*Purpose: Obesity and metabolic syndrome have recently become an epidemic with Hispanics bearing a disproportionate burden. Non-alcoholic steatohepatitis (NASH) is a severe immune-mediated stage of non-alcoholic fatty liver disease, the most common liver pathology associated with obesity, diabetes and metabolic syndrome, and can progress to liver cirrhosis and end-stage liver disease (ESLD) requiring orthotopic liver transplant (OLT) for survival. This study seeks to understand underlying immune mechanisms of disparity experienced by Hispanics undergoing OLT for NASH.

*Methods: We enrolled 128 OLT recipients in our IRB-approved study, 25 of which presented with NASH as the primary etiology for OLT (20%). We investigated histopathology of pre- and post-reperfusion biopsies, longitudinal soluble cytokines via 38-plex Luminex, and functional immune cell phenotypes generated by pre- and post-reperfusion blood via 14-color flow cytometry and ELISA.

*Results: Of the 25 NASH patients, 9 had biopsy-proven ischemia-reperfusion injury (IRI+; 36%), and 16 did not (IRI-; 67%). Of note, 6/9 IRI+ patients with NASH were self-reported Hispanic (67%) compared to only 2/16 IRI- non-Hispanic NASH patients (13%). Despite not having any signs of fatty liver or apoptosis in the pre-transplant donor allograft, 84% of NASH patients (21/25) had significant macrovesicular steatosis deposited into hepatocytes and 52% (13/25) had hepatocellular ballooning by 2 hrs post-reperfusion. Remarkably, this included 100% of Hispanic (4/4) and non-Hispanic (7/7) females and 0% of male Hispanics (0/4). Post-reperfusion blood from NASH patients produced a pro-inflammatory, pro-apoptotic macrophage phenotype with downregulated CD14/CD66a and upregulated CD16/CD11b/CD68/HLA-DR/CD80/CD86/Gal-9/TIM-3 and was capable of activating TLR4/9. Investigating a potential mechanism for the generation of this cell type revealed pre-operative blood from NASH recipients contained significantly elevated levels of IL-17A, IP-10, and MCP-1. Finally, most Hispanic NASH patients required for-cause biopsies (6/8=75%) and had worse outcomes, including ACR, AMR, chronic IRI and NASH whereas only 9% of non-Hispanics (1/11) required a for-cause biopsy and had HCV at the time of biopsy. Despite the overall cohort being predominantly male (69/104=66%), Hispanic NASH OLT-IRI patients with for-cause biopsies associated with worsened outcomes were almost entirely female (5/6=83%).

*Conclusions: Taken together, female Hispanics with NASH in our OLT cohort disproportionately suffered from immune-mediated OLT complications leading to worsened outcomes within the first year post-transplant. As such, reduction of IRI and other immunological risk factors should be considered in Hispanics with NASH requiring OLT, particularly females.

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