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Control of systemic and hepatic inflammation, in particular originating from monocytes/macrophages, is crucial to prevent liver fibrosis and its progression to end-stage cirrhosis. LC3-associated phagocytosis (LAP) is a non-canonical form of autophagy that shifts the monocyte/macrophage phenotype to an anti-inflammatory phenotype. In a recent study, we uncovered LAP as a protective mechanism against inflammation-driven liver fibrosis and systemic inflammation in the context of cirrhosis. We observed that LAP is enhanced in blood and liver monocytes from patients with liver fibrosis or those who progress to cirrhosis. Combining studies in which LAP was pharmacologically or genetically inactivated, we found that LAP limits inflammation in monocytes from cirrhotic patients, and the hepatic inflammatory profile in mice with chronic liver injury, resulting in anti-fibrogenic effects. Mechanistically, LAP-induced anti-inflammatory and antifibrogenic signaling results from enhanced expression of the Fc immunoreceptor FCGR2A/FcγRIIA and activation of an FCGR2A-mediated PTPN6/SHP-1 anti-inflammatory pathway, leading to increased engulfment of IgG into LC3 (+) phagosomes. In patients with cirrhosis progressing to multi-organ failure (acute-on chronic liver failure), LAP is lost in monocytes, and can be restored by targeting FCGR2A-mediated PTPN6/SHP-1 signaling. These data suggest that sustaining LAP may open novel therapeutic perspectives for patients with end-stage liver disease.

BackgroundIt is speculated that opioid-free anesthesia may provide adequate pain control while reducing postoperative opioid consumption. However, there is currently no evidence to support the speculation. The authors hypothesized that opioid-free balanced anesthetic with dexmedetomidine reduces postoperative opioid-related adverse events compared with balanced anesthetic with remifentanil.MethodsPatients were randomized to receive a standard balanced anesthetic with either intraoperative remifentanil plus morphine (remifentanil group) or dexmedetomidine (opioid-free group). All patients received intraoperative propofol, desflurane, dexamethasone, lidocaine infusion, ketamine infusion, neuromuscular blockade, and postoperative lidocaine infusion, paracetamol, nefopam, and patient-controlled morphine. The primary outcome was a composite of postoperative opioid-related adverse events (hypoxemia, ileus, or cognitive dysfunction) within the first 48 h after extubation. The main secondary outcomes were episodes of postoperative pain, opioid consumption, and postoperative nausea and vomiting.ResultsThe study was stopped prematurely because of five cases of severe bradycardia in the dexmedetomidine group. The primary composite outcome occurred in 122 of 156 (78%) dexmedetomidine group patients compared with 105 of 156 (67%) in the remifentanil group (relative risk, 1.16; 95% CI, 1.01 to 1.33; P = 0.031). Hypoxemia occurred 110 of 152 (72%) of dexmedetomidine group and 94 of 155 (61%) of remifentanil group patients (relative risk, 1.19; 95% CI, 1.02 to 1.40; P = 0.030). There were no differences in ileus or cognitive dysfunction. Cumulative 0 to 48 h postoperative morphine consumption (11 mg [5 to 21] versus 6 mg [0 to 17]) and postoperative nausea and vomiting (58 of 157 [37%] versus 37 of 157 [24%]; relative risk, 0.64; 95% CI, 0.45 to 0.90) were both less in the dexmedetomidine group, whereas measures of analgesia were similar in both groups. Dexmedetomidine patients had more delayed extubation and prolonged postanesthesia care unit stay.ConclusionsThis trial refuted the hypothesis that balanced opioid-free anesthesia with dexmedetomidine, compared with remifentanil, would result in fewer postoperative opioid-related adverse events. Conversely, it did result in a greater incidence of serious adverse events, especially hypoxemia and bradycardia.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

Sustained hepatic and systemic inflammation, particularly originating from monocytes/macrophages, is a driving force for fibrosis progression to end-stage cirrhosis and underlies the development of multiorgan failure. Reprogramming monocyte/macrophage phenotype has emerged as a strategy to limit inflammation during chronic liver injury. Here, we report that LC3-associated phagocytosis (LAP), a noncanonical form of autophagy, protects against hepatic and systemic inflammation during chronic liver injury in rodents, with beneficial antifibrogenic effects. LAP is enhanced in blood and liver monocytes from patients with fibrosis and cirrhosis. Pharmacological inhibition of LAP components in human monocytes from patients with cirrhosis or genetic disruption of LAP in mice with chronic liver injury exacerbates both the inflammatory signature in isolated human monocytes and the hepatic inflammatory profile in mice, resulting in enhanced liver fibrosis. Mechanistically, patients with cirrhosis showed increased monocyte expression of Fc fragment of IgG receptor IIA (FcγRIIA) and enhanced engulfment of immunoglobulin G in LC3+ phagosomes that triggers an FcγRIIA/Src homology region 2 domain-containing phosphatase-1 (SHP-1) inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) anti-inflammatory pathway. Mice overexpressing human FcγRIIA in myeloid cells show enhanced LAP in response to chronic liver injury and resistance to inflammation and liver fibrosis. Activation of LAP is lost in monocytes from patients with multiorgan failure and restored by specifically targeting ITAMi signaling with anti-FcγRIIA F(ab')2 fragments, or with intravenous immunoglobulin (IVIg). These data suggest the existence of an ITAMi-mediated mechanism by which LAP might protect against inflammation. Sustaining LAP may open therapeutic perspectives for patients with chronic liver disease.

Objective To introduce the laparoscopic approach in liver transplant recipients. Summary of background data Despite the increasingly frequent use of laparoscopy in living donor hepatectomy, the laparoscopic approach has never been reported in liver transplant recipients. Methods A 52-year-old woman (body mass index: 18.5 kg/m) with neuroendocrine liver metastases of a digestive origin underwent hybrid liver transplantation by pure laparoscopic total hepatectomy and liver graft implantation using a preexisting midline incision. The hepatic pedicle vessels were dissected after division of the bile duct without a porto-caval shunt. Left lateral sectionectomy and early division of the common trunk allowed near completion of caval dissection with no prolonged inflow occlusion. The liver graft was reduced and latero-lateral caval anastomosis was performed. Results Surgery lasted 400 minutes with 400 mL of blood loss. The anhepatic phase lasted 43 minutes. Warm ischemia time and cold ischemia times were 38 and 466 minutes, respectively. The postoperative course was uneventful. Conclusions This case study suggests that the hybrid approach may be feasible and safe in selected recipients. The decision to use this surgical approach should be made in transplant centers with significant expertise in both laparoscopic liver and pancreatic surgery. Further reducing the size of the abdominal incision is the next step, which may be achieved with the development of vascular anastomoses devices.

Introduction L’encephalopathie hepatique (EH) est une pathologie frequente en cas de maladie hepatique, aussi bien en cas d’insuffisance hepatique aigue (IHA) qu’en cas de cirrhose. En cas d’IHA, elle est associee a des perturbations de l’hemodynamique intracerebrale et de l’autoregulation cerebrale pouvant aboutir a une hypertension intracrânienne [1] . Dans ces circonstances, les modalites de surveillance neurologique sont tres peu etudiees. L’indice de pulsatilite (IP) mesure par Doppler transcrânien (DTC) pourrait permettre une meilleure surveillance dans cette population specifique. L’objectif de ce travail etait de decrire l’evolution de l’IP avant et au decours de la TH chez des patients souffrant d’EH dans un contexte d’IHA ou de cirrhose. Materiel et methodes Apres accord du comite d’ethique, des mesures d’IP au niveau de l’artere cerebrale moyenne par DTC ont ete realisees en pre- et en post-TH chez des patients cirrhotiques sans antecedent d’EH, avec antecedent d’EH aigue ou chronique et en cas d’IHA. Ces mesures etaient realisees quotidiennement jusqu’a reveil et extubation post-TH. Le stade d’EH pre-TH ou le pire stade d’EH deja decrit, selon la classification de West Haven, ont ete colliges. Les donnees demographiques, biologiques et postoperatoires ont egalement ete recueillies. Le j0 post-TH est defini dans notre service comme le jour de sortie du bloc operatoire. Les resultats sont presentes en mediane [IQR] ou pourcentage. Resultats De janvier 2013 a decembre 2014, des mesures d’IP ont ete realisees chez 41 patients : 5 patients cirrhotiques sans EH (groupe temoin), 22 cirrhotiques avec antecedent d’EH aigue ou chronique et 14 IHA. En absence d’EH, les valeurs d’IP pre- et post-TH a j0 etaient normales, respectivement 1,01 [0,84–1,03] et 1,07 [1,06–1,08]. Chez les cirrhotiques avec EH, l’IP post-TH etait legerement augmentee par rapport a l’IP pre-TH, respectivement 1,25 [1,01–1,44] et 1,05 [1–1,26]. Cette valeur se normalise ensuite des j1. En cas d’IHA, des resultats similaires sont retrouves (IP pre-TH 1,12 [1,03–1,27], IP j0 1,38 [0,96–1,52]). En cas d’IHA et d’EH severe (grade 3 et 4), les valeurs d’IP pre-TH etaient significativement superieures a celles des patients avec EH legere (grade 1 et 2) ( Fig. 1 , respectivement 1,48 [1,22–1,66] vs 1,04 [0,99–1,12], p = 0,01). Ce resultat etait retrouve a j0 mais sans atteindre le seuil de significativite (1,55 [1,49–1,67] vs 0,84 [0,75–1,08]). Discussion En cas d’IHA avec EH, la surveillance de l’IP de l’artere cerebrale moyenne par DTC en pre- et en post-TH permet de detecter des alterations de l’hemodynamique cerebrale qui se normalisent 24 a 36 heures apres la TH. La surveillance du DTC pourrait permettre, de surveiller et adapter les therapeutiques de neuroreanimation en cas d’IHA compliquee d’EH severe.