Comparative metabolome analysis reveals higher potential of haemoperfusion adsorption in providing favourable outcome in ACLF patients.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a serious illness associated with altered metabolome, organ failure and high mortality. Need for therapies to improve the metabolic milieu and support liver regeneration are urgently needed. METHODS: We investigated the ability of haemoperfusion adsorption (HA) and therapeutic plasma exchange (TPE) in improving the metabolic profile and survival in ACLF patients. Altogether, 45 ACLF patients were randomized into three groups: standard medical therapy (SMT), HA and TPE groups. Plasma metabolomics was performed at baseline, post-HA and TPE sessions on days 7 and 14 using high-resolution mass spectrometry. RESULTS: The baseline clinical/metabolic profiles of study groups were comparable. We identified 477 metabolites. Of these, 256 metabolites were significantly altered post 7 days of HA therapy (p < .05, FC > 1.5) and significantly reduced metabolites linked to purine (12 metabolites), tryptophan (7 metabolites), primary bile acid (6 metabolites) and arginine-proline metabolism (6 metabolites) and microbial metabolism respectively (p < .05). Metabolites linked to taurine-hypotaurine and histidine metabolism were reduced and temporal increase in metabolites linked to phenylalanine and tryptophan metabolism was observed post-TPE therapy (p < .05). Finally, weighted metabolite correlation network analysis (WMCNA) along with inter/intragroup analysis confirmed significant reduction in inflammatory (tryptophan, arachidonic acid and bile acid metabolism) and secondary energy metabolic pathways post-HA therapy compared to TPE and SMT (p < .05). Higher baseline plasma level of 11-deoxycorticosterone (C03205; AUROC > 0.90, HR > 3.2) correlated with severity (r2 > 0.5, p < .05) and mortality (log-rank-p < .05). Notably, 51 of the 64 metabolite signatures (ACLF non-survivor) were reversed post-HA treatment compared to TPE and SMT(p < .05). CONCLUSION: HA more potentially (~80%) improves plasma milieu compared to TPE and SMT. High baseline plasma 11-deoxycorticosterone level correlates with early mortality in ACLF patients.

Living Donor Liver Transplantation for Acute Liver Failure: Donor Safety and Recipient Outcome.

In countries where deceased organ donation is sparse, emergency living donor liver transplantation (LDLT) is the only lifesaving option in select patients with acute liver failure (ALF). The aim of the current study is living liver donor safety and recipient outcomes following LDLT for ALF. A total of 410 patients underwent LDLT between March 2011 and February 2018, out of which 61 (14.9%) were for ALF. All satisfied the King's College criteria (KCC). Median admission to transplant time was 48 hours (range, 24-80.5 hours), and median living donor evaluation time was 18 hours (14-20 hours). Median Model for End-Stage Liver Disease score was 37 (32-40) with more than two-thirds having grade 3 or 4 encephalopathy and 70% being on mechanical ventilation. The most common etiology was viral (37%). Median jaundice-to-encephalopathy time was 15 (9-29) days. Preoperative culture was positive in 47.5%. There was no difference in the complication rate among emergency and elective living liver donors (13.1% versus 21.2%; P = 0.19). There was no donor mortality. For patients who met the KCC but did not undergo LT, survival was 22.8% (29/127). The 5-year post-LT actuarial survival was 65.57% with a median follow-up of 35 months. On multivariate analysis, postoperative worsening of cerebral edema (CE; hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.01-6.31), systemic inflammatory response syndrome (SIRS; HR, 16.7; 95% CI, 2.05-136.7), preoperative culture positivity (HR, 6.54; 95% CI, 2.24-19.07), and a longer anhepatic phase duration (HR, 1.01; 95% CI, 1.00-1.02) predicted poor outcomes. In conclusion, emergency LDLT is lifesaving in selected patients with ALF. Outcomes of emergency living liver donation were comparable to that of elective donors. Postoperative worsening of CE, preoperative SIRS, and sepsis predicted outcome after LDLT for ALF.

Hyaluronic Acid-Conjugated Thermoresponsive Polymer-Based Bioformulation Enhanced Wound Healing and Gut Barrier Repair of a TNBS-Induced Colitis Injury Ex Vivo Model in a Dynamic Perfusion Device.

Impairment of intestinal epithelium is a typical feature of inflammatory bowel disease (IBD) that causes leakage of bacteria and antigens from the intestinal lumen and thus results in persistent immune activation. Hence, healing and regeneration of the damaged gut mucosa is a promising therapeutic approach to achieve deep remission in IBD. Currently, available systemic therapies have moderate effects and are often associated with numerous side effects and malignancies. In this study, we aimed to develop a topical therapy by chemically conjugating a temperature-responsive polymer, i.e., poly(N-isopropylacrylamide), along with hyaluronic acid to obtain a sprayable therapeutic formulation that upon colon instillation adheres to the damaged gut mucosa due to its temperature-induced phase transition and mucoadhesive properties. An ex vivo adhesion experiment demonstrates that this therapeutic formulation forms a thin physical coating on the mucosal lining at a physiological temperature within 5 min. Physicochemical characterization of (P(NIPAM-co-NTBAM)-HA) established this formulation to be biocompatible, hemo-compatible, and non-immunogenic. Prednisolone was encapsulated within the polymer formulation to achieve maximum therapeutic efficacy in the case of IBD-like conditions as assessed in a custom-fabricated perfusion-based ex vivo model system. Histological analysis suggests that the prednisolone-encapsulated polymer formulation nearly restored the mucosal architecture after 2,4,6-trinitrobenzenesulfonic acid-induced damage. Furthermore, a significant (p ≤ 0.001) increase in mRNA levels of Muc-2 and ZO-1 in treated groups further confirmed the mucosal epithelial barrier restoration.

A comparative histological analysis of early and late graft dysfunction in different time zones following living donor liver transplantation.

Background: Liver biopsy plays a crucial role in evaluating allograft dysfunction. Comprehensive analysis of the histological spectrum of complications, particularly rejection, in different time zones is lacking. Aim: To evaluate the histological spectrum of rejection, in four time zones, in a large Living donor liver transplant series. Patients and Methods: Retrospective analysis of 313 biopsies for the last 10 years of living donor liver transplantation (LDLT) recipients. 123 of which had rejection as diagnosis, were redistributed in four time zones [1-early (<3), 2-intermediate (3-6), 3 and 4-late (6-12 and > 12) months] and were assessed for sixteen histological parameters. Results: Biopsies in time zone 1 (26.5%), 2 (20.7%), 3 (24.6%), and 4 (28.1%)] were nearly equal. Multiple coexistent complications existed in 12% of the cases. Rejection diagnosed in time zone groups: 1 = 22 (17.9%), 2 = 27 (22%), 3 = 36 (29.3%), and 4 = 38 (30.9%). Portal inflammation mixed type (P < 0.000), portal vein (P = 0.001) and hepatic vein endothelialitis (P < 0.000), portal eosinophils (P = 0.001), and lymphocytic bile duct damage (P = 0.01) were most pronounced in group 1. Perivenulitis without hepatic vein endothelialitis was observed (P = 0.03) in groups 3, whereas bile duct atypia (P = 0.01) and duct loss (P < 0.000) were observed in group 4. Multiple episodes of rejection displayed significant association with central perivenulitis (P = 0.002) and bile duct loss (P < 0.001). Conclusions: Histological analysis in large series of LDLT recipients highlights the spectrum of complications in different time zones. Late acute and chronic rejection occurred as early as 3 months posttransplant. Central perivenulitis and bile duct atrophy were associated with repeated episodes of rejection and deterioration.