Links between donor macrosteatosis, interleukin-33 and complement after liver transplantation

BACKGROUND: As prevalence of nonalcoholic fatty liver disease increases in the population, livers with steatosis will continue to infiltrate the donor pool. Safe utilization of these extended criteria grafts is paramount given the increased risk associated with their use in transplantation. Prognostic factors that can predict liver dysfunction immediately after transplantation with macrosteatotic grafts are lacking. AIM: To understand the relationship between interleukin-33 (IL-33) and complement in recipients immediately following liver reperfusion as a marker of liver dysfunction. METHODS: Cohort consisted of patients who received a liver transplant from September 2016–September 2019 at our institution. Clinical variables were retrospectively extracted from the electronic medical record. Back-table donor biopsies were obtained with donor steatosis percentage retrospectively determined by a board-certified pathologist. Blood samples were available immediately following liver transplantation. Quantification of plasma IL-33 and complement proteins, C3a and C5a, were determined by enzyme-linked immunosorbent assay. For mRNA expression, RNA was extracted from donor biopsies and used against a 780 gene panel. RESULTS: Cohort consisted of 99 donor and recipients. Donor median age was 45 years and 55% male. Recipients had a median age of 59 years with 62% male. The main etiologies were alcoholic hepatitis, nonalcoholic steatohepatitis, and hepatocellular carcinoma. Median MELD-Na at transplant was 21. Donors were grouped based on moderate macrosteatosis (≥ 30%). Recipients implanted with moderate macrosteatotic grafts had significantly higher peak alanine aminotransferase/aspartate aminotransferase (P < 0.001 and P < 0.004), and increased incidence of early allograft dysfunction (60% compared to 18%). Circulating IL-33 levels were significantly elevated in recipients of ≥ 30% macrosteatotic grafts (P < 0.05). Recipients with detectable levels of circulating IL-33 immediately following reperfusion had significantly higher alanine aminotransferase/aspartate aminotransferase (P < 0.05 and P < 0.01). Activated complement (C3a and C5a) were elevated in recipients implanted with moderate macrosteatotic grafts. RNA expression analysis of donor biopsies revealed moderate steatotic grafts upregulated genes inflammatory processes while downregulated hepatocyte-produced complement factors. CONCLUSION: Circulating IL-33 and activated complement levels immediately following liver reperfusion in recipients of moderate macrosteatotic grafts may identify which patients are at risk of early allograft dysfunction.