Challenges in the management of MetALD after liver transplantation

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are among the leading indications for liver transplantation (LT). The definition of metabolic dysfunction- and alcohol-associated liver disease (MetALD) identifies individuals with MASLD who consume moderate levels of alcohol, representing a severe phenotype within the steatotic liver disease (SLD) spectrum. Patients with MetALD face higher risks of post-LT complications, including metabolic syndrome, graft steatosis, and fibrosis. Despite the rising prevalence of MetALD due to increasing obesity and alcohol consumption, data on its recurrence or de novo development post-LT remain limited. The management of MetALD post-LT is particularly challenging due to the interplay of metabolic factors and potential alcohol relapse. Current evidence suggests that recurrent or de novo MetALD often progresses more rapidly to advanced fibrosis than in native livers, underscoring the importance of early detection and management. Integrated approaches addressing both metabolic syndrome and alcohol-related risks are essential for optimal management. Non-invasive diagnostic modalities, such as transient elastography and specific biomarkers like phosphatidylethanol (Peth), are promising in assessing graft health and alcohol relapse, respectively. Emerging therapies, including glucagon-like peptide-1 receptor agonists (GLP1-RAs) and fibroblast growth factor-21 (FGF21) analogs, offer potential dual-action benefits targeting metabolic dysfunction and alcohol consumption. These innovations, coupled with lifestyle interventions and tailored immunosuppressive regimens, may improve patient outcomes and reduce graft failure. This review highlights the need for multidisciplinary strategies and further research to optimize the management of MetALD post-LT, aiming to improve survival and quality of life in this high-risk population.

Keywords

MASLD / ALD / liver transplantation / immunosuppression

References

[1] Wong RJ.Trends in liver disease etiology among adults awaiting liver transplantation in the United States, 2014-2019.JAMA Netw Open2020;3:e1920294

[2] Younossi ZM,Al Shabeeb R.The changing epidemiology of adult liver transplantation in the United States in 2013-2022: the dominance of metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease.Hepatol Commun2024;8:e0352 PMCID:PMC10749707

[3] 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 on the management of metabolic dysfunction-associated steatotic liver disease (MASLD).J Hepatol2024;81:492-542

[4] Ochoa-Allemant P,Wang RX.Waitlisting and liver transplantation for MetALD in the United States: an analysis of the UNOS national registry.Hepatology2025;81:532-45

[5] Vanlerberghe BTK,Sainz-Bariga M.Utility and prognostic value of diagnosing MAFLD in patients undergoing liver transplantation for alcohol-related liver disease.Clin Transplant2023;37:e14965

[6] Erard D,Chouik Y.Dual alcohol and metabolic-related liver disease: results from a population of liver transplant patients.Liver Int2024;44:422-32

[7] Thoefner LB,Pommergaard HC.Risk factors for metabolic syndrome after liver transplantation: a systematic review and meta-analysis.Transplant Rev2018;32:69-77

[8] Paik JM,Younossi Y,Younossi ZM.Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD.Hepatology2020;72:1605-16

[9] 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

[10] 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

[11] Jatana S,Verhoeff K.Liver allograft cirrhosis, retransplant, and mortality secondary to recurrent disease after transplant for MASH: a systematic review and meta-analysis.Transplantation2024;Epub ahead of print:

[12] Sourianarayanane A,McCullough AJ.Nonalcoholic steatohepatitis recurrence and rate of fibrosis progression following liver transplantation.Eur J Gastroenterol Hepatol2017;29:481-7

[13] 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

[14] Lim WH,Tan DJH.Donor diabetes and steatosis affects recipient survival following liver transplantation based on etiology of liver cirrhosis.Transplantation2024;108:473-82

[15] Gitto S,De Maria N.Nonalcoholic steatohepatitis before and after liver transplant: keeping up with the times.Expert Rev Gastroenterol Hepatol2019;13:173-8

[16] Becchetti C,Zeni N.A prospective longitudinal assessment of de novo metabolic syndrome after liver transplantation.Clin Transplant2022;36:e14532

[17] Charlton M,Aqel B.International liver transplantation society consensus statement on immunosuppression in liver transplant recipients.Transplantation2018;102:727-43

[18] Siddiqui MS,Satapathy SK.Defining an approach for therapeutic strategies in metabolic dysfunction-associated steatotic liver disease after liver transplantation.Hepatology2023;Epub ahead of print:

[19] Kim H,Lee K.Effect of PNPLA3 I148M polymorphism on histologically proven non-alcoholic fatty liver disease in liver transplant recipients.Hepatol Res2018;48:E162-71

[20] Finkenstedt A,Glodny B.Patatin-like phospholipase domain-containing protein 3 rs738409-G in recipients of liver transplants is a risk factor for graft steatosis.Clin Gastroenterol Hepatol2013;11:1667-72

[21] Trunečka P,Dlouhá D.Donor PNPLA3 rs738409 genotype is a risk factor for graft steatosis. A post-transplant biopsy-based study.Dig Liver Dis2018;50:490-5

[22] Villeret F,Erard D.Liver transplantation for NAFLD cirrhosis: age and recent coronary angioplasty are major determinants of survival.Liver Int2022;42:2428-41 PMCID:PMC9804523

[23] Van Herck J,van Malenstein H.Liver-related and cardiovascular outcome of patients transplanted for nonalcoholic fatty liver disease: a European single-center study.Transplant Proc2021;53:1674-81

[24] Kodali S,Tariq R.Alcohol relapse after liver transplantation for alcoholic cirrhosis-impact on liver graft and patient survival: a meta-analysis.Alcohol Alcohol2018;53:166-72

[25] Daniel J,Del Bello A.Integrating an addiction team into the management of patients transplanted for alcohol-associated liver disease reduces the risk of severe relapse.JHEP Rep2023;5:100832 PMCID:PMC10480527

[26] Sun K,Liu D,Yang C.Alcohol consumption and risk of metabolic syndrome: a meta-analysis of prospective studies.Clin Nutr2014;33:596-602

[27] Germani G,Rubbia-Brandt L.Management of recurrent and de novo NAFLD/NASH after liver transplantation.Transplantation2019;103:57-67

[28] Samuel D, De Martin E, Berg T, et al; European Association for the Study of the Liver. EASL clinical practice guidelines on liver transplantation. J Hepatol. 2024;81:1040-86.

[29] Ferraioli G,Berzigotti A.WFUMB guidelines/guidance on liver multiparametric ultrasound. part 2: guidance on liver fat quantification.Ultrasound Med Biol2024;50:1088-98

[30] Karlas T,Böhm S.Noninvasive characterization of graft steatosis after liver transplantation.Scand J Gastroenterol2015;50:224-32

[31] Siddiqui MS,Stromberg K.Diagnostic performance of vibration-controlled transient elastography in liver transplant recipients.Clin Gastroenterol Hepatol2021;19:367-74 PMCID:PMC7541402

[32] Chayanupatkul M,Sogaard K.The utility of assessing liver allograft fibrosis and steatosis post-liver transplantation using transient elastography with controlled attenuation parameter.Transplant Proc2021;53:159-65

[33] Alnimer L,Brombosz E.Metabolic issues in patients with metabolic dysfunction-associated steatohepatitis (MASH) and their impact on MASH recurrence following liver transplantation: a narrative review.Liver Transpl2024;Epub ahead of print:

[34] Winters AC,Schiano TD.A review of the use of transient elastography in the assessment of fibrosis and steatosis in the post-liver transplant patient.Clin Transplant2019;33:e13700

[35] Siddiqui MS, Bui AT, Syed T, Tseng M, Hassouneh R, Bhati CS; Liver Transplant Biomarker Group. Performance of vibration-controlled transient elastography and clinical prediction models in liver transplant recipients. Clin Gastroenterol Hepatol. 2023;21:1100-2.e2. PMCID:PMC9376192

[36] Mikolasevic I,Mijic M.Assessment of steatosis and fibrosis in liver transplant recipients using controlled attenuation parameter and liver stiffness measurements.Can J Gastroenterol Hepatol2021;2021:6657047 PMCID:PMC7889377

[37] Eshraghian A,Kazemi K,Geramizadeh B.Non-alcoholic fatty liver disease after liver transplantation in patients with non-alcoholic steatohepatitis and cryptogenic cirrhosis: the impact of pre-transplant graft steatosis.HPB2020;22:521-8

[38] Della-Guardia B,Felga GE,Salvalaggio PR.Diagnostic accuracy of transient elastography for detecting liver fibrosis after liver trannsplantation: a specific cut-off value is really needed?.Dig Dis Sci2017;62:264-72

[39] Eshraghian A,Taghavi A.Metabolic syndrome, hepatic fibrosis, and steatosis diagnosed by liver stiffness measurement and controlled attenuation parameter after liver transplantation: the impact on long-term survival.Expert Rev Gastroenterol Hepatol2022;16:1003-9

[40] Navin PJ,Knudsen JM.Elastography in the evaluation of liver allograft.Abdom Radiol2021;46:96-110 PMCID:PMC8497001

[41] Mikolasevic I,Blazic F.Noninvasive markers of liver steatosis and fibrosis after liver transplantation - where do we stand?.World J Transplant2021;11:37-53 PMCID:PMC8009059

[42] Singh S,Keaveny A.Diagnostic accuracy of magnetic resonance elastography in liver transplant recipients: a pooled analysis.Ann Hepatol2016;15:363-76 PMCID:PMC5032623

[43] Arab JP,Rehm J.Metabolic dysfunction and alcohol-related liver disease (MetALD): position statement by an expert panel on alcohol-related liver disease.J Hepatol2025;82:744-56

[44] Agudelo M,Nair MP.Alcohol-induced serotonergic modulation: the role of histone deacetylases.Alcohol2012;46:635-42 PMCID:PMC3455143

[45] Staufer K,Vettorazzi E,Nashan B.Urinary ethyl glucuronide as a novel screening tool in patients pre- and post-liver transplantation improves detection of alcohol consumption.Hepatology2011;54:1640-9

[46] Allen JP,Thon N.Assessing the drinking status of liver transplant patients with alcoholic liver disease.Liver Transpl2013;19:369-76

[47] Favrod-Coune T,Vionnet J,Déglon J.A false positive hair ethylglucuronide dosage in an alcohol abstinent patient after liver transplantation: a case report.Front Med2024;11:1363012 PMCID:PMC11021601

[48] Fleming MF,Oslakovic E.Phosphatidylethanol detects moderate-to-heavy alcohol use in liver transplant recipients.Alcohol Clin Exp Res2017;41:857-62 PMCID:PMC5417070

[49] Viel G,Cecchetto G,Nalesso A.Phosphatidylethanol in blood as a marker of chronic alcohol use: a systematic review and meta-analysis.Int J Mol Sci2012;13:14788-812 PMCID:PMC3509610

[50] Lim N,Thomson MJ.Protocolized screening and detection of occult alcohol use before and after liver transplant: lessons learned from a quality improvement initiative.Clin Transplant2023;37:e15036

[51] De La Torre SA, Ibrahim B, Meneses K, Saab S, Shetty A. Impact of phosphatidylethanol in the surveillance for alcohol use in post-liver transplant population: a retrospective study.Alcohol Clin Exp Res2024;48:2404-11 PMCID:PMC11629445

[52] Gustavsson L.Formation of phosphatidylethanol in rat brain by phospholipase D.Biochem Biophys Res Commun1987;142:958-63

[53] Becchetti C,Banz V.Medical management of metabolic and cardiovascular complications after liver transplantation.World J Gastroenterol2020;26:2138-54 PMCID:PMC7235200

[54] Savino A,Neri F.Metabolic-dysfunction-associated steatotic liver disease (MASLD) after liver transplantation: a narrative review of an emerging issue.J Clin Med2024;13:3871 PMCID:PMC11242808

[55] Gabrielli F,Nascimbeni F,Gitto S.Metabolic disorders in liver transplant recipients: the state of the art.J Clin Med2024;13:1014 PMCID:PMC10889804

[56] Lonardo A,Petta S,Byrne CD.Metabolic mechanisms for and treatment of NAFLD or NASH occurring after liver transplantation.Nat Rev Endocrinol2022;18:638-50

[57] Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the diabetes prevention program outcomes study.Diabetes Care2012;35:731-7 PMCID:PMC3308305

[58] Alnasrallah B,Chan LW,Pilmore H.Transplantation and diabetes (Transdiab): a pilot randomised controlled trial of metformin in impaired glucose tolerance after kidney transplantation.BMC Nephrol2019;20:147 PMCID:PMC6489311

[59] Choudhury A,Desmukh A,Eslam M.Post-liver transplant metabolic syndrome.J Clin Exp Hepatol2024;14:101368 PMCID:PMC10960134

[60] Becchetti C, Dirchwolf M, Schropp J, et al; Swiss Transplant Cohort Study. Use of statins after liver transplantation is associated with improved survival: results of a nationwide study. Aliment Pharmacol Ther. 2022;56:1194-204. PMCID:PMC9545989

[61] Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497-509.

[62] Loomba R, Abdelmalek MF, Armstrong MJ, et al; NN9931-4492 investigators. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2023;8:511-22. PMCID:PMC10792518

[63] Loomba R, Hartman ML, Lawitz EJ, et al; SYNERGY-NASH Investigators. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391:299-310.

[64] Francque SM, Bedossa P, Ratziu V, et al; NATIVE Study Group. A randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547-58.

[65] Harrison SA, Frias JP, Neff G, et al; HARMONY Study Group. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2023;8:1080-93.

[66] Loomba R,Kowdley KV.Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH.N Engl J Med2023;389:998-1008 PMCID:PMC10718287

[67] Loomba R,Grimmer K.Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial.Lancet Gastroenterol Hepatol2024;9:1090-100

[68] Sanyal AJ, Bedossa P, Fraessdorf M, et al; 1404-0043 Trial Investigators. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med. 2024;391:311-9.

[69] Winder GS,Dew MA.Alcohol and other substance use after liver transplant.Best Pract Res Clin Gastroenterol2020;46-47:101685

[70] Arab JP,Leggio L,Shah VH.Management of alcohol use disorder in patients with cirrhosis in the setting of liver transplantation.Nat Rev Gastroenterol Hepatol2022;19:45-59 PMCID:PMC8559139

[71] Sharma P,Shroff H.Management of alcohol-associated liver disease and alcohol use disorder in liver transplant candidates and recipients: challenges and opportunities.Liver Transpl2024;30:848-61

[72] Celik M,Fuehrlein B.A narrative review of current and emerging trends in the treatment of alcohol use disorder.Brain Sci2024;14:294 PMCID:PMC10969323

[73] Robinson BL,Brown RS Jr.A tale of 2 diseases: ALD and MASLD requirements and monitoring for liver transplantation.Liver Transpl2025;31:117-21

[74] Israelsen M,Tsochatzis EA.Steatotic liver disease.Lancet2024;404:1761-78

[75] Chuong V,Khom S.The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission.JCI Insight2023;8:e170671 PMCID:PMC10371247

[76] Jensen EL,Krag A.Transforming steatotic liver disease management: the emerging role of GLP-1 receptor agonists.Hepatol Commun2024;8:e0561 PMCID:PMC11469819

[77] Quddos F,Tegge A.Semaglutide and Tirzepatide reduce alcohol consumption in individuals with obesity.Sci Rep2023;13:20998 PMCID:PMC10684505

[78] Stankevic E,Juel HB.Binge drinking episode causes acute, specific alterations in systemic and hepatic inflammation-related markers.Liver Int2023;43:2680-91

[79] Choi M,Fan W.FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system.Cell Metab2023;35:429-37.e5 PMCID:PMC10009780

[80] Carrión JA,Bosch J,Gilabert R.Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation.Liver Transpl2006;12:1791-8

[81] Toniutto P,Bitetto D.Role of AST to platelet ratio index in the detection of liver fibrosis in patients with recurrent hepatitis C after liver transplantation.J Gastroenterol Hepatol2007;22:1904-8

[82] Kamphues C,Röcken C.Chances and limitations of non-invasive tests in the assessment of liver fibrosis in liver transplant patients.Clin Transplant2010;24:652-9

[83] Rigamonti C,Bastiampillai AJ.Transient elastography identifies liver recipients with nonviral graft disease after transplantation: a guide for liver biopsy.Liver Transpl2012;18:566-76

[84] Barrault C,Tran Van Nhieu J.Non-invasive assessment of liver graft fibrosis by transient elastography after liver transplantation.Clin Res Hepatol Gastroenterol2013;37:347-52

[85] Lutz HH,Kroy DC,Trautwein C.Doppler ultrasound and transient elastography in liver transplant patients for noninvasive evaluation of liver fibrosis in comparison with histology: a prospective observational study.Dig Dis Sci2015;60:2825-31

[86] Mikołajczyk-Korniak N,Ślubowska K.Dynamic elastography in diagnostics of liver fibrosis in patients after liver transplantation due to cirrhosis in the course of hepatitis C.Transplant Proc2016;48:1725-9

[87] Crespo G,García-Juárez I.Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation.Liver Transpl2016;22:298-304

[88] Arshad T,Bui AT.Evaluation of liver stiffness measurement-based scores in liver transplantation recipients.Liver Transpl2023;29:196-205 PMCID:PMC9868070

[89] Piano S,Gola E.Assessment of alcohol consumption in liver transplant candidates and recipients: the best combination of the tools available.Liver Transpl2014;20:815-22

[90] Andresen-Streichert H,Weinmann W.Improved detection of alcohol consumption using the novel marker phosphatidylethanol in the transplant setting: results of a prospective study.Transpl Int2017;30:611-20

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

[92] American Diabetes Association Professional Practice Committee. 9. pharmacologic approaches to glycemic treatment: standards of care in diabetes-2025. Diabetes Care. 2025;48:S181-206. PMCID:PMC11635045

[93] Mach F, Baigent C, Catapano AL, et al; ESC Scientific Document Group. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111-88.

[94] Agarwal A.Post-transplant dyslipidemia: mechanisms, diagnosis and management.World J Transplant2016;6:125-34 PMCID:PMC4801788

[95] Bush K,McDonell MB,Bradley KA.The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol use disorders identification test.Arch Intern Med1998;158:1789-95