The landscape of liver transplantation for patients with Alcohol-associated liver disease in USA.

BACKGROUND/AIMS: Indications for liver transplants have expanded to include patients with alcohol-associated liver disease (ALD) over the last decade. Concurrently, the liver allocation policy was updated in February 2020 replacing the Donor Service Area with Acuity Circles (AC). The aim is to compare the transplantation rate, waitlist outcomes, and post-transplant survival of candidates with ALD to non-ALD and assess differences in that effect after the implementation of the AC policy. APPROACH: Scientific Registry for Transplant Recipients data for adult liver transplant (LT) candidates was reviewed from the post-AC era (2/4/2020 - 3/1/2022) and compared with an equivalent length of time before AC were implemented. RESULTS: The adjusted transplant rates were significantly higher for those with ALD pre-AC, and this difference increased after AC implementation (transplant rate ratio comparing ALD to non-ALD=1.20, 1.13, 1.61, and 1.32 for MELD categories 37-40, 33-36, 29-32, 25-28, respectively, in the post-AC era, p <0.05 for all). The adjusted likelihood of death/removal from the waitlist was lower for ALD patients across all lower MELD categories (aSHR=0.70, 0.81, 0.84, 0.70 for MELD categories at list 25-28, 20-24, 15-19, 6-14, respectively, p <0.05). Adjusted post-transplant survival was better for those with ALD (aHR=0.81, p <0.05). Waiting list and post-transplant mortality tended to improve more for those with ALD since the implementation of AC but not significantly. CONCLUSIONS: ALD is a growing indication for liver transplantation. Although ALD patients continue to have excellent post-transplant outcomes and lower wait list mortality, candidates with ALD have higher adjusted transplant rates, and these differences have increased after AC implementation.

Peri-Transplant Inflammation and Long-Term Diabetes Outcomes Were Not Impacted by Either Etanercept or Alpha-1-Antitrypsin Treatment in Islet Autotransplant Recipients.

The instant blood-mediated inflammatory response (IBMIR) causes islet loss and compromises diabetes outcomes after total pancreatectomy with islet autotransplant (TPIAT). We previously reported a possible benefit of etanercept in maintaining insulin secretion 3 months post-TPIAT. Here, we report 2-year diabetes outcomes and peri-operative inflammatory profiles from a randomized trial of etanercept and alpha-1 antitrypsin (A1AT) in TPIAT. We randomized 43 TPIAT recipients to A1AT (90 mg/kg IV x6 doses, n = 13), etanercept (50 mg then 25 mg SQ x 5 doses, n = 14), or standard care (n = 16). Inflammatory cytokines, serum A1AT and unmethylated insulin DNA were drawn multiple times in the perioperative period. Islet function was assessed 2 years after TPIAT with mixed meal tolerance test, intravenous glucose tolerance test and glucose-potentiated arginine induced insulin secretion. Cytokines, especially IL-6, IL-8, IL-10, and MCP-1, were elevated during and after TPIAT. However, only TNFα differed significantly between groups, with highest levels in the etanercept group (p = 0.027). A1AT increased after IAT in all groups (p < 0.001), suggesting endogenous upregulation. Unmethylated insulin DNA ratios (a marker of islet loss) and 2 years islet function testing were similar in the three groups. To conclude, we found no sustained benefit from administering etanercept or A1AT in the perioperative period.

A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment.

BACKGROUND: In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence. METHODS: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT. RESULTS: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females. CONCLUSION: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment. CLINICAL TRIAL NOTATION: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).