Liver Transplantation For Nonalcoholic Steatohepatitis Research Articles

How best to combine liver transplantation and bariatric surgery?-Results from a global, web-based survey.

Obesity is a growing healthcare challenge worldwide and a significant risk factor for liver failure as seen with non-alcoholic steatohepatitis (NASH). Combining metabolic-bariatric surgery (MBS) with liver transplantation (LT) appears as attractive strategy to treat both, the underlying liver disease and obesity. However, there is an ongoing debate on best timing and patient selection. This survey was designed to explore the current treatment practice for patients with NASH and obesity worldwide. A web-based survey was conducted in 2022 among bariatric and LT surgeons, and hepatologists from Europe, North and South America and Asia. The survey completion rate was 74% (145/196). The average respondents were 41-50 years (38%), male (82.1%) and had >20 years of clinical experience (42.1%). Centres with a high LT-caseload for NASH were mainly located in the USA and United Kingdom. Almost 30% have already performed a combination of LT with MBS and 49% plan to do it. A majority of bariatric surgeons prefer MBS before LT (77.2%), whereas most of LT surgeons (52%) would perform MBS during LT. Most respondents (n = 114; 80%) favour sleeve gastrectomy over other bariatric techniques. One third (n = 42; 29.4%) has an established protocol regarding MBS for LT candidates. The most experienced centres doing LT for NASH are in the USA and United Kingdom with growing awareness worldwide. Overall, a combination of MBS and LT has already been performed by a third of respondents. Sleeve gastrectomy is the bariatric technique of choice-preferably performed either before or during LT.

Immune Features of Disparate Liver Transplant Outcomes in Female Hispanics With Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a severe immune-mediated stage of nonalcoholic fatty liver disease that is rapidly becoming the most common etiology requiring liver transplantation (LT), with Hispanics bearing a disproportionate burden. This study aimed to uncover the underlying immune mechanisms of the disparities experienced by Hispanic patients undergoing LT for NASH. We enrolled 164 LT recipients in our institutional review board-approved study, 33 of whom presented with NASH as the primary etiology of LT (20%), with 16 self-reported as Hispanic (48%). We investigated the histopathology of prereperfusion and postreperfusion biopsies, clinical liver function tests, longitudinal soluble cytokines via 38-plex Luminex, and immune cell phenotypes generated by prereperfusion and postreperfusion blood using 14-color flow cytometry and enzyme-linked immunosorbent assay. Hispanic LT recipients transplanted for NASH were disproportionately female (81%) and disproportionately suffered poor outcomes in the first year posttransplant, including rejection (26%) and death (38%). Clinically, we observed increased pro-inflammatory and apoptotic histopathological features in biopsies, increased AST/international normalized ratio early posttransplantation, and a higher incidence of presensitization to mismatched HLA antigens expressed by the donor allograft. Experimental investigations revealed that blood from female Hispanic NASH patients showed significantly increased levels of leukocyte-attracting chemokines, innate-to-adaptive switching cytokines and growth factors, HMGB1 release, and TLR4/TLR8/TLR9/NOD1 activation, and produced a pro-inflammatory, pro-apoptotic macrophage phenotype with reduced CD14/CD68/CD66a/TIM-3 and increased CD16/CD11b/HLA-DR/CD80. A personalized approach to reducing immunological risk factors is urgently needed for this endotype in Hispanics with NASH requiring LT, particularly in females.

THU-514 - Prevalence of renal dysfunction is higher in patients that receive a liver transplant for non-alcoholic steatohepatitis

THU-514 - Prevalence of renal dysfunction is higher in patients that receive a liver transplant for non-alcoholic steatohepatitis

Outcomes of liver transplantation in non-alcoholic steatohepatitis (NASH) versus non-NASH associated hepatocellular carcinoma

BackgroundNon-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) is a rising indication for liver transplantation. This unique population, with multiple comorbidities, has potential for worse post-transplant outcomes. We compared post-transplant survival of NASH and non-NASH HCC patients using a large cohort. MethodsAdults transplanted for HCC between 2008 and 2018, from United Network for Organ Sharing (UNOS) and University Health Network (UHN) databases were divided into two populations: NASH and non-NASH. Recipient characteristics and post-transplant survival were compared. Subgroup analyses were performed within and beyond Milan criteria. Results2071 of 20,672 (10.0%) patients underwent transplantation for NASH HCC, with annual proportional increase of 1.2%UHN (p = 0.02) and 1.3%UNOS (p < 0.001). The 1-,3-,5-year post-transplant survival were 90.8%, 83.9%, 76.3% NASH HCC versus 91.9%, 82.1%, 74.9% non-NASH HCC (p = 0.94). No survival differences were observed in populations within or beyond Milan. Competing-risk analysis demonstrated no differences in risk for cardiovascular-related death (HR1.24, 95%CI 0.87–1.55, p = 0.16), or HCC recurrence-related death (HR1.21, 95%CI 0.89–1.65, p = 0.23). NASH HCC patients had lower risk of liver-related deaths (HR0.57, 95%CI 0.34–0.98, p = 0.04). DiscussionNASH HCC is a rising indication for liver transplantation. Despite demographic differences, no post-transplantation survival differences were observed between NASH and non-NASH HCC. This justifies equivalent organ allocation, irrespective of NASH status.

S3037 Hepatocellular Carcinoma With Para-Celiac Lymph Node Metastasis Presenting as Unknown Primary Neoplasm in the Post-Liver Transplant Setting

Introduction: Metastatic HCC without primary liver lesion is an exceedingly rare clinicopathologic entity. Only a handful of case reports have been reported to date, mostly involving bony structures without primary liver cancer. To our knowledge, we hereby present the first case of metastatic HCC involving the para-celiac lymph nodes in the post-liver transplant setting. Case Description/Methods: A 73-year-old male who previously underwent liver transplant for non-alcoholic steatohepatitis was admitted to GI for the evaluation of a suspicious pancreatic tail cyst. He denied acute GI symptoms. Laboratory studies revealed normal liver enzymes. CT abdomen and pelvis showed a 2-cm lesion located under the right hemidiaphragm, posterior to the right hepatic lobe. Subsequently, the patient underwent diagnostic EUS with biopsy for both lesions. EUS revealed an irregularly shaped oval cyst in the tail, round cysts in the body and neck, and a complex of small cysts in the pancreatic head. The 45 x 55-mm para-celiac mass was irregularly shaped, hypoechoic, homogenous solid lesion, located lateral to the celiac axis. It had well-defined endosonographic borders. Immunostaining of the fine-needle biopsy (FNB) of the para-celiac mass was positive for Hep Par-1 and pancytokeratin, consistent with metastatic HCC (Figure 1; A&B). Fine-needle aspiration (FNA) of the pancreatic cysts was negative for malignancy. Alpha-fetoprotein level was 11.1 ng/mL. The diagnosis of HCC of unknown primary was finally made. The patient then underwent an uneventful surgical resection. Discussion: To our research, this is the first reported case of metastatic HCC without primary liver lesion involving the para-celiac lymph nodes in a post-transplant patient. With regard to pathogenesis, one theory implicates the presence of ectopic liver tissue that transforms into HCC. The presence of micro-HCC that regresses spontaneously or gets destroyed by the immune system can also be a plausible explanation. Standard diagnostic protocol for HCC consists of imaging (CT or MRI) and/or biopsy. Even in patients with cirrhosis, the diagnostic modality of choice is imaging and liver biopsy is less frequently performed. Biopsy is recommended for atypical hepatic lesions on imaging or nonclassical enhancement patterns or detection in the absence of cirrhosis. No standardized treatment exists for metastatic HCC with unknown primary. This report illustrates that clinicians should consider HCC while evaluating patients for the primary origin of metastatic carcinoma.Figure 1.: Immunostaining of the para-celiac mass. Endoscopic ultrasound-guided fine-needle biopsy (FNB) specimen indicating positive status for Hep Par-1 and pancytokeratin.

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

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

SAT265 - Derivation of a cardiac risk index for use in liver transplantation for non-alcoholic steatohepatitis

SAT265 - Derivation of a cardiac risk index for use in liver transplantation for non-alcoholic steatohepatitis

Relatively Poor Long-term Outcomes Following Liver Transplantation for NASH in the United States.

Nonalcoholic steatohepatitis (NASH) continues to increase in frequency as an indication for liver transplantation (LT). Data on long-term outcomes for these patients are limited. We aimed to compare long-term patient and graft survival in patients undergoing LT for NASH in the United States to other indications. We analyzed data from the Scientific Registry of Transplant Recipients of adult patients who underwent primary deceased-donor LT from January 1, 2005, to December 31, 2019. NASH has increased as an indication for LT by 4.5-fold, from 5.2% in 2005 to 23.4% in 2019. Patient (61.2%) and graft survival (59.2%) at 10 y are significantly poorer for NASH than for all other indications other than alcohol. Patients transplanted for NASH have higher body mass index (32.2 versus 27.6) and greater frequency of diabetes (13% versus 11.6%) than any other indication ( P < 0.001). Portal vein thrombosis, location in intensive care unit, dialysis, and pre-LT diabetes ( P < 0.001 for all) are independently predictive of patient death and graft loss. Body mass index is not predictive. NASH patients undergoing simultaneous liver kidney have markedly worse 10-y patient and graft survival than liver-only (52.3% versus 62.1%). Graft loss was attributed to recurrence of NASH in <1% of patients. LT for NASH is associated with relatively poor long-term patient and graft survival when compared with patients transplanted for other indications, NASH patients undergoing simultaneous liver kidney have the worst long-term outcomes.

Differential fuel utilization in liver transplant recipients and its relationship with non-alcoholic fatty liver disease.

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT).MethodsPatients receiving LT for non‐alcoholic steatohepatitis (NASH) (n = 35) and non‐NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole‐body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation).ResultsThe two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post‐prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI‐PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat‐free muscle volume and directly with visceral adipose tissue.ConclusionReduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non‐alcoholic fatty liver disease after LT.

Portrait of Regional Trends in Liver Transplantation for Nonalcoholic Steatohepatitis in the United States.

Nonalcoholic steatohepatitis (NASH) is one of the most common etiologies of liver transplantation (LT) in the United States. We investigated regional trends in waitlist candidates, LT rates, and recipient survival among patients with NASH. Using the United Network for Organ Sharing database by Organ Procurement and Transplantation Network regions, we investigated waitlist registration, LT rates, and survival for NASH between January 2004 and December 2019. The absolute number and percentage of total LT performed for NASH increased substantially in all Organ Procurement and Transplantation Network regions. In 2019, region 11 had the highest percentage of NASH-related LT with 31.4% followed by region 10 (25.3%) and region 8 (23.1%). Between 2015 and 2019, region 5 had the highest rising percentage in LT for NASH at 208%, followed by region 1 (194%) and region 4 (183%). The proportion of NASH hepatocellular carcinoma (NASH-HCC) was the highest in region 9 at 37.7% and lowest in region 10 (19.2%), region 3 (20.6%), and region 11 (20.8%). In multivariate analysis, diabetes (HR 1.18, P < 0.001), dialysis before LT (hazard ratio [HR] 1.53, P < 0.001), HCC (HR 1.19, P < 0.00), portal vein thrombosis (HR 1.24, P < 0.001), donor age (HR 1.026, P = 0.03), and recipient age (HR 1.24, P = <0.001) were associated with worse survival. LT for patients with NASH has dramatically increased across all regions since 2004, but with substantial heterogeneity among regions in the proportion with HCC and post-LT survival. Identifying contributing factors to these regional differences is warranted.

A Single-Center Study of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Recurrence in Recipients of Liver Transplant for Treatment of Nonalcoholic Steatohepatitis Cirrhosis.

Nonalcoholic steatohepatitis is a growing indication for liver transplant. We examined multiple granular elements to determine risk factors for recurrence of nonalcoholic steatohepatitis or recurrence of nonalcoholic fatty liver disease. This is a retrospective, single-center study of patients who underwent liver transplant for nonalcoholic steatohepatitis. Demographic differences were assessed with the Wilcoxon and Pearson tests for continuous and discrete variables, respectively. We used a linear mixed effects model to estimate mean changes in body mass index and laboratory measurements. Time to graft loss was analyzed with the Cox proportional hazards model. From 1998 to 2017, there were 275 patients at our center who underwent liver transplant as treatment for nonalcoholic steatohepatitis cirrhosis. Of these patients, 31 (11%) were diagnosed with recurrent nonalcoholic steatohepatitis and 60 (22%) had recurrent nonalcoholic fatty liver disease. Patients with or without recurrence of either nonalcoholic steatohepatitis or nonalcoholic fatty liver disease were similar with regard to Model for End-Stage Liver Disease score, body mass index, sex, ethnicity, comorbidity, and donor characteristics, including donor macrosteatosis. Exposures to several medication classes were examined, but there was no association with recurrence of either nonalcoholic steatohepatitis or nonalcoholic fatty liver disease. Changes in aspartate aminotransferase and alanine aminotransferase levels over time were correlated with recurrence of either nonalcoholic steatohepatitis or nonalcoholic fatty liver disease versus levels observed in the groups with no recurrent disease. There was no difference in graft survival for the groups with recurrence of either nonalcoholic steatohepatitis or nonalcoholic fatty liver disease. Recurrence of nonalcoholic fatty liver disease and recurrence of nonalcoholic steatohepatitis were not associated with increased mortality after liver transplant. There were notable steady increases in body mass index after transplant for all patients who received liver transplant as treatment for nonalcoholic steatohepatitis.

Metabolic syndrome following liver transplantation in nonalcoholic steatohepatitis.

Metabolic syndrome is a major clinical disorder involving metabolic dysregulation characterized clinically with features of central obesity, insulin resistance (IR), type 2 diabetes, hypertension, and dyslipidemia. Metabolic syndrome is strongly associated with the rising prevalence nonalcoholic steatohepatitis, a leading indication for orthotopic liver transplantation in the Western world. The presence or recurrence of metabolic syndrome following liver transplantation can contribute to the development and recurrence of nonalcoholic fatty liver disease (NAFLD) in the liver allograft. In this review, we discuss the endogenous and exogenous drivers of post-transplant metabolic syndrome, role of chronic immunosuppression, and the prevalence and clinical significant of post-transplant metabolic syndrome on nonalcoholic steatohepatitis.

Characterization of Gut Microbiome in Liver Transplant Recipients With Nonalcoholic Steatohepatitis.

Twenty-one patients who received LT for NASH and had a protocol liver biopsy performed beyond 1-y post-LT were included prospectively (January 2018-December 2018). Genomic DNA extraction, next-generation sequencing, and quantitative PCR analysis were performed on stool samples collected within 1.1 ± 1.6 y from time of liver biopsy. Recurrent NAFLD was noted in 15 of the 21 included patients. Stool microbiome analysis at the genus level showed significant loss of Akkermansia and increasing Fusobacterium associated with NAFLD recurrence. Quantitative PCR analysis revealed significantly decreased relative abundance of Firmicutes in patients with NAFLD activity scores (NASs) ≥5 as compared with patients with lower NAS scores, whereas Bacteroidetes were significantly increased with higher NAS (P < 0.05). Firmicutes (P = 0.007) and Bifidobacterium group (P = 0.037) were inversely correlated, whereas Bacteroidetes (P = 0.001) showed a positive correlation with higher hepatic steatosis content. The Firmicutes/Bacteroidetes ratios were higher in patients without NAFLD or NASH as compared with patients diagnosed with NAFLD or NASH at the time of sample collection. Akkermansia, Firmicutes, and Bifidobacterium may play protective roles in the development of recurrent NAFLD in LT recipients, whereas Fusobacteria and Bacteroidetes may play pathogenic roles. These findings highlight the potential role of the "gut-liver" axis in the pathogenesis of NAFLD recurrence after LT.

THU225 - Recent trends and intention-to-treat survival of liver transplantation for non-alcoholic steatohepatitis: an Italian liver transplant registry study. On behalf of AISF, FIRE, SITO and CNT

THU225 - Recent trends and intention-to-treat survival of liver transplantation for non-alcoholic steatohepatitis: an Italian liver transplant registry study. On behalf of AISF, FIRE, SITO and CNT

Recent trends and intention-to-treat survival of liver transplantation for nonalcoholic steatohepatitis: an Italian liver transplant registry study

Introduction and Aim: A recent European Liver Transplant registry study showed that the proportion of liver transplants performed for nonalcoholic steatohepatitis (NASH) in Europe has increased from 2002 through 2016, and that the post-transplant outcome in patients with NASH is comparable to that of other disease indications. There are few data on recent trends in waiting list inscriptions/dynamics, and on intention-to-treat transplant survival of NASH patients, however.

Sa1587 – Ethnic Disparities in the Outcomes of Liver Transplantation for Non-Alcoholic Steatohepatitis

Sa1587 – Ethnic Disparities in the Outcomes of Liver Transplantation for Non-Alcoholic Steatohepatitis

THU-342-Development of a model to predict survival in recipients of liver transplant for non-alcoholic steatohepatitis

THU-342-Development of a model to predict survival in recipients of liver transplant for non-alcoholic steatohepatitis

Characteristics and risk factors for recurrence of nonalcoholic steatohepatitis following liver transplantation

Objectives: Nonalcoholic steatohepatitis (NASH), which is a common and increasing indication for liver transplantation (LT), is known to recur after LT. Since the recurrence of NASH can lead to graft failure, the identification of predictive factors is needed and preventive strategies should be implemented.Methods: We retrospectively examined 95 patients who had undergone LT for NASH or alcoholic liver disease (ALD) as a primary indication. We evaluated peritransplant characteristics and histological findings 1-year post LT among liver transplant patients due to NASH or ALD.Results: Pre-LT body mass index (BMI) was higher and pre-LT diabetes was more prevalent in NASH patients than in ALD patients (p < .01). The difference of BMI persisted at 3 months and 1 year after LT. There were no differences between the groups regarding histopathological findings including the degree of steatosis and fibrosis in 1-year biopsy. In multivariate analysis, recipient age and 1-year BMI were independent risk factors for post-LT fatty liver disease development. Regarding predictive factors of NASH recurrence, the prevalence of pre-LT insulin-dependent diabetes was significantly higher in patients who developed NASH recurrence than those who did not. The increase of HbA1c at 1-year post-LT checkup was higher in patients who developed recurrence than those who did not, although the difference did not reach statistical significance.Conclusions: The results of this study suggest that insulin-dependent diabetes has detrimental effects on NASH recurrence following LT. Optimal glycemic control should be recommended, but studies are needed to prove its preventive effect on NASH recurrence.

Characteristics and risk factors of fatty liver disease development and nonalcoholic steatohepatitis recurrence after liver transplantation

Introduction: Nonalcoholic steatohepatitis (NASH), which is a common and increasing indication for liver transplantation (LT), is known to recur after LT. Since the recurrence of NASH can lead to graft failure, the identification of predictive factors and preventive strategies need to be implemented. Method: We retrospectively identified 694 consecutive patients who had undergone LT at Karolinska University Hospital between June 2007 and February 2017. Of these, 95 patients who received LT for NASH or alcoholic liver disease (ALD) as a primary indication were included. Peritransplant characteristics and histological findings 1 year post-LT among NASH patients were evaluated in comparison with ALD patients. Risk factors of post-LT fatty liver disease development and NASH recurrence were assessed. Result: Among 27 NASH patients, pre-LT body mass index (BMI) was higher (31.3 vs. 28.6, p=0.0095) and pre-LT diabetes was more prevalent than in ALD patients (p<0.0001). The difference of BMI persisted at 3 months and 1 year after LT. There were no differences between the groups regarding histopathological findings including the degree of steatosis and fibrosis in 1-year biopsy. In multivariate analysis, recipient age and 1-year BMI were independent risk factors for post-LT fatty liver disease development. Regarding predictive factors of NASH recurrence, the prevalence of pre-LT insulin dependent diabetes was significantly higher in patients who developed NASH recurrence than those who did not. The increase of HbA1c at 1-year post-LT check-up was higher in patients who developed recurrence than those who did not, although the difference did not reach statistical significance (Δ 15 vs. 5 mmol/mol, p=0.051). Conclusion: The results of this study suggests that insulin dependent diabetes has detrimental effects on NASH recurrence following LT. Optimal glycemic control should be recommended, but studies are needed to prove its preventive effect on NASH recurrence.

Incidence of Recurrent NASH-Related Allograft Cirrhosis.

Cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is projected to become the leading indication for liver transplantation (LT) in the USA in the next decade. The long-term implications of post-LT NASH, specifically on the development of allograft cirrhosis, are not well known. A retrospective cohort of patients at a single large center undergoing LT for NASH from 2000 to 2015 was identified using a prospectively collected database. A total of 226 patients undergoing LT for NASH were identified. Mean follow-up for the cohort was 7years. Seventy-five percent of patients underwent at least one liver biopsy post-LT. Eighty-one patients (36%) developed recurrence of biopsy-proven NASH. Fifteen patients developed bridging fibrosis but only four patients (1.8%) progressed to recurrent NASH cirrhosis at a mean of 9years post-LT. Body mass index at the time of LT was statistically higher in the NASH allograft cirrhosis group. Recurrent disease was less common and less severe in those transplanted with black donors. All four patients with recurrent NASH cirrhosis developed evidence of portal hypertension, but all remained alive at follow-up. Although recurrent NASH following LT is common, the development of allograft cirrhosis is rare. These findings are useful when counseling patients and important to consider during their post-LT care.