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Disease recurrence after liver transplantation for NAFLD cirrhosis is ineluctable

Open AccessPublished:January 02, 2023DOI:https://doi.org/10.1016/j.jhepr.2022.100668

      Highlights

      • NAFLD is a growing indication for liver transplantation
      • Cohort of 150 patients with at least one liver biopsy
      • Median follow-up after LT was 4.7 years
      • Recurrence of the initial disease is frequent and rapid after LT
      • Grade ≥2 steatosis at 1 year is highly predictive of recurrence of NASH and advanced fibrosis

      Abstract

      Background and Aims

      Liver transplantation (LT) is the treatment of end-stage non-alcoholic fatty liver disease (NAFLD) (related decompensated cirrhosis and/or hepatocellular carcinoma). The aim of our study was to evaluate the risk of disease recurrence after LT and the factors influencing it.

      Method

      This retrospective multicenter study included adult transplanted for NAFLD cirrhosis between 2000 and 2019 in 20 participating French-speaking centers. Disease recurrence (steatosis, steatohepatitis and fibrosis) was diagnosed from liver graft biopsies.

      Results

      We analyzed 150 patients with at least one graft liver biopsy available ≥6 months, among 361 patients transplanted for NAFLD. The median age at LT was 61.3 years [54.4-64.6]. The median follow-up after LT was 4.7 years [2.8-8.1]. Steatosis and steatohepatitis cumulative recurrence rate at 5 years was 80.0% and 60.3%, respectively. Significant risk factors in multivariate analysis for steatohepatitis recurrence were a recipient age at LT < 65 years (OR: 4.214; p=0.044), an HDLc rate<1.15mmol/L after LT (OR: 3.463; p=0.013) and a grade ≥2 steatosis on the graft at 1 year (OR: 10.196; p=0.001). The cumulative incidence of advanced fibrosis (F3–F4) was 20.0% at 5 years and significant risk factors from multivariate analysis were metabolic syndrome before LT (OR: 8.550; p=0.038), long-term use of cyclosporine (OR: 11.388; p=0.031) and grade ≥2 steatosis at 1 year (OR: 10.720; p=0.049). No re-LT was performed for NAFLD-cirrhosis recurrence.

      Conclusion

      Our results strongly suggest that recurrence of initial disease after LT for NAFLD is ineluctable and progressive: the means to prevent it remain to be further evaluated.

      Lay Summary

      NAFLD is a growing indication for liver transplantation, but the analysis of disease recurrence, based on graft liver biopsies, has been poorly studied. Cumulative incidence at 5 years of steatosis, steatohepatitis and NAFLD-related significant fibrosis recurrence was 85.0%, 60.3% and 48.0%, respectively. Grade ≥2 steatosis on graft biopsy at 1 year (present in 25% of patients) is highly predictive of recurrence of steatohepatitis and advanced fibrosis: bariatric surgery should be discussed in these patients specifically.

      Graphical abstract

      Keywords

      ABREVIATIONS

      ABM
      Agence de la Biomédecine
      AZA
      Azathioprine
      BMI
      Body Mass Index
      BS
      Bariatric Surgery
      CAP
      Controlled Attenuation Parameter
      CNI
      Calcineurin Inhibitor
      CST
      Corticosteroid
      CV
      Cardiovascular
      CYA
      Cyclosporine
      ESLD
      End-Stage Liver Disease
      HAS
      Haute Autorité de Santé
      HCC
      Hepatocellular Carcinoma
      HBV
      Hepatitis B virus
      HCV
      Hepatitis C Virus
      HDL-c:
      High-Density Lipoproteins Cholesterol
      IQR
      Interquartile Range
      LDL-c:
      Low-Density Lipoproteins
      LT
      Liver Transplantation
      MELD
      Model for End-Stage Liver Disease
      MDRD
      Modification of Diet in Renal Disease
      MMF
      Mycophenolate Mofetil
      MS
      Metabolic Syndrome
      mTOR-i:
      m-TOR inhibitor
      NAFL:
      Non-Alcoholic Fatty Liver
      NAFLD
      Non-Alcoholic Fatty Liver Disease
      NASH
      Non-Alcoholic Steatohepatitis
      OSAS
      Obstructive Sleep Apnea syndrome
      SAF
      Steatosis, Activity and Fibrosis
      TAC
      Tacrolimus

      Conflict of interest statement:

      No conflict of interest to declare.

      Financial support statement:

      Bourse d’appels offres à recherche 2018 – Agence de la Biomédecine.

      Authors contributions:

      Jérôme Dumortier had the idea of the project and participated in analysis and interpretation of data.
      François Villeret collected the data.
      François Villeret and Domitille Erard performed statistical analysis.
      François Villeret and Jérôme Dumortier participated in writing of the manuscript.
      François Villeret Sébastien Dharancy, Domitille Erard, Armand Abergel, Louise Barbier, Camille Besch, Olivier Boillot, Karim Boudjema, Audrey Coilly, Filomena Conti, Christophe Corpechot, Christophe Duvoux, François Faitot, Stéphanie Faure, Claire Francoz, Emiliano Giostra, Jean Gugenheim, Jean Hardwigsen, Marie-Noëlle Hilleret Jean-Baptiste Hiriart, Pauline Houssel-Debry, Nassim Kamar, Guillaume Lassailly, Marianne Latournerie, Georges-Philippe Pageaux, Didier Samuel, Claire Vanlemmens, Faouzi Saliba and Jérôme Dumortier were involved in medical care of the patients and approved the final version of the manuscript.

      Introduction

      Non-alcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease in the world with a prevalence of nearly 24.1% in the USA adult population and 23.7% in Europe with many disparities: NAFLD affects an estimated 18.2% of the French population
      • Paik J.M.
      • Golabi P.
      • Younossi Y.
      • Mishra A.
      • Younossi Z.M.
      Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of NAFLD.
      ,
      • Nabi O.
      • Lacombe K.
      • Boursier J.
      • Mathurin P.
      • Zins M.
      • Serfaty L.
      Prevalence and Risk Factors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in General Population: the French Nationwide NASH-CO Study.
      . NAFLD is a spectrum of disease that ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) characterized by steatosis, inflammation, hepatocyte ballooning, and varying degrees of hepatic fibrosis which may progress to cirrhosis and end-stage liver disease
      • Sheka A.C.
      • Adeyi O.
      • Thompson J.
      • Hameed B.
      • Crawford P.A.
      • Ikramuddin S.
      Nonalcoholic Steatohepatitis: A Review.
      . Hepatocellular carcinoma (HCC) can develop on a cirrhotic or non-cirrhotic liver. Currently, no specific treatment is available for NAFLD and the only effective treatment is weight lost, for instance after bariatric surgery (BS)
      • Lassailly G.
      • Caiazzo R.
      • Ntandja-Wandji L.-C.
      • Gnemmi V.
      • Baud G.
      • Verkindt H.
      • et al.
      Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.
      . Liver transplantation (LT) may be indicated in case of decompensated NAFLD-related cirrhosis and/or HCC. LT for NAFLD is a growing indication worldwide: it is the second leading cause of LT in the USA but remains less frequent in Europe
      • Haldar D.
      • Kern B.
      • Hodson J.
      • Armstrong M.J.
      • Adam R.
      • Berlakovich G.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study.
      ,
      • Younossi Z.M.
      • Stepanova M.
      • Ong J.
      • Trimble G.
      • AlQahtani S.
      • Younossi I.
      • et al.
      Nonalcoholic Steatohepatitis is the Most Rapidly Increasing Indication for Liver Transplantation in the United States.
      . In 2019, NAFLD represented 12% and 7.9% of all LT in UK and in France, respectively

      National Health Service Blood and Transplant. Annual Report On Liver Transplantation. 2020;

      ,

      Agence de la Biomédecine. Le rapport médical et scientifique 2020 [Internet]. 2020;Available from: https://rams.agence-biomedecine.fr/

      . Patient survival at 5 years after LT for NAFLD without HCC has been reported to be 75.4% in Europe compared to 75% for alcohol-associated liver disease and 80% for Hepatitis B virus (HBV)-related disease
      • Haldar D.
      • Kern B.
      • Hodson J.
      • Armstrong M.J.
      • Adam R.
      • Berlakovich G.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study.
      .
      Few studies have analyzed the recurrence of NAFLD after, especially based on liver biopsy
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • Rivera M.
      • Driscoll C.
      • Stravitz R.T.
      • et al.
      Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis.
      • Bhagat V.
      • Mindikoglu A.L.
      • Nudo C.G.
      • Schiff E.R.
      • 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.
      • Vallin M.
      • Guillaud O.
      • Boillot O.
      • Hervieu V.
      • Scoazec J.-Y.
      • Dumortier J.
      Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis.

      Saeed N, Glass L, Sharma P, Shannon C, Sonnenday CJ, Tincopa MA. Incidence and Risks for Non Alcoholic Fatty Liver Disease and Steatohepatitis Post Liver Transplant: Systematic Review and Meta-analysis. Transplantation. 2019;

      . The persistence of metabolic syndrome (MS) factors after LT, and even its aggravation because of immunosuppressive treatment, may suggest a recurrence of the initial disease on the graft. Recurrence rate of NAFLD is therefore estimated to be more than 80% at 5 years after LT. There is a need to better assess the prevalence of recurrence of NAFLD on the graft, its evolution and the associated risk factors.
      The aim of the present study, based on a large retrospective cohort, was to describe the recurrence of initial disease (steatosis, NASH and fibrosis) on the graft after LT for NAFLD, based on liver biopsies, and to identify the factors influencing it.

      Patients and methods

      Study Population:

      We included all adult patients transplanted in all French LT centers and in Geneva (Switzerland), based on the national database of the French Agence de la Biomédecine (ABM) and local databases (the “NASH” item did not exist in the ABM thesaurus before January the 1st 2018). We first selected all patients transplanted between January the 1st 2000 to 31 December 2019 for "other causes of cirrhosis", "cirrhosis of unknown cause", "metabolic disease" or "HCC" and “NASH” disease after January 2018 in the ABM database. All medical records were reviewed and patients were finally included after histopathological examination of available liver biopsy before the LT or the native liver compatible with a NAFLD cirrhosis, metabolic risks factors (diabetes, obesity or overweight, arterial hypertension) and the absence of other confounding etiology (alcohol consumption>10 g per week, autoimmune disease, viral hepatitis, Wilson's disease or hemochromatosis). The aim of this study was to investigate the recurrence of the initial disease based on graft biopsies performed ≥ 6 months after LT: the population is defined as all transplanted patients with a graft biopsy ≥ 6 months after LT.
      This study was conducted in accordance with the Declaration of Helsinki. According to French law (Loi Jardé), retrospective studies do not require Institutional Review Board approval.

      Clinical and biological characteristics at the time of listing

      Cirrhosis characteristics at the LT registration time were specified including MELD score, CHILD-PUGH score and cirrhosis complications. Metabolic characteristics were recorded: dry weight at LT listing (without ascites or after paracentesis), height and higher body mass index (BMI) in their life were collected. BMI (kg/m2) was calculated from these values. Lipid profile, glycated hemoglobin (HbA1c) and diabetes therapy were collected. MS was defined according to the American Heart Association, replacing waist circumference with BMI over 30kg/m2
      • Alberti K.G.M.M.
      • Eckel R.H.
      • Grundy S.M.
      • Zimmet P.Z.
      • Cleeman J.I.
      • Donato K.A.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
      . Cardiovascular (CV) events, CV check-up and pulmonary disease before LT were collected.
      All patients received grafts from cadaveric or living donors. Donor’s characteristics (age, weight and BMI) were collected.

      Follow-up after LT

      Initial immunosuppressive regimen was based on a calcineurin-inhibitor (CNI): cyclosporine (CYA) or tacrolimus (TAC). Induction therapy by polyclonal antibodies or anti-interleukin-2 receptor antibodies was mainly administered in case of acute kidney injury. Starting on postoperative day 1, methylprednisolone was tapered to reach a maintenance dose of 0 to 5 mg/day at 6 months post-transplantation. Azathioprine (AZA), mycophenolate mofetil (MMF) or sirolimus/everolimus (mTOR-i: mTOR inhibitor) was either administered as part of an initial triple immunosuppressive regimen or introduced during follow-up as a maintenance immunosuppressive agent. Outpatient follow-up visits were usually conducted once a week during the first month after discharge from the hospital, twice a month during the second and third months, monthly for the rest of the first year, and every 3 or 12 months thereafter, regardless of the length of the observation period after LT. Additional visits were made when necessary. A complete laboratory investigation, including hematology, liver parameters, coagulation, electrolytes, total protein, renal parameters, fasting blood glucose, a lipid profile, and blood calcineurin inhibitor trough levels or mTOR-i levels, was conducted at each visit.
      The prevalence of arterial hypertension, diabetes, dyslipidemia and specific associated drugs were recorded. CV events after LT were collected (defined by coronary heart disease, stroke or cardiac arrhythmia, and cardiorespiratory arrest). The presence of steatosis on non-invasive imaging examens (ultrasound or Computer Tomography scan, Magnetic Resonance Imaging, liver stiffness measurement) was specified.
      Biological standards are considered abnormal if they are above or below the laboratory standard.
      The end of follow-up corresponded to death, the last medical examination or date of loss to follow-up. All data were retrospectively collected until June 30th 2020.

      Diagnosis of disease recurrence on liver graft

      Histopathological data were collected from available liver graft biopsies. Depending on local center policy, protocol liver biopsy was performed after LT at 1, 2, 3, 5, 10 and 15 years in some. The liver pathology team at each LT center reviewed all biopsy samples. Steatosis was graded on a 0–3 semi-quantitative scale: (0) steatosis absent or in < 5% of hepatocytes;
      • Paik J.M.
      • Golabi P.
      • Younossi Y.
      • Mishra A.
      • Younossi Z.M.
      Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of NAFLD.
      steatosis in up to one-third of the hepatocytes;
      • Nabi O.
      • Lacombe K.
      • Boursier J.
      • Mathurin P.
      • Zins M.
      • Serfaty L.
      Prevalence and Risk Factors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in General Population: the French Nationwide NASH-CO Study.
      steatosis in one to two-thirds of the hepatocytes; and
      • Sheka A.C.
      • Adeyi O.
      • Thompson J.
      • Hameed B.
      • Crawford P.A.
      • Ikramuddin S.
      Nonalcoholic Steatohepatitis: A Review.
      steatosis in more than two-thirds of the hepatocytes. The grading of NASH (inflammation and hepatocyte ballooning) was performed according to the SAF (Steatosis, Activity and Fibrosis) scoring system
      • Bedossa P.
      • Poitou C.
      • Veyrie N.
      • Bouillot J.-L.
      • Basdevant A.
      • Paradis V.
      • et al.
      Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients.
      . The diagnosis of NASH was defined as a SAF activity score (presence of steatosis, ballooning and lobular inflammation according to the flip algorithm) ≥ 2
      • Bedossa P.
      • Poitou C.
      • Veyrie N.
      • Bouillot J.-L.
      • Basdevant A.
      • Paradis V.
      • et al.
      Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients.
      . Liver fibrosis was scored by NASH Clinical Research Network on a five-stage scale: (0) no fibrosis;
      • Paik J.M.
      • Golabi P.
      • Younossi Y.
      • Mishra A.
      • Younossi Z.M.
      Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of NAFLD.
      perisinusoidal zone 3 or periportal fibrosis (1 A: mild, zone 3, perisinusoidal; 1 B: moderate, zone 3, perisinusoidal; 1C: Portal/periportal);
      • Nabi O.
      • Lacombe K.
      • Boursier J.
      • Mathurin P.
      • Zins M.
      • Serfaty L.
      Prevalence and Risk Factors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in General Population: the French Nationwide NASH-CO Study.
      perisinusoidal fibrosis with portal or periportal fibrosis;
      • Sheka A.C.
      • Adeyi O.
      • Thompson J.
      • Hameed B.
      • Crawford P.A.
      • Ikramuddin S.
      Nonalcoholic Steatohepatitis: A Review.
      perisinusoidal fibrosis with portal or periportal fibrosis with focal or porto-central bridging fibrosis; and
      • Lassailly G.
      • Caiazzo R.
      • Ntandja-Wandji L.-C.
      • Gnemmi V.
      • Baud G.
      • Verkindt H.
      • et al.
      Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.
      cirrhosis
      • Kleiner D.E.
      • Brunt E.M.
      • Van Natta M.
      • Behling C.
      • Contos M.J.
      • Cummings O.W.
      • et al.
      Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
      . Significant and advanced fibrosis were defined as a liver fibrosis stage ≥ F2 and ≥F3, respectively. For the analysis of fibrosis recurrence, we excluded possible factors that could aggravate fibrosis lesions such as cell rejection, or biliary obstacle. We excluded from the analysis of recurrence of initial disease on the graft patients with post-LT alcohol consumption >10 g per week.

      Statistical analysis

      All data were analyzed using SPSS software, version 23.0 (IBM, Armonk, NY, USA). Data were described in their totality using median with interquartile range [IQR] or mean with standard deviation (SD) for continuous variables and number (percentage) for categorical variables. Categorical variables were compared with the Chi-square or Fischer’s exact tests and quantitative variables were compared using the Student t-test or non-parametric tests (Mann-Whitney or Kruskall-Wallis tests) when appropriate.
      The main event of interest was NAFLD recurrence. Steatosis, NASH and fibrosis recurrence rates were estimated using the Kaplan–Meier method. Determination of the risk factors for NASH recurrence was performed using Log Rank analysis or Mann-Whitney analysis (for quantitative variables). All significant variables in the univariate analysis with a level set at p < 0.1 were incorporated into multivariate models analyzed with binary logistic Cox regression. Logistic regression analyses (univariate and multivariate) were used to calculate the risk for liver steatosis, liver fibrosis and various parameters.

      Results

      Study population and metabolic characteristics at time of listing for LT

      One hundred and fifty patients underwent liver biopsy ≥ 6 months after LT, among our global cohort of 361 patients transplanted from all 19 French LT centers and Geneva (Switzerland) (i.e. 20 French-speaking centers). These patients with available liver biopsy do not differ from (except for the duration of post-LT follow-up) patients without graft biopsy regarding pre and post-LT characteristics (Table 1). Patients were transplanted between January 2001 and June 2018. Median [IQR] follow-up after LT was 4.7 years [2.8-8.1] (range; 0.7-18.7 years). More than half of the patients had a MS when listed for LT. The median [IQR] BMI at time of LT time was 30.9 kg/m2 [26.7-33.9] but the median [IQR] higher BMI in their life was 35.0 kg/m2 [30.9-39.3]. In patients transplanted for HCC, the median [IQR] BMI at time of LT time was 30.3 kg/m2 [26.8 - 34.5] compared to 31.0 kg/m2 [27.3 – 33.3] in patients transplanted for ESLD (End-Stage Liver Disease) (not statistically significant; p=0.522). Thirty patients (20.0%) have at least one cardiovascular history before LT. Five patients (3.33%) had pre-LT angioplasty.
      Table 1Characteristics of patients with liver biopsy before and after LT (on patient alive at 1-year n=286).
      Whole cohort alive at 12 months after LTCenters with biopsy protocol
      Patient with liver biopsy after LT (n=150)Patient without liver biopsy after LT (n=136)With liver biopsy (n=103)Without liver biopsy (n=19)p
      Comparison in whole cohort between patients with liver biopsy vs no liver biopsy.
      p
      Comparison of patients in centers performing protocol biopsies (with and without biopsies).
      p
      Comparison of patients with liver biopsy in whole cohort with patients with liver biopsy in centers performing protocol biopsies.
      Gender (M/F)98/52102/3463/4016/30.0760.0100.499
      Median age at LT (years) (IQR)61.3 (54.4-64.6)61.9 (57.9-65.7)61.1 (57.5-65.5)62.7 (57.7-65.8)0.0660.1780.770
      HCC77 (51.3%)75 (55.1%)45 (43.7%)12 (63.2%)0.5190.4640.233
      Median MELD score at LT listing (IQR)13.1 (9.1 – 21.1)14.6 (8.1-21.6)14.3 (9.7-21.0)12.6 (6.0-23.0)0.9120.5830.848
      Median CHILD-PUGH score at LT listing (IQR)B9 (B7–C12)B9 (A6-C12)C10 (B8–C12)C10 (B7–C12)0.4480.5870.498
      Median follow-up (years) (IQR)4.9 (3.0-8.3)3.5 (2.3-6.2)4.5 (2.9-7.4)3.4 (1.7-4.9)0.0010.0010.0001
      Characteristics before LT
      BMI at LT time (kg/m2) (IQR)30.9 (26.7-33.9)31.1 (26.8-34.2)31.0 (27.2-33.9)34.0 (31.2-37.6)0.6080.1830.721
      Metabolic syndrome77 (51.3%)84 (61.8%)52 (50.5%)15 (78.9%)0.0760.1430.213
      Diabetes mellitus112 (74.7%)103 (75.7%)78 (75.7%)17 (89.5)0.8350.0770.341
      Median glycated hemoglobin level (%) (IQR)5.8 (5.1-7.3)5.7 (5.1-6.7)5.9 (5.1-6.6)6.4 (5.6-7.2)0.4230.7270.278
      Arterial Hypertension122 (81.3%)114 (83.8%)77 (74.8%)19 (100%)0.6640.0670.146
      Statin therapy20 (13.3%)16 (11.8%)15 (14.6%)4 (21.1%)0.6600.8540.267
      Fibrate therapy4 (2.7%)3 (2.2%)3 (2.9%)0 (0.0%)0.7680.2200.214
      Bariatric surgery5 (3.3%)3 (2.2%)4 (3.9%)0 (0.0%)0.5640.5400.680
      Cardiovascular history30 (20.0%)30 (22.1%)20 (19.4%)6 (31.6%)0.1470.5490.212
      Median serum creatinine level (μmol/L) (IQR)80.5 (67.0-100.0)85.0 (70.0-107.5)80.0 (67.0-100.5)77.0 (64.5-114.5)0.1460.4340.487
      Medium glomerular filtration rate (MDRD) (μmol/L) (IQR)82.1 (60.3-106.7)77.9 (58.7-100.8)80.6 (59.8-106.5)90.3 (60.2-104.7)0.7070.9880.149
      Characteristics after LT
      BMI at 1 year after LT (kg/m2) (IQR)29.5 (26.6-33.6)29.4 (26.4-32.0)29.5 (25.8-33.8)32.0 (29.9-34.9)0.5190.0790.478
      Diabetes post-LT111 (74.0%)99 (72.8%)78 (75.7%)19 (100%)0.6690.0380.352
      Arterial hypertension post-LT141 (94.0%)111 (81.6%)96 (93.2%)18 (94.7%)0.2450.1980.458
      Dyslipidemia or lipid drugs81 (54.0%)93 (68.3%)53 (51.5%)6 (31.6%)0.3210.5410.254
      Metabolic syndrome post-LT127 (84.7%)118 (86.8%)86 (83.5%)18 (94.7%)0.1800.8900.176
      Donors characteristics
      Median age (years) (IQR)58.5 (43-68.3)59.0 (47.0-69.0)57.0 (44.0-69.5)57.0 (53.0-65.0)0.4520.1300.170
      Gender (M/F)73/4870/3645/247/40.6910.1200.240
      Median BMI (kg/m2) (IQR)24.8 (22.5-29.1)24.8 (22.6-27.7)24.9 (22.6-28.9)24.3 (22.3-27.9)0.5550.2570.360
      Grade ≥1 steatosis66 (44.0%)42 (30.9%)49 (47.6%)9 (47.4%)0.4780.8750.699
      Grade ≥2 steatosis13 (8.7%)8 (5.9%)9 (8.7%)1 (5.3%)0.2470.7430.547
      Stage ≥1 fibrosis36 (24.0%)25 (18.4%)16 (15.5%)3 (15.8%)0.3640.7880.272
      Stage ≥2 Fibrosis3 (2.0)8 (5.9%)2 (1.9%)0 (0.0%)0.7850.8900.450
      BMI: body mass index; HCC: Hepatocellular Carcinoma; LT: Liver Transplantation; MELD: Model for End-Stage Liver Disease.
      Univariate analysis was performed using Log Rank analysis or Mann-Whitney analysis (for quantitative variables). All significant variables in the univariate analysis with a level set at p < 0.1 were incorporated into multivariate models analyzed with binary logistic Cox regression. Values in bold are considered significant (<0.005).
      Comparison in whole cohort between patients with liver biopsy vs no liver biopsy.
      ∗∗ Comparison of patients in centers performing protocol biopsies (with and without biopsies).
      ∗∗∗ Comparison of patients with liver biopsy in whole cohort with patients with liver biopsy in centers performing protocol biopsies.
      Table 2Risk factors for steatosis and NASH recurrence.
      Steatosis recurrenceUnivariate p valueNASH recurrence
      Univariate p valueMultivariate analysisMultivariate analysis
      OR (95%CI)p valueOR (95%CI)p value
      Clinical characteristics before LT
      Gender (M/F)0.2690.634
      Age at LT time0.0120.004
      Age ≥ 50 years0.1450.285
      Age ≥ 55 years0.2760.0981.470 (0.542-3.988)
      Because these variables are not independent, different multivariate analysis models were tested.
      0.449
      Because these variables are not independent, different multivariate analysis models were tested.
      Age ≥ 60 years0.4520.0401.673 (0.716-3.193)
      Because these variables are not independent, different multivariate analysis models were tested.
      0.235
      Because these variables are not independent, different multivariate analysis models were tested.
      Age ≥ 62 years0.3070.0020.397 (0.145-1.089)
      Because these variables are not independent, different multivariate analysis models were tested.
      0.073
      Because these variables are not independent, different multivariate analysis models were tested.
      Age ≥ 65 years0.3830.0350.237 (0.058-0.964)
      Because these variables are not independent, different multivariate analysis models were tested.
      0.044
      Because these variables are not independent, different multivariate analysis models were tested.
      Body Mass Index at LT time0.1490.020
      ≥ 20 kg/m20.8090.564
      ≥ 25 kg/m20.8170.215
      ≥ 30 kg/m20.0560.00015.086 (1.000-28.857)**0.050**
      ≥ 31 kg/m20.0022.727 (1.048-7.098)0.0400.000111.017 (2.073-58.538)**0.005**
      ≥ 32 kg/m20.0031.766 (0.726-4.297)
      Because these variables are not independent, different multivariate analysis models were tested.
      0.2100.0015.715 (1.116-29.270)**0.036**
      ≥ 35 kg/m20.2010.293
      HCC pre-LT0.5380.856
      Pre-LT diabetes0.1080.892
      Pre-LT HbA1c ≥ 7%0.6020.621
      Pre-LT insulin therapy0.1150.272
      Pre-LT arterial hypertension0.4110.439
      Pre-LT metabolic syndrome0.0431.029 (0.501-2.115)0.9370.0460.775 (0.286 – 2.098)0.616
      Active smoking before LT0.8100.836
      Donors characteristics
      Age of the donor (years)0.4970.120
      Age ≥ 60 years0.0911.466 (0.832-2.584)0.1850.575
      Age ≥ 70 years0.8210.651
      Donors age + recipients age (years)0.185
      ≥ 120 years0.2600.926
      ≥ 135 years0.8290.984
      Donor BMI (kg/m2)0.3780.333
      Graft steatosis (≥ 5%)0.1620.191
      Grade ≥ 2 steatosis0.1210.137
      Metabolic events after LT
      BMI at 1 year after LT0.0080.054
      ≥ 30 kg/m20.00010.976 (0.426-2.240)0.9550.00010.277 (0.286-1.216)***0.089***
      ≥ 32 kg/m20.0021.197 (0.654-2.191)0.5600.0080.521 (0.193-1.409)***0.199***
      ≥ 35 kg/m20.0231.313 (0.623-2.766)0.4740.227
      Weight difference 1-year post-LT (kg)0.1480.805
      Diabetes post-LT0.9740.635
      Arterial hypertension post-LT0.4520.587
      TG ≥ 1.7mmol/L post-LT0.2480.527
      LDLc ≥ 3.70mmol/L post-LT0.4740.566
      HDLc < 1.15mmol/L0.4020.0503.463 (1.301-9.220)0.013
      HbA1c ≥ 6.5%0.2050.150
      HbA1c ≥ 7%0.3330.330
      HbA1c ≥ 8%0.0521.676 (0.939-2.990)0.0800.194
      Metabolic syndrome post-LT0.3630.655
      Immunosuppressive regimen
      Tacrolimus0.1630.098
      MMF0.1010.629
      CYA0.3750.934
      mTOR-i0.9300.675
      CST0.0710.337 (0.074-1.547)0.1620.307
      AZA0.3770.673
      Specifics therapies after LT
      Statin therapy0.9850.519
      Fibrate therapy0.3290.377
      Insulin therapy0.1570.573
      Dyslipidemia or lipid drugs0.0471.831 (0.883-3.795)0.1040.910
      Complications after LT
      CV events0.0500.764 (0.444-1.313)0.3300.420
      OSAS0.0561.130 (0.605-2.109)0.7010.363
      Acute rejection0.6270.587
      Disease recurrence on the graft at 1 year
      Grade ≥1 steatosis0.00210.521 (2.127-52.046)****0.004****
      Grade ≥2 steatosis0.000110.196 (3.553-29.257)****0.001****
      Grade 3 steatosis0.00012.729 (0.845-8.815)****0.093****
      Each variable was tested in univariate analysis. All variables with a p value < 0.010 were retained for the multivariate model.
      AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      Univariate analysis was performed using Log Rank analysis or Mann-Whitney analysis (for quantitative variables). All significant variables in the univariate analysis with a level set at p < 0.1 were incorporated into multivariate models analyzed with binary logistic Cox regression. Values in bold are considered significant (<0.005).
      Because these variables are not independent, different multivariate analysis models were tested.
      Table 3Risk factors for significant and advanced fibrosis recurrence.
      Significant fibrosis (grade ≥ 2)Advanced fibrosis (grade 3-4)
      Univariate p valueMultivariate analysisUnivariate p valueMultivariate analysis
      OR (95%CI)p valueOR (95%CI)p value
      Clinical characteristics before LT
      Gender (M/F)0.8500.691
      Age at LT time0.0340.008
      Age ≥ 50 years0.1050.00016.436 (0.316-103.912)
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.226
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      Age ≥ 55 years0.1600.0012.083(0.249-17.411)
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.498
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      Age ≥ 60 years0.0680.422 (0.201-0.889)0.0230.0220.492 (0.076-3.186)
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.457
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      Age ≥ 62 years0.1010.0660.965 (0.153-6.069)
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.970
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      Age ≥ 65 years0.2140.225
      Body Mass Index at LT time0.1210.068
      ≥ 20 kg/m20.5300.873
      ≥ 25 kg/m20.6280.059
      ≥ 30 kg/m20.0801.161 (0.417-3.233)
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.775
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.0054.546 (0.154-112.25)**0.952**
      ≥ 31 kg/m20.0131.569 (0.580-4.243)
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.375
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.0063.848 (0.268-55.191)**0.321**
      ≥ 32 kg/m20.0071.738 (0.657-4.594)
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.265
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.
      0.0051.591 (0.001-2486)**0.902**
      ≥ 35 kg/m20.2890.688
      HCC pre-LT0.2850.0160.175 (0.016-1.896)0.152
      Pre-LT diabetes0.3780.413
      Pre-LT HbA1c ≥ 7%0.2460.826
      Pre-LT insulin therapy0.6000.646
      Pre-LT arterial hypertension0.7330.187
      Pre-LT metabolic syndrome0.4250.0698.550 (1.125-64.983)0.038
      Active smoking before LT0.6770.447
      Donors characteristics
      Age of the donor (years)0.0740.552
      Age ≥ 60 years0.7130.828
      Age ≥ 70 years0.6480.868
      Donors age + recipients age (years)0.0160.099
      ≥ 120 years0.3760.476
      ≥ 135 years0.6480.452
      Donor BMI (kg/m2)0.1700.161
      Graft steatosis (≥ 5%)0.0051.894 (0.915-3.923)**0.086**0.0994.454 (1.257-103.209)0.126
      Grade ≥ 2 steatosis0.0282.837 (1.266-6.358)**0.011**0.605
      Metabolic events after LT
      BMI at 1 year after LT0.1210.019
      ≥ 30 kg/m20.0071.198 (0.443-3.240)***0.723***0.0013.578 (0.002-6102)0.737
      ≥ 32 kg/m20.0131.547 (0.679-3.525)***0.299***0.059
      ≥ 35 kg/m20.1300.160
      Weight difference 1-year post-LT (kg)0.9230.458
      Diabetes post-LT0.4990.999
      Arterial hypertension post-LT0.6090.634
      TG ≥ 1.7mmol/L post-LT0.3530.363
      LDLc ≥ 3.70mmol/L post-LT0.2440.890
      HDLc < 1.15mmol/L0.7260.937
      HbA1c ≥ 6.5%0.1270.324
      HbA1c ≥ 7%0.1900.606
      HbA1c ≥ 8%0.2490.109
      Insulin therapy0.9010.420
      Metabolic syndrome post-LT0.6410.739
      Immunosuppressive regimen
      Tacrolimus0.3700.756
      MMF0.7380.971
      CYA0.9900.00511.388 (1.257-103.209)0.031
      mTOR-i0.5540.466
      CST0.2770.934
      AZA0.6810.873
      CNI free therapy0.3700.756
      Specifics therapies after LT
      Statin therapy0.2900.840
      Fibrate therapy0.7330.769
      Insulin therapy0.9010.420
      Dyslipidemia or lipid drugs0.6810.680
      Complications after LT
      OSAS0.6500.954
      Acute rejection0.9730.656
      Disease recurrence on the graft at 1 year
      Grade ≥1 steatosis0.00015.373 (1.593-18.121)****0.007****0.103
      Grade ≥2 steatosis0.00013.564 (1.605-7.917)****0.002****0.00110.720 (1.006-114.259)0.049
      Grade 3 steatosis0.0014.596 (1.630-12.961)****0.004****0.109
      NASH recurrence0.00015.217 (2.013-13.519)****0.001****0.131
      Each variable was tested in univariate analysis. All variables with a p value < 0.010 were retained for the multivariate model.
      Univariate analysis was performed using Log Rank analysis or Mann-Whitney analysis (for quantitative variables). All significant variables in the univariate analysis with a level set at p < 0.1 were incorporated into multivariate models analyzed with binary logistic Cox regression. Values in bold are considered significant (<0.005).
      Because these variables are not independent, different multivariate analysis models were tested AZA: azathioprine; BMI: body mass index; CNI: Calcineurin Inhibitor; CST: corticosteroids; CYA: cyclosporine A; CV: Cardiovascular; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MMF: mycophenolate mofetil; mTOR-i: mTOR inhibitor; TG: triglycerides.

      Metabolic syndrome after LT (Table 1 and Supplementary Table 1)

      After LT, 94.0% of patients had hypertension, with 24 cases of de novo arterial hypertension (representing 85.7% of patients at risk). De novo diabetes developed in 28.9% of patients at risk after LT: 74.0% of patients had diabetes in the LT follow-up. After LT, 78.0% have dyslipidemia or were with anti-lipid therapy after LT. A de novo Obstructive Sleep Apnea syndrome (OSAS) after LT was diagnosed in 10.7% of patients.
      The cumulative incidence of MS after LT at 1, 5 and 10 years was 73.5%, 86.2% and 92.5%, respectively (Figure 1); 73.1% of patients had a BMI over 25 kg/m2 and 59.3% were obese during follow-up. The median [IQR] BMI at 1 year and 5 years after LT was 29.5 kg/m2 [26.6-33.6] and 32.3 kg/m2 [28.2 – 35.5], respectively.
      Figure thumbnail gr1
      Figure 1Cumulative incidence of metabolic syndrome after LT (according to Kaplan-Meier estimates). The cumulative incidence of MS at 1, 5 and 10 years was 73.5%, 86.2% and 92.5%, respectively. There was no difference between patients with and without liver biopsy (p=0.896). (Kaplan–Meier analysis)
      Five patients (3.3%) had history of BS: 3 before LT and 2 after LT. The median [IQR] time between the BS and the LT was 11.0 years [8.2-11.8] and the median [IQR] weight loss after BS was 20.0 kg [10.0-35.0]. No complication of BS was reported in these patients, including ESLD secondary to BS. Two (1.3%) patients underwent a BS after LT, with the median [IQR] time between LT and BS was 3.4 years [3.2-3.5]. Sleeve gastrectomy was the only type of BS after LT. A patient with NASH recurrence histologically proven at 1 year after LT underwent a sleeve gastrectomy at 3 years after LT allowing an improvement of the hepatic histology with complete regression of steatosis, NASH resolution and reduction of fibrosis stage from 3 to 2 on the liver biopsy 5-years after LT. A BS was under discussion for 10 (6.7%) patients at the end of follow-up.
      Eight patients (5.3%) entered an intensive nutrition program (defined by specialized rehabilitation services) after LT.

      NAFLD recurrence after LT and associated risk factors

      One hundred and fifty patients underwent at least one liver graft biopsy after LT (222 liver biopsies in total, 94.3% performed as protocol biopsy). In centers performing protocol biopsies after LT, a liver graft biopsy was available at 1 year for 103 patients (out of 110 patients with ≥ 12 months follow-up, i.e 93.6%), 25 at 5 years (out of 28 patients with ≥ 5 years follow-up, i.e. 89.3%) and 12 at 10 years (out of 13 patients ≥ 10 years follow-up, i.e. 92.3%) (Supplementary Table 2). Cumulative incidence rates of steatosis, NASH and advanced fibrosis did not significantly differ when comparing the entire cohort and centers performing protocol biopsies (Figure 2).
      Figure thumbnail gr2
      Figure 2Grade ≥1 (A), grade ≥2 (B) and grade ≥3 (C) steatosis recurrence and NASH (D), NAFLD-related ≥ grade 2 fibrosis (E) and NAFLD-related ≥ grade 3 fibrosis (F) cumulative incidence after LT in whole cohort and centers with biopsy protocol. (Based on 150 liver biopsies) (According to Kaplan-Meier estimates). A: Steatosis ≥1 grade recurrence was 68.0% at 1 year and 85.0% at 5 years in whole cohort. P=0.381. B: Steatosis ≥2 grade recurrence was 27.8% at 1 year and 64.5% at 5 years in whole cohort. P=0.713. C: Steatosis ≥3 grade recurrence was 5.0% at 1 year and 30.3% at 5 years in whole cohort. P=0.378. D: NASH recurrence was 14.9% at 1 year and 60.3% at 5 years in whole cohort. P=0.823. E: NAFLD-related ≥ grade 2 fibrosis was 18.2% at 1 year and 48.0% at 5 years in whole cohort. P=0.333. F: NAFLD-related ≥ grade 3 fibrosis was 1.4% at 1 year and 20.0% at 5 years in whole cohort. P=0.745. (Kaplan–Meier analysis)

      3.1 Steatosis recurrence on the graft (Figure 2-A/B/C and Table 2)

      Steatosis (≥ 5% i.e., all stages) cumulative recurrence on the graft concerned the majority of patients (68.0%) at 1 year and 85.0% at 5 years after LT (Figure 2-A). The cumulative incidence of grade 2 steatosis recurrence on the graft at 1 and 5 years after LT was 27.8% and 64.5%, respectively; one third of recipients developed at least grade 2 steatosis (Figure 2-B). The cumulative incidence of grade 3 steatosis is shown in Figure 2-C. In multivariate analysis, only the BMI ≥ 31kg/m2 at time of LT (OR: 2.727; 95%CI: 1.048-7.098; p=0.040) was significantly associated with a risk of steatosis recurrence. There was a trend for patients with unmanaged diabetes (defined as HbA1c ≥ 8%). We found no relationship with weight gain or BMI at 1 year after LT. At 1 and 5 years after LT, in patients with grade ≥ 1 steatosis on biopsy, 33.6% and 75.0% respectively had steatosis on imaging US scan performed at the same time as the liver biopsy. At 1 and 5 years after LT, in patients with grade ≥ 2 steatosis on liver biopsy, 63.2% and 100% respectively had steatosis on imaging US scan performed at the same time as the liver biopsy. Seven patients (4.7%) had non-invasive assessment of steatosis by Controlled Attenuation Parameter (CAP) after LT.

      3.2 NASH recurrence on the graft (Figure 2-D and Table 2)

      NASH cumulative incidence recurrence rate was 14.9% at 1 year and 60.3% at 5 years post-LT (Figure 2-D). The median [IQR] delay between the LT and the NASH recurrence was 2.07 years [1.1-4.8]. On the 43 cases of NASH recurrence (28.7%), 33 patients (76.7%) had steatosis on US or CT scan.
      The median [IQR] values of ALAT, ASAT and GGT at NASH recurrence diagnosis were respectively 35 IU/L [20-56], 32.0 IU/L [22 – 44] and 43 IU/L [28-87]. Twenty-six (60.5%) patients had GGT above the upper limit, 12 (27.9%) ALAT above the upper limit and 10 (23.3%) ASAT above the upper limit at the time of NASH recurrence diagnosis.
      In multivariate analysis, risk factors of NASH recurrence were an age at the time of LT less than 65 years (OR: 4.214; 95%CI: 1.038-17.108; p=0.044), a post-LT HDL-c level less than 1.15 mmol/L (OR: 3.463; 95%Cl: 1.304-18.780; p=0.019), a grade 1 steatosis on the graft at 1 year after LT (OR: 10.521; 95%Cl: 2.127-52.046; p=0.004), or a grade 2 steatosis (OR: 10.196; 95%Cl: 3.553-29.257; p=0.001). Donor characteristics (age, BMI or steatosis on the graft) were not associated with NASH recurrence.

      3.3 Recurrence of NAFLD-related fibrosis on the graft (Figure 2-E/F and Table 3)

      Significant fibrosis (stage ≥ 2) cumulative incidence after LT was 18.2% at 1 year, 48.0% at 5 years and 65.0% at 10 years (Figure 2-E). There was no significant difference between the entire cohort and the protocol centers in which biopsies were not clinically directed (p=0.333). In multivariate analysis, risk factors to NAFLD-related significant fibrosis included a recipient age at time of LT < 60 years (OR: 2.368; 95%Cl: 1.125-4.986; p=0.023), an initial graft steatosis over grade 2 (OR: 2.837; 95%Cl: 1.266-6.358; p=0.011) and the presence at 1 year after LT of a grade ≥ 1 steatosis (OR: 5.373; 95%Cl: 1.593-18.121; p=0.007), grade ≥ 2 (OR: 3.564; 95%Cl:1.605-7.917; p=0.002), grade ≥3 (OR: 4.596; 95%Cl: 1.630-12.961; p=0.004) or NASH recurrence (OR: 5.217; 95%Cl: 2.013-13.519; p=0.001).
      Cumulative incidence of advanced fibrosis (F3–F4) was 20.0% at 5 years and 48.0% at 10 years (Figure 2-F). Six patients (4.0%) had recurrent NAFLD cirrhosis after LT after a median delay of 7.1 years; one patient presented a decompensated cirrhosis 15 years after LT. Concerning NAFLD-related advanced fibrosis, risk factors identified in multivariate analysis were a MS before LT (OR: 8.550; 95%Cl: 1.125-64.983; p=0.038), a long-term use of CYA (OR: 11.388; 95%Cl: 1.257-103.209; p=0.031) and grade 2 steatosis at 1 year (OR: 10.720; 95%Cl: 1.006-114.259; p=0.049). Initial graft steatosis does not affect the occurrence of advanced fibrosis. The age of the recipient did not influence the occurrence of advanced fibrosis.
      Non-invasive evaluation of fibrosis by liver stiffness measurement was performed in 9 patients (6.0%) during follow-up.
      Figure 3 shows the cumulative incidence of advanced NAFLD-related fibrosis according to the presence of at least 1 risk factor: without any risk factor, the risk of advanced fibrosis was estimated at 5.3% at 5 years compared to 58.3% with at list one risk factor (p=0.001).
      Figure thumbnail gr3
      Figure 3Advanced fibrosis cumulative incidence according to the presence of risk factors. (Based on 150 liver biopsies) (According to Kaplan-Meier estimates). Risk factors considered for analysis: Pre-LT metabolic syndrome, grade ≥2 steatosis at 1 year after LT and long-term use of CYA. In group with risk factors, incidence of advanced fibrosis was 5.3% at 1 year after LT, 58.3% at 5 years and 77.7% at 10 years. In group without risk factors, incidence of advanced fibrosis was 0.0% at 1 year, 5.3% at 5 years and 48.4% at 10 years after LT. The difference is significant between the 2 groups of patients (p=0.001). (Kaplan–Meier analysis)

      Discussion

      We report herein the largest available cohort studying recurrence of initial disease after LT for NAFLD, including more than 150 patients with available post-LT liver biopsy. Previous single center series reported only a few dozen of cases
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • Rivera M.
      • Driscoll C.
      • Stravitz R.T.
      • et al.
      Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis.
      • Bhagat V.
      • Mindikoglu A.L.
      • Nudo C.G.
      • Schiff E.R.
      • 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.
      • Vallin M.
      • Guillaud O.
      • Boillot O.
      • Hervieu V.
      • Scoazec J.-Y.
      • Dumortier J.
      Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis.
      ,
      • Malik S.M.
      • deVera M.E.
      • Fontes P.
      • Shaikh O.
      • Ahmad J.
      Outcome after liver transplantation for NASH cirrhosis.
      . We found that recurrence of NAFLD was observed in almost all patients 10 years after LT, that NASH recurrence occurred in more than half of the patients at 5 years, and that NAFLD-related significant and advanced fibrosis occurred in 48.0% and 20.0% at 5 years, respectively. The median follow-up of our patients was 4.7 years: this is because most LT were performed after 2015 and protocol graft biopsies are usually planed at 1, 5 and 10 years. Our results, despite a median follow-up time of less than 5 years, strongly support a highly frequent recurrence of the initial disease. We previously reported that the survival of the overall cohort was 79.8% at 5-years
      • Villeret F.
      • Dharancy S.
      • Erard D.
      • Abergel A.
      • Barbier L.
      • Besch C.
      • et al.
      Liver transplantation for NAFLD cirrhosis: Age and recent coronary angioplasty are major determinants of survival.
      .
      Since most of our patients have a MS at time of LT, our results are not surprising. BMI at LT time of LT was high in our population: we tried to take as much as possible of the dry, non-ascites weights of these patients. The impact of ascites seems minimal as there is no difference between patients transplanted for CHC indication and those transplanted for ESLD. The relatively low median CHILD score may explain a low weight of ascites on body weight and BMI before LT. Estimation of MS in patients with ELSD may be underestimated due to possible disappearance of MS components in the advanced stages of liver disease. MS not only usually persists, but may worsen and occur de novo after LT. The aggravation of MS is mainly related to post-LT dyslipidemia: 62.6% of all patients developed de novo dyslipidemia after LT, probably favored by immunosuppressive drugs. In the context of LT (all etiologies of initial liver disease considered) MS incidence after LT is estimated to range 44-58%
      • Siddiqui M.S.
      • Sterling R.K.
      Posttransplant metabolic syndrome.
      . Recurrence of MS after LT for NAFLD was estimated to be 62.5% at 5.4 years after LT in an USA study, which is lower than our data
      • Malik S.M.
      • deVera M.E.
      • Fontes P.
      • Shaikh O.
      • Sasatomi E.
      • Ahmad J.
      Recurrent disease following liver transplantation for nonalcoholic steatohepatitis cirrhosis.
      . This high proportion of MS recurrence/occurrence after LT can be explained by the pre-existing MS before LT, associated with immunosuppressive treatment, including CNI, mTOR-i and corticosteroids, which promote diabetes, dyslipidaemia, arterial hypertension and weight gain
      • Carter D.
      • Dieterich D.T.
      • Chang C.
      Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis in Liver Transplantation.
      . The second explanation can be the very low proportion of patients who have undergone BS or specialized nutritional rehabilitation program in our cohort.
      We strongly confirm here the impact of MS on the graft with recurrence of steatosis, NASH and fibrosis. Available studies come from the USA and only one European study investigated the recurrence of NAFLD on the graft, in 11 patients
      • Vallin M.
      • Guillaud O.
      • Boillot O.
      • Hervieu V.
      • Scoazec J.-Y.
      • Dumortier J.
      Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis.
      . The largest available study included 34 patients, and disclosed that NAFLD and NASH recurrence occurred in 88% and 44% of patients, respectively, after a median follow-up of 47 months after LT
      • Bhagat V.
      • Mindikoglu A.L.
      • Nudo C.G.
      • Schiff E.R.
      • 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.
      . Our study is based on 150 patients with at least one liver biopsy performed after LT: recurrence of steatosis was frequent and early, since recurrence rate of NASH was 60.3% at 5 years after LT. Not all patients of the global cohort had a liver biopsy, and one of the limitations of our work could be a selection bias regarding the indication of liver biopsies (disturbed liver tests, steatosis on imaging or clinical arguments). Nevertheless, there was no difference between patients who had a biopsy and those who did not, except that the median follow-up was a little bit longer for patients with available biopsy (4.9 vs. 3.5 months). In addition, liver biopsies were in most cases (> 90%) protocol biopsies at 1, 5 and 10 years, according to different centers strategy: this high proportion of protocol biopsy allows to reduce as much as possible a possible selection bias. There was no difference in recurrence of steatosis, NASH and advanced fibrosis between the whole population with graft biopsy and patients with protocol biopsy after LT (figure 2 and supplementary table 2). Finally, recurrence of initial graft disease was diagnosed on liver biopsies interpreted at each of the LT centers. All the biopsies were not reviewed centrally, but histological lesions were graded (and reported) according to standard validated scores. In addition, less than ten patients underwent non-invasive investigation of steatosis by CAP and fibrosis by liver stiffness measurement or blood tests: these tests are not validated after LT
      • Siddiqui M.S.
      • Idowu M.O.
      • Stromberg K.
      • Sima A.
      • Lee E.
      • Patel S.
      • et al.
      Diagnostic Performance of Vibration-Controlled Transient Elastography in Liver Transplant Recipients.
      ,
      • Bhat M.
      • Tazari M.
      • Sebastiani G.
      Performance of transient elastography and serum fibrosis biomarkers for non-invasive evaluation of recurrent fibrosis after liver transplantation: A meta-analysis.
      and the small number of patients did not allow statistical analyses.
      In available literature, studies on NAFLD recurrence need to be interpreted with caution: some studies included cryptogenic cirrhosis and/or assessment of fibrosis/steatosis on the graft by imaging methods, identifying therefore only steatosis (not NASH), with a significant lack of sensitivity. Our study finds a poor correlation between histologically proven steatosis and imaging, especially for grade 1 steatosis. Few studies (and only some patients included in each study) have analyzed results of liver graft biopsies
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • Rivera M.
      • Driscoll C.
      • Stravitz R.T.
      • et al.
      Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis.
      ,
      • Bhagat V.
      • Mindikoglu A.L.
      • Nudo C.G.
      • Schiff E.R.
      • 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.
      ,
      • Yalamanchili K.
      • Saadeh S.
      • Klintmalm G.B.
      • Jennings L.W.
      • Davis G.L.
      Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease.
      ,
      • Sourianarayanane A.
      • Arikapudi S.
      • McCullough A.J.
      • Humar A.
      Nonalcoholic steatohepatitis recurrence and rate of fibrosis progression following liver transplantation.
      . In a meta-analysis including 17 studies (2,378 patients), the cumulative incidence of recurrent NAFLD and NASH was 82% and 38%, respectively, more than 5 years after LT

      Saeed N, Glass L, Sharma P, Shannon C, Sonnenday CJ, Tincopa MA. Incidence and Risks for Non Alcoholic Fatty Liver Disease and Steatohepatitis Post Liver Transplant: Systematic Review and Meta-analysis. Transplantation. 2019;

      . Recurrence of steatosis and NASH has an impact on graft fibrosis. After elimination of other causes of fibrosis, the cumulative incidence of significant fibrosis was 48.0% at 5 years and 65.0% at 10 years in our study. In the study from Bathi et al., NALFD-significant fibrosis recurrence was estimated to be 42.2% at 47 months, and this is consistent with our results
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • Rivera M.
      • Driscoll C.
      • Stravitz R.T.
      • et al.
      Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis.
      . No re-transplantation for recurrence of the initial disease was performed in our cohort. This low rate of re-LT is consistent with the literature: in a study of 1,295 patients, only 1 re-LT was performed and none in the Bhati's study
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • Rivera M.
      • Driscoll C.
      • Stravitz R.T.
      • et al.
      Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis.
      ,
      • Agopian V.G.
      • Kaldas F.M.
      • Hong J.C.
      • Whittaker M.
      • Holt C.
      • Rana A.
      • et al.
      Liver transplantation for nonalcoholic steatohepatitis: the new epidemic.
      . Recurrence of cirrhosis occurred with a median time of 7 years after LT in our study, and therefore probably occurs in elderly transplanted patients, over 70 years old, generally considered too old for a second LT.
      Our study did not aim to compare NAFLD patients with a non-NAFLD population. However, in the literature, few studies have analyzed recurrence vs. development of de novo NAFLD on the graft (i.e. in patients transplanted for non-NAFLD cirrhosis)
      • Vallin M.
      • Guillaud O.
      • Boillot O.
      • Hervieu V.
      • Scoazec J.-Y.
      • Dumortier J.
      Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis.
      . In a retrospective study, 80 patients, transplanted for non-NAFLD cirrhosis (Alcohol related-disease with no relapse after LT, HBV or HCV infection) and presenting a de novo NAFLD after LT, were compared to 11 patients with recurrent NAFLD. Advanced fibrosis (71.4% vs.12.5%) and NASH (71.4% vs.17.2%) were more frequent and faster in patients with recurrent NAFLD compared to de novo NAFLD. These data were confirmed by a meta-analysis: at 5 years after LT, NASH recurrence was estimated at 38% vs.17% for de novo NASH

      Saeed N, Glass L, Sharma P, Shannon C, Sonnenday CJ, Tincopa MA. Incidence and Risks for Non Alcoholic Fatty Liver Disease and Steatohepatitis Post Liver Transplant: Systematic Review and Meta-analysis. Transplantation. 2019;

      . A recent study confirmed that the development of recurrent NASH is earlier than de novo NASH (2.8 years versus 4.8 years, p = 0.02)
      • Balitzer D.
      • Tsai J.-H.
      • Gill R.M.
      Clinicopathologic features of de novo non-alcoholic steatohepatitis in the post-transplant setting.
      .
      Since our study shows a rapid and frequent recurrence of the initial disease on the graft and an evolution towards advanced fibrosis, it is of great relevance to identify risk factors in order to limit disease recurrence and/or progression. Few studies, which evaluated disease recurrence of NAFLD, are summarized in Table 4: only some of them have identified risk factors for recurrence of steatosis or fibrosis. Factors associated with recurrence of the initial disease on the graft can be separated into 3 categories: components of the MS (BMI before and after LT, dyslipidemia and diabetes), factors related to immunosuppressive drugs (CYA or corticosteroids) and demographic factors (such as the age at transplantation). Patients’ factors are not modifiable, and it is therefore necessary to try to manage the other factors to decrease the risk of disease recurrence on the graft. Regarding MS, intensive nutritional management is required along with treatment of diabetes, dyslipidemia and hypertension. The benefit of BS has been demonstrated in non-transplanted patients: in a recent French study, at 5 years after BS, NASH had resolved in 84% of patients and an improvement of liver fibrosis in 76% of patients
      • Lassailly G.
      • Caiazzo R.
      • Ntandja-Wandji L.-C.
      • Gnemmi V.
      • Baud G.
      • Verkindt H.
      • et al.
      Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.
      . Several small studies in LT patients are available and timing for BS and type of BS has to be defined

      Serrano OK, Peterson KJ, Vock DM, Berglund D, Kandaswamy R, Lake JR, Pruett TL, Chinnakotla S. Clinical Impact of Antecedent Bariatric Surgery on Liver Transplant Outcomes: A Retrospective Matched Case-control Study. Transplantation. 2020;

      • Tsamalaidze L.
      • Stauffer J.A.
      • Arasi L.C.
      • Villacreses D.E.
      • Franco J.S.S.
      • Bowers S.
      • et al.
      Laparoscopic Sleeve Gastrectomy for Morbid Obesity in Patients After Orthotopic Liver Transplant: a Matched Case-Control Study.
      • Zamora-Valdes D.
      • Watt K.D.
      • Kellogg T.A.
      • Poterucha J.J.
      • Di Cecco S.R.
      • Francisco-Ziller N.M.
      • et al.
      Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy.
      . BS could probably be discussed in a majority of patients after LT. Current data suggest that sleeve gastrectomy could be performed 6 to 12 months after LT: the BS type allows access to the bile ducts and a good absorption of immunosuppressant. In our study, only 5 patients had history of BS, including only 2 patients after LT. According to the French Haute Autorité de Santé (HAS) criteria, BS is indicated in cases of a BMI greater than 40kg/m2, or 35kg/m2 with metabolic complications (NASH, hypertension, OSAS, type 2 diabetes, disabling osteoarticular diseases)

      Haute Autorité de Santé. Obésité:prise en charge chirurgicale chez l’adulte [Internet]. 2009;Available from: https://www.has-sante.fr/upload/docs/application/pdf/2011-10/reco2clics_obesite_adulte_chirurgie.pdf

      . Taking these criteria, 41 (27.3%) of our patients met these criteria at 1 year after LT (personal data): from whom 21 have grade 2 steatosis on liver biopsy at 12 months. One of the explanations for the low proportion of BS in our population is probably the relatively old age of the patients: the expected benefit of BS is validated in patients with an age below 65 years
      • Mechanick J.I.
      • Youdim A.
      • Jones D.B.
      • Timothy Garvey W.
      • Hurley D.L.
      • Molly McMahon M.
      • et al.
      Clinical Practice Guidelines for the Perioperative Nutritional, Metabolic, and Nonsurgical Support of the Bariatric Surgery Patient—2013 Update: Cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery.
      . Nevertheless, several recent studies have suggested that BS could be performed in patients over 65 years of age, with follow-up of up to 6 years and good efficacy on weight, physical activity and biological parameters
      • Cunha J.B.
      • Fialho M.C.M.P.
      • Arruda S.L.M.
      • Nóbrega O.T.
      • Camargos E.F.
      Clinical and Metabolic Improvement after Bariatric Surgery in Older Adults: A 6-Year Follow-Up.
      • Susmallian S.
      • Barnea R.
      • Weiss Y.
      • Raziel A.
      Outcome of bariatric surgery in older patients.
      • Goldberg I.
      • Yang J.
      • Nie L.
      • Bates A.T.
      • Docimo S.
      • Pryor A.D.
      • et al.
      Safety of bariatric surgery in patients older than 65 years.
      . Another possibility needing further evaluation in these “elderly” patients would be endoscopic BS that could also be an alternative approach
      • Salomone F.
      • Sharaiha R.Z.
      • Boškoski I.
      Endoscopic bariatric and metabolic therapies for non-alcoholic fatty liver disease: Evidence and perspectives.
      . Another explanation may be reluctance on the part of the patient or surgeon to perform a BS after a LT. Nevertheless, current data, based on series of small numbers, show good results of BS after LT

      Serrano OK, Peterson KJ, Vock DM, Berglund D, Kandaswamy R, Lake JR, Pruett TL, Chinnakotla S. Clinical Impact of Antecedent Bariatric Surgery on Liver Transplant Outcomes: A Retrospective Matched Case-control Study. Transplantation. 2020;

      ,
      • Zamora-Valdes D.
      • Watt K.D.
      • Kellogg T.A.
      • Poterucha J.J.
      • Di Cecco S.R.
      • Francisco-Ziller N.M.
      • et al.
      Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy.
      . The second modifiable factor after LT is immunosuppressive treatments: all maintenance immunosuppressive drug classes (CNI, mTOR-i and corticosteroids) have deleterious metabolic profile except antimetabolites (MMF and azathioprine). MMF monotherapy is possible but only in selected patients with long delay since LT and can therefore not be generally recommended
      • Lassailly G.
      • Dumortier J.
      • Saint-Marcoux F.
      • El Amrani M.
      • Boulanger J.
      • Boleslawski E.
      • et al.
      Real life experience of mycophenolate mofetil monotherapy in liver transplant patients.
      . Avoiding steroids and minimizing CNI and/or mTORi is feasible but probably has a minimal impact. We believe it is essential to reduce the dosage of immunosuppressive drugs to a minimum, and to perform a liver biopsy at 12 months of LT to determine steatosis. Recurrence of grade 2 steatosis on the graft at 12 months seems to be strongly associated with both recurrence of NASH and advanced fibrosis: we suggest discussing BS in these patients, who represent about a quarter of NAFLD transplanted patients in our population.
      Table 4Recurrence of Initial Graft Disease after Liver Transplantation for NAFLD Cirrhosis (Major studies with liver histological evaluation).
      StudiesFollow-up after LT (years)Steatosis recurrence on liver biopsiesNASH recurrence on liver biopsiesAdvances fibrosis on liver biopsiesRisk factors for NAFLD recurrenceRisk factors for NASH recurrenceRisk factors for advanced fibrosis recurrence
      Univariate analysisMultivariate analysisUnivariate analysisMultivariate analysisUnivariate analysisMultivariate analysis
      Bhagat and al. (2009)(10)0.521/64 (32.8%)
      Steatosis between 34-66%.
      0/64 (0%)
      Yalamanchili and al. (2010)(23)1

      5

      10
      3/18 (18%)

      8/18 (44%)
      0/18 (0%)

      1/18 (6%)

      3/18 (16%)
      0/18

      1/18 (5.5%)

      2/18 (11.1%)
      Dureja and al. (2011)
      • Dureja P.
      • Mellinger J.
      • Agni R.
      • Chang F.
      • Avey G.
      • Lucey M.
      • et al.
      NAFLD recurrence in liver transplant recipients.
      0.934/88 (38.6%)9/88 (10.2%)3/88 (3.4%)BMI pre-LT

      BMI post-LT

      Corticoids

      Post-LT triglycerides

      Post-LT Diabetes

      Arterial hypertension
      BMI pre-LT (OR: 1.15)

      BMI post-LT (OR: 1.22)

      Post-LT triglycerides (OR: 1.01)
      Malik and al. (2009)(16)1.255/79 (69.6%)19/79 (24.1%)7/79 (7.6%)
      Vallin and al. (2014)(11)1

      5
      11/11 (100%)

      7/7 (100%)
      9/11 (81.8%)

      5/7 (71.4%)
      2/11 (18.2%)

      5/7 (71.4%)
      Sourianarayanane and al. (2017)(24)1

      3

      5
      7/44 (16%)
      Steatosis between 34-66%.


      4/18 (22%)
      Steatosis between 34-66%.


      6/17 (35%)
      Steatosis between 34-66%.
      3/44 (6.8%)

      4/18 (22.2%)

      5/17 (29.4%)
      1/44 (2.3%)

      0/18 (0%)

      1/17 (5.9%)
      Bhati and al. (2017)
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • Rivera M.
      • Driscoll C.
      • Stravitz R.T.
      • et al.
      Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis.
      3.930/34 (88,2%)14/34(41.2%)7/34 (20.6%)Post-LT Diabetes

      Post-LT triglycerides
      Post-LT Diabetes

      Post-LT triglycerides
      Villeret and al. (2022)1

      5
      81/150 (62.0%)
      Cumulative incidence rate.


      104/150 (85.0%)
      Cumulative incidence rate.
      10/150 (10.4%)
      Cumulative incidence rate.


      34/150 (60.3%)
      Cumulative incidence rate.
      0/150 (0.0%)
      Cumulative incidence rate.


      10/150 (20.0%)
      Cumulative incidence rate.
      BMI at LT

      Pre-LT MS

      Donors Age > 60Y

      BMI at 1 year post LT

      Post-LT Hb1Ac > 8% lipid drugs
      BMI pre-LT (OR: 2.7)Age at LT

      BMI pre-LT

      BMI at 1 year

      Post-LT HDLc < 1.15mmol/L

      Steatosis recurrence at 1 year
      Age < 65 y at LT (OR:4.214 )

      Post-LT HDLc < 1.15mmol/L (OR : 3.463 )

      Grade 2 Steatosis recurrence at 1 year (OR :10.196)
      Age at LT

      BMI pre-LT

      Pre-LT MS

      No HCC at LT

      BMI at 1 year

      Long term CYA

      Grade 2 steatosis recurrence at 1 year
      Pre-LT MS (OR : 8.6)

      Long term CYA (OR: 11.4)

      Grade 2 steatosis recurrence at 1 year (OR : 10.7)
      BMI: Body Mass Index; CYA: CYA: cyclosporine A; HCC: Hepatocellular Carcinoma; HDL-c: High-Density Lipoproteins Cholesterol; LDL-c: Low-Density Lipoproteins; LT: Liver Transplantation; MS: Metabolic Syndrome; OR: Odds ratio.
      Steatosis between 34-66%.
      ∗∗ Cumulative incidence rate.
      In conclusion, we report here the largest cohort based on liver biopsies of NAFLD recurrence after LT. The recurrence of steatosis and steatohepatitis on the graft was rapid and very frequent. Several associated factors have been identified and need to be confirmed in other large studies. The performance of a protocol biopsy at 12 months after LT appears to be determining to identify patients at risk of progression to NASH or advanced fibrosis. In these patients with grade 2 steatosis, representing about 25% of patients, BS should be discussed. The management of metabolic factors and the place of BS need to be evaluated to reduce the risk of recurrence of the initial disease in this exponentially growing population of LT patients.

      Data availability statement:

      Due to the sensitive nature of the questions asked in this study, survey respondents were assured raw data would remain confidential and would not be shared.

      Acknowledgements

      We thank all LT teams that participated in this study.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

      References

        • Paik J.M.
        • Golabi P.
        • Younossi Y.
        • Mishra A.
        • Younossi Z.M.
        Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of NAFLD.
        Hepatol. Baltim. Md. 2020; 72: 1605-1616
        • Nabi O.
        • Lacombe K.
        • Boursier J.
        • Mathurin P.
        • Zins M.
        • Serfaty L.
        Prevalence and Risk Factors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in General Population: the French Nationwide NASH-CO Study.
        Gastroenterology. 2020; 159: 791-793.e2
        • Sheka A.C.
        • Adeyi O.
        • Thompson J.
        • Hameed B.
        • Crawford P.A.
        • Ikramuddin S.
        Nonalcoholic Steatohepatitis: A Review.
        JAMA. 2020; 323: 1175-1183
        • Lassailly G.
        • Caiazzo R.
        • Ntandja-Wandji L.-C.
        • Gnemmi V.
        • Baud G.
        • Verkindt H.
        • et al.
        Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.
        Gastroenterology. 2020; 159: 1290-1301.e5
        • Haldar D.
        • Kern B.
        • Hodson J.
        • Armstrong M.J.
        • Adam R.
        • Berlakovich G.
        • et al.
        Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study.
        J. Hepatol. 2019; 71: 313-322
        • Younossi Z.M.
        • Stepanova M.
        • Ong J.
        • Trimble G.
        • AlQahtani S.
        • Younossi I.
        • et al.
        Nonalcoholic Steatohepatitis is the Most Rapidly Increasing Indication for Liver Transplantation in the United States.
        Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2020;
      1. National Health Service Blood and Transplant. Annual Report On Liver Transplantation. 2020;

      2. Agence de la Biomédecine. Le rapport médical et scientifique 2020 [Internet]. 2020;Available from: https://rams.agence-biomedecine.fr/

        • Bhati C.
        • Idowu M.O.
        • Sanyal A.J.
        • Rivera M.
        • Driscoll C.
        • Stravitz R.T.
        • et al.
        Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis.
        Transplantation. 2017; 101: 1867-1874
        • Bhagat V.
        • Mindikoglu A.L.
        • Nudo C.G.
        • Schiff E.R.
        • 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 Transplant. Off. Publ. Am. Assoc. Study Liver Dis. Int. Liver Transplant. Soc. 2009; 15: 1814-1820
        • Vallin M.
        • Guillaud O.
        • Boillot O.
        • Hervieu V.
        • Scoazec J.-Y.
        • Dumortier J.
        Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis.
        Liver Transplant. Off. Publ. Am. Assoc. Study Liver Dis. Int. Liver Transplant. Soc. 2014; 20: 1064-1071
      3. Saeed N, Glass L, Sharma P, Shannon C, Sonnenday CJ, Tincopa MA. Incidence and Risks for Non Alcoholic Fatty Liver Disease and Steatohepatitis Post Liver Transplant: Systematic Review and Meta-analysis. Transplantation. 2019;

        • Alberti K.G.M.M.
        • Eckel R.H.
        • Grundy S.M.
        • Zimmet P.Z.
        • Cleeman J.I.
        • Donato K.A.
        • et al.
        Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
        Circulation. 2009; 120: 1640-1645
        • Bedossa P.
        • Poitou C.
        • Veyrie N.
        • Bouillot J.-L.
        • Basdevant A.
        • Paradis V.
        • et al.
        Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients.
        Hepatol. Baltim. Md. 2012; 56: 1751-1759
        • Kleiner D.E.
        • Brunt E.M.
        • Van Natta M.
        • Behling C.
        • Contos M.J.
        • Cummings O.W.
        • et al.
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatol. Baltim. Md. 2005; 41: 1313-1321
        • Malik S.M.
        • deVera M.E.
        • Fontes P.
        • Shaikh O.
        • Ahmad J.
        Outcome after liver transplantation for NASH cirrhosis.
        Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg. 2009; 9: 782-793
        • Villeret F.
        • Dharancy S.
        • Erard D.
        • Abergel A.
        • Barbier L.
        • Besch C.
        • et al.
        Liver transplantation for NAFLD cirrhosis: Age and recent coronary angioplasty are major determinants of survival.
        Liver Int. Off. J. Int. Assoc. Study Liver. 2022;
        • Siddiqui M.S.
        • Sterling R.K.
        Posttransplant metabolic syndrome.
        Int. J. Hepatol. 2012; 2012891516
        • Malik S.M.
        • deVera M.E.
        • Fontes P.
        • Shaikh O.
        • Sasatomi E.
        • Ahmad J.
        Recurrent disease following liver transplantation for nonalcoholic steatohepatitis cirrhosis.
        Liver Transpl. 2009; 15: 1843-1851
        • Carter D.
        • Dieterich D.T.
        • Chang C.
        Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis in Liver Transplantation.
        Clin. Liver Dis. 2018; 22: 213-227
        • Siddiqui M.S.
        • Idowu M.O.
        • Stromberg K.
        • Sima A.
        • Lee E.
        • Patel S.
        • et al.
        Diagnostic Performance of Vibration-Controlled Transient Elastography in Liver Transplant Recipients.
        Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2020;
        • Bhat M.
        • Tazari M.
        • Sebastiani G.
        Performance of transient elastography and serum fibrosis biomarkers for non-invasive evaluation of recurrent fibrosis after liver transplantation: A meta-analysis.
        PloS One. 2017; 12e0185192
        • Yalamanchili K.
        • Saadeh S.
        • Klintmalm G.B.
        • Jennings L.W.
        • Davis G.L.
        Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease.
        Liver Transplant. Off. Publ. Am. Assoc. Study Liver Dis. Int. Liver Transplant. Soc. 2010; 16: 431-439
        • Sourianarayanane A.
        • Arikapudi S.
        • McCullough A.J.
        • Humar A.
        Nonalcoholic steatohepatitis recurrence and rate of fibrosis progression following liver transplantation.
        Eur. J. Gastroenterol. Hepatol. 2017; 29: 481-487
        • Agopian V.G.
        • Kaldas F.M.
        • Hong J.C.
        • Whittaker M.
        • Holt C.
        • Rana A.
        • et al.
        Liver transplantation for nonalcoholic steatohepatitis: the new epidemic.
        Ann. Surg. 2012; 256: 624-633
        • Balitzer D.
        • Tsai J.-H.
        • Gill R.M.
        Clinicopathologic features of de novo non-alcoholic steatohepatitis in the post-transplant setting.
        Diagn. Pathol. 2022; 17: 65
      4. Serrano OK, Peterson KJ, Vock DM, Berglund D, Kandaswamy R, Lake JR, Pruett TL, Chinnakotla S. Clinical Impact of Antecedent Bariatric Surgery on Liver Transplant Outcomes: A Retrospective Matched Case-control Study. Transplantation. 2020;

        • Tsamalaidze L.
        • Stauffer J.A.
        • Arasi L.C.
        • Villacreses D.E.
        • Franco J.S.S.
        • Bowers S.
        • et al.
        Laparoscopic Sleeve Gastrectomy for Morbid Obesity in Patients After Orthotopic Liver Transplant: a Matched Case-Control Study.
        Obes. Surg. 2018; 28: 444-450
        • Zamora-Valdes D.
        • Watt K.D.
        • Kellogg T.A.
        • Poterucha J.J.
        • Di Cecco S.R.
        • Francisco-Ziller N.M.
        • et al.
        Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy.
        Hepatol. Baltim. Md. 2018; 68: 485-495
      5. Haute Autorité de Santé. Obésité:prise en charge chirurgicale chez l’adulte [Internet]. 2009;Available from: https://www.has-sante.fr/upload/docs/application/pdf/2011-10/reco2clics_obesite_adulte_chirurgie.pdf

        • Mechanick J.I.
        • Youdim A.
        • Jones D.B.
        • Timothy Garvey W.
        • Hurley D.L.
        • Molly McMahon M.
        • et al.
        Clinical Practice Guidelines for the Perioperative Nutritional, Metabolic, and Nonsurgical Support of the Bariatric Surgery Patient—2013 Update: Cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery.
        Surg. Obes. Relat. Dis. 2013; 9: 159-191
        • Cunha J.B.
        • Fialho M.C.M.P.
        • Arruda S.L.M.
        • Nóbrega O.T.
        • Camargos E.F.
        Clinical and Metabolic Improvement after Bariatric Surgery in Older Adults: A 6-Year Follow-Up.
        J. Nutr. Health Aging. 2020; 24: 865-869
        • Susmallian S.
        • Barnea R.
        • Weiss Y.
        • Raziel A.
        Outcome of bariatric surgery in older patients.
        Surg. Obes. Relat. Dis. Off. J. Am. Soc. Bariatr. Surg. 2018; 14: 1705-1713
        • Goldberg I.
        • Yang J.
        • Nie L.
        • Bates A.T.
        • Docimo S.
        • Pryor A.D.
        • et al.
        Safety of bariatric surgery in patients older than 65 years.
        Surg. Obes. Relat. Dis. Off. J. Am. Soc. Bariatr. Surg. 2019; 15: 1380-1387
        • Salomone F.
        • Sharaiha R.Z.
        • Boškoski I.
        Endoscopic bariatric and metabolic therapies for non-alcoholic fatty liver disease: Evidence and perspectives.
        Liver Int. 2020; 40: 1262-1268
        • Lassailly G.
        • Dumortier J.
        • Saint-Marcoux F.
        • El Amrani M.
        • Boulanger J.
        • Boleslawski E.
        • et al.
        Real life experience of mycophenolate mofetil monotherapy in liver transplant patients.
        Clin. Res. Hepatol. Gastroenterol. 2020;
        • Dureja P.
        • Mellinger J.
        • Agni R.
        • Chang F.
        • Avey G.
        • Lucey M.
        • et al.
        NAFLD recurrence in liver transplant recipients.
        Transplantation. 2011; 91: 684-689