral part of liver transplant care. World J. Gastroenterol. 22, 1513–1522 (2016).
Hammad, A., Kaido, T., Aliyev, V., Mandato, C. & Uemoto, S. Nutritional therapy in liver transplantation. Nutrients https://doi.org/10.3390/nu9101126 (2017).
Lassailly, G. et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology 159, 1290–1301.e5 (2020).
Aminian, A. et al. Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis. JAMA 326, 2031–2042 (2021).
de Brito, E. S. M. B. et al. Gastric bypass compared with sleeve gastrectomy for nonalcoholic fatty liver disease: a systematic review and meta-analysis. Obes. Surg. 31, 2762–2772 (2021).
Diwan, T. S., Rice, T. C., Heimbach, J. K. & Schauer, D. P. Liver transplantation and bariatric surgery: timing and outcomes. Liver Transpl. 24, 1280–1287 (2018).
Morris, M. C. et al. Delayed sleeve gastrectomy following liver transplantation: a 5-year experience. Liver Transpl. 25, 1673–1681 (2019).
Targher, G., Tilg, H. & Byrne, C. D. Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol. Hepatol. 6, 578–588 (2021).
Burra, P. et al. EASL clinical practice guidelines: liver transplantation. J. Hepatol. 64, 433–485 (2016).
Martin, P., DiMartini, A., Feng, S., Brown, R. Jr & 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 59, 1144–1165 (2014).
Barman, P. M. & VanWagner, L. B. Cardiac risk assessment in liver transplant candidates: current controversies and future directions. Hepatology 73, 2564–2576 (2021).
Xiao, J. et al. A meta-analysis and systematic review on the global prevalence, risk factors and outcomes of coronary artery disease in liver transplantation recipients. Liver Transpl. 28, 689–699 (2021).
Russo, M. W. The care of the postliver transplant patient. J. Clin. Gastroenterol. 51, 683–692 (2017).
Gonwa, T. A. et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation 72, 1934–1939 (2001).
Pruthi, J. et al. Analysis of causes of death in liver transplant recipients who survived more than 3 years. Liver Transpl. 7, 811–815 (2001).
Watt, K. D. Metabolic syndrome: is immunosuppression to blame? Liver Transpl. 17, S38–S42 (2011).
Bhat, M., Usmani, S. E., Azhie, A. & Woo, M. Metabolic consequences of solid organ transplantation. Endocr. Rev. 42, 171–197 (2021).
Toniutto, P. et al. An essential guide for managing post-liver transplant patients: what primary care physicians should know. Am. J. Med. 135, 157–166 (2021).
Watt, K. D. S. & Charlton, M. R. Metabolic syndrome and liver transplantation: a review and guide to management. J. Hepatol. 53, 199–206 (2010).
Franssen, R., Vergeer, M., Stroes, E. S. & Kastelein, J. J. Combination statin-fibrate therapy: safety aspects. Diabetes Obes. Metab. 11, 89–94 (2009).
Tarantino, N. et al. Fenofibrate/simvastatin fixed-dose combination in the treatment of mixed dyslipidemia: safety, efficacy, and place in therapy. Vasc. Health Risk Manag. 13, 29–41 (2017).
Neuberger, J. et al. Sport and exercise in improving outcomes after solid organ transplantation: overview from a UK meeting. Transplantation 103, S1–S11 (2019).
Charlton, M. et al. Everolimus is associated with less weight gain than tacrolimus 2 years after liver transplantation: results of a randomized multicenter study. Transplantation 101, 2873–2882 (2017).
Mantovani, A. et al. Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials. Metabolites https://doi.org/10.3390/metabo11020073 (2021).
Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).
Newsome, P. N. et al. A Placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N. Engl. J. Med. 384, 1113–1124 (2021).
Mantovani, A., Byrne, C. D. & Targher, G. Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review. Lancet Gastroenterol. Hepatol. 7, 367–378 (2022).
Brown, S. A., Izzy, M. & Watt, K. D. Pharmacotherapy for weight loss in cirrhosis and liver transplantation: translating the data and underused potential. Hepatology 73, 2051–2062 (2021).
Pelaez-Jaramillo, M. J., Cardenas-Mojica, A. A., Gaete, P. V. & Mendivil, C. O. Post-liver transplantation diabetes mellitus: a review of relevance and approach to treatment. Diabetes Ther. 9, 521–543 (2018).
Brown, E., Heerspink, H. J. L., Cuthbertson, D. J. & Wilding, J. P. H. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet 398, 262–276 (2021).
Mantovani, A., Petracca, G., Csermely, A., Beatrice, G. & Targher, G. Sodium-glucose cotransporter-2 inhibitors for treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Metabolites https://doi.org/10.3390/metabo11010022 (2020).
Guckelberger, O. Long-term medical comorbidities and their management: hypertension/cardiovascular disease. Liver Transplant. 15, S75–S78 (2009).
Mells, G. & Neuberger, J. Long-term care of the liver allograft recipient. Sem. Liver Dis. 29, 102–120 (2009).
Fussner, L. A. et al. Cardiovascular disease after liver transplantation: when, what, and who is at risk. Liver Transpl. 21, 889–896 (2015).
Goh, G. B. et al. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver Int. 35, 979–985 (2015).
Rodríguez-Perálvarez, M. et al. Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis. Am. J. Transpl. 12, 2797–2814 (2012).
Cullaro, G., Verna, E. C., Lee, B. P. & Lai, J. C. Chronic kidney disease in liver transplant candidates: a rising burden impacting post–liver transplant outcomes. Liver Transpl. 26, 498–506 (2020).
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.
The authors declare no competing interests.
Peer review information
Nature Reviews Endocrinology thanks Alfred Barritt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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