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. Author manuscript; available in PMC: 2023 May 2.
Published in final edited form as: Liver Transpl. 2021 Nov 5;28(4):623–635. doi: 10.1002/lt.26313

Evaluating Outcomes Related to Donor and Recipient Metabolic Environment: Macrosteatotic Allografts and Nonalcoholic Steatohepatitis

Peter J Altshuler 1, Hien Dang 1, Adam M Frank 1, Ashesh P Shah 1, Jaime Glorioso 1, Tingting Zhan 2, Arturo Rios Diaz 1, Osama Shaheen 1, Carlo B Ramirez 1, Warren R Maley 1, Adam S Bodzin 1
PMCID: PMC10152802  NIHMSID: NIHMS1890975  PMID: 34564931

Abstract

Background & Aims

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) affects both recipient and donor populations in liver transplant. Presently, it is unclear whether transplantation of macrosteatotic allografts is affected by the metabolic milieu of liver transplant recipients. This study investigates fatty liver disease at the intersection of donor and recipient.

Approach & Results

Retrospective review of the Organ Procurement and Transplantation database identified 5,167 NASH and 26,289 non-NASH transplant recipients from 1/1/2004-6/12/2020. 12,569 donors had allografts with no (<5%) macrosteatosis, 16,140 had mild (5-29%) and 2,747 moderate-severe (≥30%) macrosteatosis. Comparing NASH recipients to propensity score matched (PSM) non-NASH recipients demonstrated non-inferior graft and patient survival up to 10 years in NASH patients. Similar trends were observed in subgroup analyses of transplants within each strata of allograft macrosteatosis. Assessing allograft macrosteatosis specifically in the NASH population demonstrated that allografts with ≥30% macrosteatosis were associated with reduced early graft survival (30-day: 93.32% vs. 96.54%, p=0.02; 1-year: 84.53% vs. 88.99%, p=0.05) compared to PSM grafts with <30% macrosteatosis. Long-term graft survival at 5 and 10 years, however, was similar.

Conclusion

The use of carefully selected macrosteatotic allografts can be successful in both NASH and non-NASH recipients. Metabolic environment of NASH patients does not appear to adversely affect outcomes with regards to the allograft when controlled for numerous confounders. It is, however, important to remain cognizant of the potential for high-risk macrosteatotic allografts to negatively affect outcomes.

Keywords: NASH, NAFLD, metabolic syndrome, macrosteatosis, propensity match, liver transplant

Introduction

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) is reshaping the landscape of liver transplantation from both donor and recipient standpoints. Related to the obesity epidemic and high rates of metabolic syndrome in the United States, NAFLD is present in over 25% of the population, one quarter of which have progressed to nonalcoholic steatohepatitis (NASH)1,2. NASH currently represents the most common etiology of liver failure requiring transplant listing in females and the second most common in males within the United States3; determining optimal donor and recipient strategies related to fatty liver disease is, therefore, a priority for the field of liver transplantation.

NAFLD and NASH are a progressive spectrum of diseases involving steatotic replacement of the liver parenchyma. Utilization of donors affected by this spectrum represents a particular challenge as allograft macrosteatosis is associated with reperfusion injury and early allograft loss4,5. These findings have led to discard rates as high as 44% for allografts with ≥ 30% macrosteatosis6. Recipients with NASH also represent a uniquely challenging population, as the underlying metabolic syndrome generally associated with the disease predisposes them to additional systemic comorbordities7. These patients, too, can be placed at a disadvantage as their comorbid profile may bias against their listing for liver transplant8.

Recent studies have intended to better understand the impact of fatty liver disease from both recipient and donor standpoint. From the recipient perspective survival after transplant in recipients with NASH appears equal to, or greater than, transplantation for non-NASH diseases9. From a donor standpoint, allograft macrosteatosis increases reperfusion injury which increases risk of primary non-function (PNF) and early allograft dysfunction (EAD)10–12. These risks, however, can be mitigated if optimal donors are selected and cold ischemia time limited10–13. Despite this growing body of literature, little has been examined regarding the intersection of the two where macrosteatotic allografts are used in recipients with NASH. This study intended to address fatty liver disease at its overlap between donor and recipient in liver transplantation, hypothesizing that transplantation outcomes in the metabolically-deranged NASH population compared to non-NASH counterparts may be affected by the metabolic milieu when using macrosteatotic allografts.

Experimental Procedures

Patient population

This study was designed as a retrospective review of the federally-maintained, deidentified UNOS Organ Procurement and Transplantation Network (OPTN) database. All adult (≥18 year-old) deceased donor liver transplant recipients in the United States with documented allograft macrosteatosis between 1/1/2004 and 6/12/2020 were included. NASH patients were identified through their listed diagnosis of end-stage liver disease. To account for the high rate of undiagnosed NASH in patients with cryptogenic cirrhosis,14,15 those with cryptogenic cirrhosis and underlying diabetes or BMI ≥ 30 were considered as NASH patients. Recipients were divided by diagnosis of NASH (NASH: n=5,167, non-NASH: n=26,289). Donors were then divided by degree of allograft macrosteatosis: none (<5%; n=12,569), mild (5-29%; n=16,140) and moderate-severe (≥30%; n=2,747).

Recipient and donor populations were assessed in three separate contexts. First, to determine the relative safety of utilizing macrosteatotic grafts in NASH patients, transplant outcomes were compared in NASH and propensity score matched (PSM) non-NASH recipients within each strata of allograft macrosteatosis. Second, the specific impact of transplanting macrosteatotic grafts into NASH recipients was determined by comparing moderate-severely macrosteatotic grafts to a PSM non or mildly macrosteatotic group specifically within the NASH population. Finally, donors with moderate-severely macrosteatotic allografts were evaluated to determine characteristics most highly associated with early allograft failure after transplant. Approval to conduct this analysis was obtained from the Thomas Jefferson University Institutional Review Board.

Statistical analysis

Continuous variables were evaluated for normality using the Shapiro Wilk test. Non-normally distributed variables were compared with a Wilcoxon rank-sum test and were represented as median(interquartile range (IQR)). Categorical variables were compared using a chi-square (χ2) test and were represented as number(percentage of population). Post-transplant patient and graft survival were reported graphically with Kaplan-Meier curves and numerically by time-varying Cox proportional hazards ratios (HRs) and 95% confidence intervals (95% CIs). Two-sided statistical significance was set a priori at p<0.05. All statistical analyses were performed using Stata/MP 16.1 (Statacorp, College Station, TX).

Propensity Score Matched analysis

Propensity score matching was used to reduce inherent variability and selection bias associated with both recipient and donor cohorts of interest. This was performed using 1:1 matching using a caliper width of 0.2. Variables selected in the model were associated with graft failure at 1 year or determined a priori as clinically significant. Recipient variables included were as follows: age, sex, race, MELD score, Status 1A listing, hospitalization status at time of transplant, pre-transplant hemodialysis, pre-transplant portal vein thrombosis (PVT), presence of hepatocellular carcinoma (HCC), previous abdominal surgery, previous liver transplant, and multiorgan recipient. Donor variables were: age, sex, cause of death, pre-donation inotropic support, and donation after cardiac death (DCD), Body mass index (BMI) and presence of diabetes, being highly correlated with fatty liver disease in both recipient and donor, were excluded to avoid additional confounding. Appropriate matching was confirmed through histogram analysis of propensity score distributions and by Rubin’s Bias and Ratio tests comparing matched cohorts16. Full details regarding the propensity score model and the contexts in which they were utilized are found in Supplementary Figure S1.

This propensity score model was run in two separate contexts. In the first, NASH recipients were compared to PSM non-NASH recipients. Here, NASH and PSM non-NASH patients were compared within subgroups of transplants using non (<5%), mildly (5-29%) or moderate-severely (>30%) macrosteatotic allografts. Additional analyses of NASH and non-NASH transplants independent of degree of allograft macrosteatosis are presented in Supplementary Table S1. Following this NASH patients were isolated, and recipients transplanted with ≥30% macrosteatotic allografts were compared to PSM recipients of grafts with <30% macrosteatosis. The primary outcome assessed was graft survival. Secondary outcomes assessed for patient survival, rates of PNF of the liver allograft, and rates of graft failure due to rejection and recurrent disease.

Regression modeling

Donor predictors of graft loss at 1 year in transplants utilizing allografts with ≥30% and <30% macrosteatosis were assessed using Cox proportional hazard regression models. Donor covariates assessed were: age, cause of death, BMI, presence of diabetes, hypertension, >20 pack-year smoking history, heavy alcohol use, elevated alanine transaminase (AST), total bilirubin, creatinine, need for inotropic support and presence of bacteremia. Potential recipient and procurement-related confounders were addressed by model adjustment with factors predictive of post-transplant graft failure not related to development of macrosteatosis. Covariates in the final multivariable model were those associated with graft loss at p<0.2 in the univariate analysis. Schoenfeld’s residuals were evaluated to ensure validity of the assumptions used in Cox methodology.

Population validation and assessing for potential era and population-level effects

Important subpopulations and temporal trends exist within the overall NASH and non-NASH cohorts that present the potential to confound data presented in the main text. To ensure these potential confounders were appropriately controlled, several supplementary analyses were performed. The first subpopulation assessed was the HCC cohort. As HCC is known to confer inferior long-term graft and patient survival17, NASH and non-NASH HCC patients from the overall, macrosteatosis-independent PSM analysis were isolated and compared (Supplementary Tables S2/3). Secondly, widespread use of direct-acting antiviral therapy for hepatitis C virus (HCV) have dramatically improved outcomes for liver transplant recipients with HCV since 201318,19. To address this, as well any potential temporal trends potentially uncaptured by the study accrual period, a separate evaluation of NASH to PSM non-NASH patients transplanted only between 11/23/2013 (the date of regulatory approval of simeprevir and sofosbuvir) and 6/12/2020 was performed (Supplementary Tables S4/5).

Results

Comparing outcomes in NASH vs. PSM non-NASH recipients using non-macrosteatotic allografts

After dividing NASH and non-NASH recipients by degree of allograft macrosteatosis, NASH recipients were compared to PSM non-NASH patients within subgroups of allograft macrosteatosis. Baseline comparison of the cohort of patients receiving non-macrosteatotic (<5%) allografts revealed that NASH and PSM non-NASH recipients were largely similar, although NASH patients carried higher BMI (31.43 vs. 27.25, p<0.01) and increased rates of diabetes (54.48% vs.20.40%, p<0.01, Table 1). Compared to PSM non-NASH transplants, donors in the NASH cohort had higher BMI (27.43 vs. 26.79, p<0.01), increased rates of diabetes (20.99% vs. 16.89%, p<0.01), arose more frequently in the setting of anoxia (36.04% vs. 33.84%, p=0.05), and had higher creatinine at transplant (1.27 vs. 1.10, p<0.01).

Table 1:

Propensity matched baseline characteristics between NASH and non-NASH recipients by degree of allograft macrosteatosis

No macrosteatosis (<5%) Mild macrosteatosis (5-29%) Moderate-Severe macrosteatosis ( ≥30%)
NASH Non-NASH p-value NASH Non-NASH p-value NASH Non-NASH p-value
Number 1,906 1,906 2,537 2,537 460 460
Recipient characteristics
Age 61 (54-65) 60 (55-65) 0.10 61 (54-65) 60 (55-64) 0.01 60 (54-64) 59 (52-64) 0.21
Female sex 765 (40.14%) 786 (41.24%) 0.51 967 (38.12%) 993 (39.14%) 0.47 139 (30.22%) 152 (33.04%) 0.39
Ethnicity 0.69 0.54 0.55
White 1,537 (80.64%) 1,548 (81.22%) 2,077 (81.87%) 2,068 (81.51%) 370 (80.43%) 360 (78.26%)
Black 38 (1.99%) 43 (2.26%) 52 (2.05%) 64 (2.52%) 11 (2.39%) 16 (3.48%)
Other 331 (17.37%) 315 (16.53%) 408 (16.08%) 405 (15.96%) 79 (17.18%) 84 (18.26%)
BMI 31.43 (27.80-35.61) 27.25 (31.56-35.88) <0.01 31.85 (27.83-35.83) 27.76 (24.27-31.74) <0.01 31.91 (28.75-36.25) 27.75 (24.88-31.13) <0.01
ICU status at transplant 181 (9.50%) 199 (10.44%) 0.36 239 (9.42%) 279 (11.00%) 0.07 35 (7.61%) 43 (9.35%) 0.41
Status 1A 7 (0.37%) 13 (0.68%) 0.26 8 (0.32%) 15 (0.59%) 0.21 1 (0.22%) 2 (0.43%) 0.99
MELD 22 (16-29) 22 (15-31) 0.42 22 (16-29) 22 (15-30) 0.49 20 (15-25) 19 (14-27) 0.75
Disabled functional status 720 (37.78%) 725 (38.04%) 0.89 973 (38.35%) 947 (37.33%) 0.47 164 (35.65%) 150 (32.61%) 0.37
Hepatocellular carcinoma 268 (14.06%) 269 (14.11%) 0.99 370 (14.58%) 380 (14.98%) 0.72 66 (14.35%) 68 (14.78%) 0.93
Diabetes mellitus 1,010 (54.48%) 378 (20.40%) <0.01 1,353 (55.15%) 492 (19.95%) <0.01 255 (58.35%) 96 (21.33%) <0.01
Portal vein thrombus 295 (15.58%) 277 (14.66%) 0.44 395 (15.28%) 377 (15.00%) 0.78 66 (14.38%) 67 (14.69%) 0.93
Hemodialysis 250 (13.12%) 249 (13.06%) 0.99 325 (12.81%) 349 (13.76%) 0.34 41 (8.91%) 46 (10.00%) 0.65
Previous abdominal surgery 961 (50.42%) 978 (51.31%) 0.60 1,331 (52.46%) 1,383 (54.51%) 0.15 241 (52.39%) 257 (55.87%) 0.32
Previous liver transplant 16 (0.84%) 22 (1.15%) 0.42 27 (1.06%) 32 (1.26%) 0.60 4 (0.87%) 6 (1.30%) 0.75
Donor characteristics
Age 51 (38-62) 51 (38-61) 0.89 52 (41-61) 53 (41-62) 0.80 47 (37-57) 49 (38-57) 0.64
Female sex 918 (48.16%) 922 (48.37%) 0.92 1,161 (45.76%) 1,165 (45.92%) 0.93 194 (42.17%) 195 (42.39%) 0.99
BMI 27.43 (23.73-32.51) 26.79 (23.27-31.33) <0.01 30.10 (25.84-35.79) 38.82 (25.00-33.88) <0.01 32.48 (27.62-38.46) 30.44 (25.66-35.91) <0.01
Diabetes mellitus 400 (20.99%) 322 (16.89%) <0.01 541 (21.32%) 463 (18.25%) 0.01 97 (21.09%) 84 (18.26%) 0.32
Hypertension 1,225 (64.27%) 1,168 (61.28%) 0.06 1,653 (65.16%) 1,547 (60.98%) <0.01 293 (63.70%) 281 (61.09%) 0.45
Smoking history 456 (23.92%) 488 (25.60%) 0.24 635 (25.03%) 675 (26.61%) 0.21 87 (18.91%) 105 (22.83%) 0.17
Heavy alcohol use 319 (16.74%) 355 (18.63%) 0.14 505 (19.91%) 538 (21.21%) 0.27 94 (20.43%) 106 (23.04%) 0.38
Creatinine (mg/dL) 1.27 (0.81-2.30) 1.10 (0.80-1.88) <0.01 1.20 (0.81-1.90) 1.18 (0.84-1.88) 0.72 1.20 (0.87-1.90) 1.20 (0.90-1.80) 0.73
AST (u/L) 42 (26-82) 41 (24-79) 0.21 41 (24-83) 42 (25-80) 0.58 44 (26-81) 49 (28-94) 0.17
Inotrope support 997 (52.31%) 990 (51.94%) 0.85 1,352 (53.29%) 1,334 (52.58%) 0.63 254 (55.22%) 260 (56.52%) 0.74
DCD 140 (7.35%) 148 (7.76%) 0.67 184 (7.25%) 205 (8.08%) 0.29 28 (6.09%) 23 (5.00%) 0.56
LDRI 1.69 (1.38-2.02) 1.67 (1.36-2.02) 0.35 1.68 (1.39-1.99) 1.69 (1.40-2.04) 0.18 1.62 (1.36-1.95) 1.61 (1.35-1.88) 0.18
Cause of death 0.05 0.79 0.57
Anoxia 687 (36.04%) 645 (33.84%) 834 (32.87%) 827 (32.60%) 147 (31.96%) 133 (28.91%)
CVA 801 (42.03%) 801 (42.03%) 1,135 (44.74%) 1,160 (45.72%) 208 (45.22%) 211 (45.87%)
Head trauma 356 (18.68%) 413 (21.67%) 510 (20.10%) 484 (19.08%) 87 (18.91%) 101 (21.96%)
CNS tumor 7 (0.37%) 2 (0.1%) 12 (0.47%) 16 (0.63%) 9 (1.96%) 5 (1.09%)
Other 55 (2.89%) 45 (2.36%) 46 (1.81%) 50 (1.97%) 9 (1.96%) 10 (2.17%)
Transplant details
Multiorgan 133 (6.98%) 135 (7.08%) 0.95 187 (7.37%) 180 (7.09%) 0.75 28 (6.09%) 36 (7.83%) 0.36
CIT (hours) 6.07 (4.97-7.87) 6.10 (4.90-8.00) 0.93 6.25 (5.00-8.00) 6.25 (5.00-8.00) 0.88 6.43 (5.14-8.00) 6.50 (5.20-7.92) 0.89
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Values are listed as median +/− interquartile range unless otherwise stated

BMI: body mass index,NASH: non-alcoholic steatohepatitis, AST: aspartate aminotransferase, CVA: cerebrovascular accident, CNS: central nervous system, LDRI: Liver Donor Risk Index, DCD: donation after cardiac death, CIT: cold ischemia time

In transplants using non-macrosteatotic allografts, NASH patients demonstrated improved long-term outcomes compared to their propensity matched non-NASH counterparts. Here, graft survival for NASH vs. non-NASH patients was 96.89% vs. 96.48% at 30 days (p=0.50), 89.12% vs. 88.09% at 1 year (p=0.50), 77.10% vs. 73.53% at 5 years (p=0.03) and 62.48% vs. 57.60% at 10 years (p=0.02, Table 2, Figure 1B). Patient survival was 97.90% vs. 97.84% at 30 days (p=0.94), 91.07% vs. 90.48% at 1 year (p=0.64), 79.07% vs. 76.19% at 5 years (p=0.08) and 63.53% vs. 59.91% at 10 years (p=0.06). Graft loss from recurrent disease was 2.86% in NASH patients vs. 5.59% in non-NASH patients (p=0.06), while rates of PNF were similar between groups (1.68% vs. 2.36%, p=0.17).

Table 2:

Propensity matched transplant outcomes in NASH and non-NASH recipients by degree of allograft macrosteatosis

No macrosteaosis (<5%) Mild macrosteatosis (5-29%) Moderate-Severe macrosteatosis ( ≥30%)
NASH Non-NASH HR 95% CI p-value NASH Non-NASH HR 95% CI p-value NASH Non-NASH HR 95% CI p-value
Number 1,906 1,906 2,537 2,537 460 460
Primary non-function 32 (1.68%) 45 (2.36%) - - 0.17 54 (2.13%) 61 (2.40%) - - 0.57 13 (2.83%) 13 (2.83%) - - 0.99
Graft loss due to rejection 16 (3.82%) 23 (4.28%) - - 0.75 26 (4.36%) 28 (3.81%) - - 0.68 2 (1.87%) 2 (1.57%) - - 0.99
Graft loss due to recurrent disease 12 (2.86%) 30 (5.59%) - - 0.06 12 (2.01%) 26 (3.54%) - - 0.10 0 (0.00%) 10 (7.87%) - - <0.01
Graft survival
30-day 96.89% 96.48% 0.88 0.62-1.26 0.50 96.22% 95.78% 0.89 0.68-1.18 0.43 93.27% 95.51% 1.52 0.86-2.67 0.15
1-year 89.12% 88.09% 0.92 0.76-1.11 0.38 88.57% 86.35% 0.83 0.71-0.98 0.03 85.29% 87.90% 1.25 0.86-1.81 0.24
5-year 77.10% 73.53% 0.85 0.74-0.98 0.03 75.97% 71.89% 0.85 0.73-0.94 0.01 75.97% 73.73% 1.00 0.75-1.36 0.96
10-year 62.48% 57.60% 0.85 0.74-0.97 0.02 56.92% 56.15% 0.87 0.78-0.98 0.02 56.34% 55.37% 1.00 0.77-1.32 0.96
Patient survival
30-day 97.90% 97.84% 0.98 0.63-1.52 0.94 97.66% 97.29% 0.86 0.60-1.22 0.40 95.23% 96.39% 1.33 0.69-2.55 0.34
1-year 91.07% 90.48% 0.95 0.76-1.18 0.64 90.87% 88.45% 0.78 0.65-0.94 0.01 88.21% 89.61% 1.15 0.76-1.73 0.51
5-year 79.07% 76.19% 0.87 0.74-1.02 0.08 78.13% 73.83% 0.79 0.69-0.91 <0.01 78.51% 75.99% 0.96 0.70-1.33 0.81
10-year 63.53% 59.91% 0.87 0.76-1.00 0.06 58.33% 57.35% 0.85 0.76-0.96 0.01 57.56% 56.56% 0.97 0.73-1.30 0.86
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Figure 1:

Figure 1:

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Kaplan Meier graft survival curves in NASH and propensity matched non-NASH cohorts. A) in all transplants; B) using non-macrosteatotic (<5%) grafts; C) using mildly macrosteatotic (5-29%) grafts; and D) using moderate-severely (≥ 30%) macrosteatotic grafts

Comparing outcomes in NASH vs. PSM non-NASH recipients using mildly macrosteatotic allografts

NASH and PSM non-NASH recipients of mildly (5-29%) macrosteatotic allografts were subsequently compared. In this group, NASH patients were older (61 vs. 60, p=0.01) with higher BMI (31.85 vs. 27.76, p<0.01 and more frequently diabetic (55.15% vs. 19.95%, p<0.01, Table 1). Donors used in NASH transplants carried higher BMI (30.10 vs. 28.82) and increased incidences of diabetes (21.32% vs. 18.25%) and hypertension (65.16% vs. 60.98%), but were otherwise similar to those used in non-NASH transplants.

Similar trends were observed in graft and patient survival for the mildly macrosteatotic group compared to the non-macrosteatotic population (Table 2, Figure 1C). Here, graft survival in NASH patients was 96.22% a compared to. 95.78% in non-NASH patients at 30 days (p=0.43), 88.57% vs. 86.35% at 1 year (p=0.03), 75.97% vs. 71.89% at 5 years (p=0.01) and 56.92% vs. 56.15% at 10 years (p=0.02). Patient survival was 97.66% vs. 97.29% at 30 days, 90.87% vs. 88.45% at 1 year (p=0.01), 78.13% vs. 73.83% at 5 years (p<0.01) and 58.33% vs. 57.35% at 10 years (p=0.01). Graft failure due to rejection was 4.36% in NASH patients compared to 3.81% in non-NASH recipients (p=0.68), while graft failure from recurrent disease was 2.01% vs. 3.54% (p=0.10). PNF rates were again comparable between NASH and non-NASH patients (2.13% vs. 2.40%, p=0.57).

Comparing outcomes in NASH vs. PSM non-NASH recipients using moderate-severely macrosteatotic allografts

Finally, recipients of moderate-severely (≥30%) macrosteatotic allografts were isolated and non-NASH patients propensity matched to NASH patients. In this group, NASH recipients had higher BMI (31.91 vs. 27.75, p<0.01) and were more likely to be diabetic (57.35% vs. 21.33%, p<0.01, Table 1). Donors used for NASH recipients also had higher BMI (32.48 vs. 30.44, p<0.01) but were otherwise similar.

Graft and patient survival were both comparable for NASH and PSM non-NASH patients in the moderate-severely macrosteatotic subgroup. Here, graft survival for NASH and non-NASH recipients was 93.27% vs. 95.51% at 30 days (p=0.15), 95.29% vs. 87.90% at 1 year (p=0.24), 75.97% vs. 73.73% at 5 years (p=0.96) and 56.34% vs. 55.37% at 10 years (p=0.96; Table 2, Figure 1D). Patient survival similarly was 95.23% vs. 96.39% at 30 days (p=0.34), 88.21% vs. 89.61% at 1 year (p=0.51), 78.51% vs. 75.99% at 5 years (p=0.81) and 57.96% vs. 56.56% (p=0.86). In this group graft failure from recurrent disease was less common in non-NASH patients (0.00% vs. 7.87%, p<0.01), while PNF rates were the same (2.83% vs. 2.83%, p=0.99).

Assessing the impact of allograft macrosteatosis in NASH recipients

Next, NASH patients were isolated. Using a 30% macrosteatosis cutoff, NASH recipients of non or mildly macrosteatotic allografts (<30%) were matched to those receiving moderate to severely (≥30%) macrosteatotic grafts. Prior to matching, 518 patients were identified in the ≥ 30% macrosteatosis group and 4,649 in the < 30% cohort; after matching, 510 patients remained in each.

Baseline characteristics and outcomes were then assessed for NASH patients receiving ≥30% allografts and PSM NASH recipients of <30% allografts. In this comparison, only donor BMI (≥30%: 31.12 vs. <30%: 28.83, p<0.01) was significantly different between cohorts (Table 3). Here, 30-day graft survival was 93.32% vs. 96.54% (HR: 1.99; 95% CI: 1.11-3.57, p=0.02) while patient survival was 95.09% vs. 97.93% (HR: 2.45; 95% CI: 1.17-5.13; p=0.02, Table 4). At 1 year, graft survival was 84.53% vs. 88.99% (HR: 1.44; 95% CI: 1.01-2.06, p=0.05) while patient survival was 87.14% vs. 91.11% (HR: 1.47; 95% CI: 0.98-2.20; p=0.06). At 5 and 10 years, both graft and patient survival were comparable. Rates of graft loss attributed to recurrent disease (1.63% vs. 2.19%, p=0.99) and rejection (0.00% vs. 2.19%, p=0.25) were similar, as was incidence of PNF (2.55% vs. 1.37%, p=0.26).

Table 3:

Propensity matched baseline characteristics of NASH recipients by degree of allograft macrosteatosis

Propensity Matched
Allograft Macrosteatosis ≥ 30% <30% p-value
Number 510 510
Recipient characteristics
Age 60 (54-65) 61 (55-65) 0.50
Female sex 176 (34.51%) 179 (35.10%) 0.89
Ethnicity 0.49
White 412 (80.78%) 416 (81.57%)
Black 11 (2.16%) 16 (3.14%)
Other 87 (17.06%) 78 (15.29%)
BMI 31.94 (28.70-35.98) 31.73 (27.67-35.74) 0.35
ICU status at transplant 39 (7.65%) 33 (6.47%) 0.54
Status 1A 1 (0.20%) 0 (0.00%) 0.99
MELD 20 (15-26) 20 (14-27) 0.64
Disabled functional status 186 (36.47%) 171 (33.53%) 0.36
Hepatocellular carcinoma 67 (13.14%) 61 (11.96%) 0.64
Diabetes mellitus 284 (58.68%) 272 (55.51%) 0.33
Portal vein thrombosis 91 (17.88%) 94 (18.58%) 0.81
Hemodialysis 62 (12.16%) 51 (10.00%) 0.32
Previous abdominal surgery 280 (54.90%) 285 (55.88%) 0.80
Previous liver transplant 4 (0.78%) 1 (0.20%) 0.37
Donor characteristics
Age 47 (36-57) 48 (36-57) 0.78
Female sex 214 (41.96%) 242 (47.45%) 0.90
BMI 32.12 (27.31-38.19) 28.83 (24.90-34.79) <0.01
Diabetes mellitus 100 (19.61%) 109 (21.37%) 0.53
Hypertension 321 (62.94%) 327 (64.12%) 0.75
Tobacco use 98 (19.22%) 114 (22.35%) 0.25
Heavy alcohol use 105 (20.59%) 98 (19.22%) 0.64
Creatinine (mg/dL) 1.20 (0.86-1.90) 1.26 (0.80-2.20) 0.10
AST (u/L) 45 (25-84) 43 (24-84) 0.74
Inotrope support 287 (56.27%) 274 (53.73%) 0.45
DCD 28 (5.49%) 30 (5.88%) 0.89
LDRI 1.62 (1.34-1.95) 1.60 (1.32-1.94) 0.30
Cause of death 0.20
Anoxia 162 (31.76%) 161 (31.57%)
CVA 231 (45.29%) 236 (46.27%)
Head trauma 96 (18.82%) 94 (18.43%)
CNS tumor 11 (2.16%) 3 (0.59%)
Other 10 (1.96%) 16 (3.14%)
Transplant details
Multiorgan 44 (8.63%) 40 (7.84%) 0.73
CIT (hours) 6.44 (5.15-8.00) 6.33 (5.00-8.00) 0.34
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Values are listed as median +/− interquartile range unless otherwise stated

BMI: body mass index,NASH: non-alcoholic steatohepatitis, AST: aspartate aminotransferase, CVA: cerebrovascular accident, CNS: central nervous system, LDRI: Liver Donor Risk Index, DCD: donation after cardiac death, CIT: cold ischemia time

Table 4:

Propensity matched transplant outcomes in NASH patients by degree of allograft macrosteatosis

Propensity Matched
Allograft macrosteatosis ≥ 30% < 30% HR 95% CI p-value
Number 510 510
Primary non-function 13 (2.55%) 7 (1.37%) - - 0.26
Graft loss due to rejection 0 (0.00%) 3 (2.19%) - - 0.25
Graft loss due to recurrent disease 2 (1.63%) 3 (2.19%) - - 0.99
Graft survival
30-day 93.32% 96.54% 1.99 1.11-3.57 0.02
1-year 84.53% 88.99% 1.44 1.01-2.06 0.05
5-year 74.69% 74.93% 1.13 0.85-1.50 0.41
10-year 55.34% 53.35% 1.06 0.82-1.37 0.63
Patient survival
30-day 95.09% 97.93% 2.45 1.17-5.13 0.02
1-year 87.14% 91.11% 1.47 0.98-2.20 0.06
5-year 76.94% 76.99% 1.12 0.82-1.52 0.48
10-year 56.39% 52.79% 1.02 0.78-1.34 0.86
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Defining high risk moderate-severely macrosteatotic allografts

Regression modeling was used to identify donor factors associated with poor graft survival in allografts with moderate to severe macrosteatosis. On univariate analysis, CVA as cause of death (HR: 1.58, 95% CI: 1.29-1.95, p<0.01) and history of smoking (HR: 1.28, 95% CI; 1.28-1.62, p=0.03) were associated with graft failure at 1 year (Figure 2). Age ≥ 60 and BMI ≥ 40, while not independently predictive on univariate regression, both met the threshold value of p<0.2 for incorporation into the final multivariable model. This final model was adjusted for recipient and transplant-related variables predictive of graft failure. Here, CVA as cause of death remained a significant predictor of poor graft survival (HR: 1.50, 95% CI: 1.21-1.87, p<0.01). Age ≥ 60 was associated with a HR of 1.26 (95% CI 0.97-1.64, p=0.08), smoking demonstrated a HR of 1.21 (95% CI: 0.96-1.54, p=0.12) and BMI ≥ 40 carried a HR of 1.31 (95% CI 0.98-1.75, p=0.06); however, all failed to reach statistical significance.

Figure 2:

Figure 2:

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Donor characteristics associated with graft failure at 1 year in allografts with ≥30% and <30% macrosteatosis

As a control, a parallel regression model was performed in transplants using allografts with < 30% macrosteatosis. In this analysis, age ≥ 60 (HR: 1.21, 95% CI: 1.13-1.31, p<0.01) and CVA as cause of death (HR: 1.33, 95% CI: 1.24-1.42, p<0.01) were predictive of graft failure at 1 year on univariate analysis, while BMI ≥ 40 was protective against graft failure (HR: 0.86, 95% CI: 0.75-0.98, p=0.02; Figure 2). On multivariable regression, only age ≥ 60 and CVA as cause of death remained as significant predictors of graft loss.

Discussion

This study was a large-scale retrospective database analysis focusing on NAFLD and NASH from both donor and recipient perspectives in liver transplantation. Here, the increasingly prevalent interface of macrosteatotic allografts and NASH recipients was evaluated using three distinct approaches. First, graft and patient-related outcomes were evaluated in transplants for NASH compared to propensity matched non-NASH recipients using allografts with no, mild or moderate-severe macrosteatosis. In each of these settings accounting for recipient, donor and operative-level differences, short- and long-term outcomes in the NASH cohort were at least equivalent to their non-NASH counterparts. The second approach assessed NASH recipients alone, comparing ≥30% macrosteatotic grafts to a PSM matched group of grafts with <30% macrosteatosis. Here, early graft and patient survival was decreased in the moderate-severely macrosteatotic group while 5- and 10-year survival was similar. Finally, uni- and multivariable regression models identified high-risk donor characteristics associated with early graft loss in moderate to severely (≥30%) macrosteatotic allografts. Factors associated with graft loss on univariate regression were smoking and CVA as cause of death, while multivariable regression identified CVA alone as an independent predictor of graft loss regardless of the degree of allograft macrosteatosis.

The underlying metabolic syndrome associated with the development of NAFLD and NASH contributes to a NASH recipient population that carries higher rates of concomitant cardiovascular and endocrine comorbidities compared to non-NASH patients7,20,21. These comorbidities may contribute to a bias against listing patients with NASH for transplant, as was shown by Danford et al. in a single institution review of liver transplant listing patterns8. Several studies, however, have demonstrated equivalent, if not improved outcomes in transplantation in the NASH9,10,22–25. This study not only reaffirmed these data on a national scale but further evaluated these patients in the context of allograft macrosteatosis. Compared to non-NASH patients, NASH recipients had equal, if not improved patient and graft survival at 1 year and beyond, with decreased rates of PNF seen most prominently when using allografts with <30% macrosteatosis. Studies have suggested that NASH patients undergoing liver transplant are subject to high rates of post-transplant recurrent NAFLD and NASH, with nearly 90% of patients demonstrating recurrent NAFLD and 40% recurrent NASH on biopsy25. This risk has been shown to be particularly prominent in patients with metabolic syndrome, which may confer as much as a 3-fold increase in risk of developing recurrent NASH after transplant26. While the findings presented in this study project favorably on transplantation for patients with NASH regardless of the degree of allograft macrosteatosis, it is important to consider that the overall rates of graft loss from recurrent disease in all cohorts may be underestimated as patient mortality may have been attributed to alternative causes incited by underlying recurrent disease. Ultimately, this remains an important step in determining definitive post-transplant prognostication for these patients.

A potentially important, albeit secondary observation of this study related to transplantation of obese recipients. NASH has been intimately tied to obesity28,29, which has not reliably been shown to increase post-transplant morbidity and mortality despite nearly 50% of transplant centers identifying a BMI ‘ceiling’ of 45 as a relative contraindication to liver transplant30,31. This study utilized a propensity model that did not account for recipient obesity, and a significantly greater BMI was observed in NASH recipients at all levels of analysis. Despite this, NASH patients continued to fare similarly or better to non-NASH patients. As obesity rates rise alongside fatty liver disease, these findings warrant further investigation into re-evaluating this cutoff in the NASH population.

Significant work has also been done to determine the impact of NAFLD on the donor population and improve outcomes using these grafts 9,10,32. This, along with the increasing prevalence of donors with NAFLD, has resulted in increased use of macrosteatotic allografts12,15. To date, few studies, however, have assessed the disease as it impacts both simultaneously. In a similarly designed analysis Northup et al. found that both macrosteatotic grafts and obese recipients were independently predictive of mortality at 30 days, while combining the two conferred the highest mortality33. This study focused on NAFLD specifically and demonstrated that using moderate-severely macrosteatotic allografts did not significantly affect the long-term superior survival seen in NASH vs. non-NASH recipients. These findings are in congruence with the recent study by Eshraghian et al. in which allograft macrosteatosis was not associated with post-transplant NAFLD in patients with NASH and cryptogenic cirrhosis34. Lipid deposits vanish by 7 days post-transplant in biopsies of macrosteatotic allografts35, further bolstering the notion that donor macrosteatosis does not affect liver composition in the long-term. While further investigations into the biologic response of metabolically-deranged donors to macrosteatotic allografts may provide additional clarity, the similar long-term outcomes in NASH and non-NASH patients suggest that recipient underlying recipient metabolic environment does not significantly impact their biologic response to allograft lipid deposition.

This study evaluated the impact of allograft macrosteatosis on post-transplant patient and graft survival specifically within the NASH population. Here, early graft loss and patient mortality was higher in both unadjusted and PSM comparisons of transplants using allografts with ≥30% macrosteatosis. Interestingly though, PNF rates remained similar between the groups. These findings are counter to previous studies showing an increase in PNF rates using moderate-severely macrosteatotic allografts36–38. They may, however, may be explained in part by unaccounted selection strategies and clinician tendency to employ these grafts in transplants for recipients with lower physiologic MELD39.

Reliably determining allograft macrosteatosis remains an important priority in liver allocation. While frozen section pathologist reports of macrosteatosis have been shown to be largely accurate, consistent and reproducible38–40, a critical evaluation of macrosteatosis from procuring surgeon can help improve sensitivity in detecting macrosteatosis to optimize allograft use and minimize risk. This is particularly true in determining nuances of macrosteatosis, as biopsies do not always accurately assess higher risk characteristics such as inflammation, hepatocyte ballooning and bridging fibrosis40,42. Adjunctive imaging modalities and scoring systems are also limited in their ability to reliably characterize liver quality43. The multivariable regression in this study assessed for donor characteristics that may help determine which moderate-severely macrosteatotic allografts were highest risk of early graft loss. Advanced donor age and CVA as a cause of death have been demonstrated as predictive of poor graft outcomes44–46 and were similarly predictive of early graft loss in our side-by-side comparison of non-macrosteatotic allografts. Importantly, these findings should taken in context of the known influence of operative factors on outcomes using macrosteatotic allografts38, as well as the comparable long-term survival observed between allografts with ≥30% macrosteatosis and those with lesser macrosteatosis. The impact of donor BMI has been controversial; a recent meta-analysis by Takagi et al. (2020) determined donor BMI to not be predictive of graft or patient survival in adult deceased donor liver transplant47. With parallel regression analysis performed in non-macrosteatotic allografts failing to identify BMI as predictive of graft loss, it is possible that the risk conferred by higher donor BMI is specific to macrosteatotic allografts. Finally, while smoking fell short of achieving statistical significance in predicting graft loss, smoking itself has being closely associated with the development of fibrosis in NAFLD patients48–50. Given the overlying metabolic disturbances associated with fatty liver disease, these findings suggest that there may be more nuanced biological alterations within macrosteatotic livers not fully captured by quantifying degree of hepatic steatosis alone.

There were several notable limitations in this study. The data source was a federally maintained national database providing large-scale, generalizable patient populations but with limited granularity in donor, procurement and recipient data. As a result, the precise impact of allograft macrosteatosis on reperfusion injury, early allograft dysfunction and rates of de-novo or recurrent NASH were unable to be determined. Similarly, there may exist a graded allograft risk not identified by this study’s stratification of moderate-severely macrosteatotic allografts as ≥30%. Additionally the retrospective nature of the study introduced selection bias as a significant barrier to achieving comparable populations as clinicians attempt to minimize risk from both donor and recipient standpoints. The propensity model used in this study attempted to minimize this bias while preventing additional confounding that may have been incurred matching populations based off of variables associated with the development of NAFLD and NASH. The design did not, however, account several potential remaining confounders including the impact direct-acting antiviral therapy has had on prolonging graft and patient survival in the HCV population, and temporal trends in liver transplant outcomes. Subgroup analyses addressing each of these potential confounders separately addressed in Supplementary Materials, however, were all consistent with our primary reported analyses and further validated study findings.

The increasing epidemiologic burden of NAFLD and NASH uniquely impacts liver transplantation as it affects both donor and recipient populations. As NASH becomes a predominant cause of ESLD requiring transplant listing, practice patterns must adapt to ensure optimal organ access within this population. Similarly, macrosteatotic allografts must be carefully evaluated and matched to recipients to minimize undue complications and compromising outcomes. Caution must still be taken in transplanting moderate-severely macrosteatotic allografts regardless of recipient disease etiology. While NASH patients carry greater comorbidities than non-NASH counterparts, the diagnosis of NASH itself does not appear to confer a disadvantage when using allografts across any level of macrosteatosis. Ultimately, then, by exploring the nuances of the fatty liver disease from both donor and recipient, this study advocates for considering NASH recipients as carrying comparable risk to non-NASH patients regardless of the degree of allograft macrosteatosis. As the intersection between donor allograft macrosteatosis and recipient NASH becomes increasingly present, it is essential to anticipate and pre-emptively evolve practice patterns to optimize organ utilization and outcomes.

Supplementary Material

Supplemental Material

Acknowledgments:

This work was supported in part by Health Resources and Services Administration contract 234-2005-370011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Financial Support:

Peter Altshuler was supported by National Institutes of Health institutional training grant T32GM008562. Hien Dang was supported the American Liver Foundation.

Abbreviations:

BMI

Body mass index

CIT

Cold ischemia time

CNS

Central nervous system

CVA

Cerebrovascular accident

DCD

Donation after cardiac death

EAD

Early allograft dysfunction

ESLD

End stage liver disease

HCC

Hepatocellular carcinoma

ICU

Intensive care unit

LDRI

Liver donor risk index

MELD

Model for End Stage Liver Disease

NAFLD

Nonalcoholic fatty liver disease

NASH

Nonalcoholic steatohepatitis

OPTN

Organ Procurement and Transplantation Network

PNF

Primary non function

PSM

Propensity score matched

UNOS

United Network for Organ Sharing

Footnotes

Conflicts of interest: The authors associated with this work have no conflicts of interest and no relevant financial disclosures.

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