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Summary Background Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients. Methods In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death. Findings Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47–66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44–84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p<0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p<0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI −7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients. Inte...

The lower rates of SVR in patients infected with subtype 4r are related to the frequent preexistence at treatment baseline and subsequent selection by DAA treatment of both NS5A and NS5B S282 RASs. Our study suggests that these patients should be identified and receive a triple DAA combination regimen as first-line treatment. This article is protected by copyright. All rights reserved.

Kupffer cells, the resident macrophages of the liver, play a major role in the pathogenesis of alcoholic liver disease. We have previously demonstrated that CB2 receptor protects against alcoholic liver disease by inhibiting alcohol-induced inflammation and steatosis via the regulation of Kupffer cell activation. Here, we explored the mechanism underlying these effects and hypothesized that the anti-inflammatory properties of CB2 receptor in Kupffer cells rely on activation of autophagy. For this purpose, mice invalidated for CB2 receptor (CB2Mye−/− mice) or for the autophagy gene ATG5 (ATG5Mye−/− mice) in the myeloid lineage, and their littermate wild-type mice were subjected to chronic-plus-binge ethanol feeding. CB2Mye−/− mice showed exacerbated alcohol-induced pro-inflammatory gene expression and steatosis. Studies in cultured macrophages demonstrated that CB2 receptor activation by JWH-133 stimulated autophagy via a heme oxygenase-1 dependent pathway. Moreover, JWH-133 reduced the induction of inflammatory genes by lipopolysaccharide in wild-type macrophages, but not in ATG5-deficient cells. The CB2 agonist also protected from alcohol-induced liver inflammation and steatosis in wild-type mice, but not in ATG5Mye−/− mice demonstrating that macrophage autophagy mediates the anti-inflammatory and anti-steatogenic effects of CB2 receptor. Altogether these results demonstrate that CB2 receptor activation in macrophages protects from alcohol-induced steatosis by inhibiting hepatic inflammation through an autophagy-dependent pathway.

Background & Aims: Hepatic ischemia-reperfusion injury is a complication of liver surgery that involves mitochondrial dysfunction resulting from mitochondrial permeability transition pore (mPTP) opening. Cyclophilin D (PPIF or CypD) is a peptidyl-prolyl cis-trans isomerase that regulates mPTP opening in the inner mitochondrial membrane. We investigated whether and how recently created small-molecule inhibitors of CypD prevent opening of the mPTP in hepatocytes and the resulting effects in cell models and livers of mice undergoing ischemia-reperfusion injury. Methods:We measured the activity of 9 small-molecule inhibitors of Cyps in an assay of CypD activity. The effects of the small-molecule CypD inhibitors or vehicle on mPTP opening were assessed by measuring mitochondrial swelling and calcium retention in isolated liver mitochondria from C57BL/6J (wild-type) and Ppif -/-(CypD knock-out) mice, and in primary mouse and human hepatocytes by fluorescence microscopy. We induced ischemiareperfusion injury in livers of mice given a small-molecule CypD inhibitor or vehicle before and during reperfusion, and collected samples of blood and liver for histologic analysis. Results:The compounds inhibited peptidyl-prolyl isomerase activity (IC50 values, 0.2 to 16.2 µM) and, as a result, calcium-induced mitochondrial swelling, by preventing mPTP opening (IC50 values, 1.4 to 132 µM) in a concentration-dependent manner. The most potent inhibitor (C31) bound CypD with high affinity and inhibited swelling in mitochondria from livers of wild-type and Ppif -/mice (indicating an additional, CypD-independent effect on mPTP opening) and in primary human and mouse hepatocytes. Administration of C31 in mice with ischemia-reperfusion injury before and during reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage compared with vehicle.

Failure to achieve sustained virological response (SVR) with hepatitis C virus (HCV) direct-acting antiviral-based regimens is commonly associated with emergence of resistance-associated variants (RAVs). To avoid cross-resistance, recent guidelines recommend that patients who have failed on nonstructural protein 5A (NS5A) inhibitors should be retreated with sofosbuvir (SOF; NS5B inhibitor) combined with simeprevir (SIM; protease inhibitor [PI]); however, supporting evidence is lacking. This "real-world" study comprised patients who had failed to achieve SVR on previous NS5A-based therapy with daclatasvir (DCV) plus pegylated interferon (Peg-IFN) and ribavirin (RBV), with (n 5 3) or without (n 5 13) asunaprevir (ASV; PI). All 16 patients were retreated for 12 weeks with SOF plus SIM, without RBV. Antiviral efficacy was evaluated using the primary endpoint of SVR12 (SVR 12 weeks post-treatment); on-treatment response was also assessed. Patients (N 5 16; 13 male; mean age: 54 years [range, 43-73]) were chronically infected with HCV genotype (GT) 1 (1a, n 5 11; 1b, n 5 3) or 4 (n 5 2); they had advanced fibrosis or compensated cirrhosis (FibroScan, 9.6-70 kPa; cirrhosis, n 5 9); median baseline HCV-RNA level was 1.38 3 10 6 IU/mL. No patient discontinued treatment because of adverse events or virological failure. All patients achieved HCV RNA below lower limit of quantification (<12 IU/mL) by end of treatment (EOT) and 10 of 16 had a rapid response (week 4). SVR12 was achieved by 14 of 16 patients; the remaining 2 relapsed by 4 weeks post-EOT (both were GT 1a infected with cirrhosis; 1 had previously failed DCV-ASV plus Peg-IFN and RBV). Presence of SIM RAVs/polymorphisms (R155K and Q80K) at study baseline did not predict retreatment failure. Conclusion: Our findings support the concept of retreating NS5A inhibitor failures with SOF combined with SIM. However, the most difficult-to-cure patients may need more than 12 weeks of treatment and/or the addition of RBV. (HEPATOLOGY 2016;63:1809-1816 T reatment of chronic hepatitis C virus (HCV) infection has advanced significantly over the last 5 years, with the introduction of drug combination regimens based on direct-acting antiviral (DAA) agents. Sustained virological response (SVR) rates of the order of 60%-100% have been achieved when one DAA is combined with pegylated interferon (Peg-IFN) alpha and ribavirin (RBV), with SVR rates varying according to HCV genotype, disease severity, the DAA used, and the preexistence at treatment baseline of resistance-associated variants (RAVs). (1)

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Liver progenitor cells (LPCs)/ductular reactions (DRs) are associated with inflammation and implicated in the pathogenesis of chronic liver diseases. However, how inflammation regulates LPCs/DRs remains largely unknown. Identification of inflammatory processes that involve LPC activation and expansion represent a key step in understanding the pathogenesis of liver diseases. In the current study, we found that diverse types of chronic liver diseases are associated with elevation of infiltrated interleukin (IL)‐17‐positive (+) cells and cytokeratin 19 (CK19)+ LPCs, and both cell types colocalized and their numbers positively correlated with each other. The role of IL‐17 in the induction of LPCs was examined in a mouse model fed a choline‐deficient and ethionine‐supplemented (CDE) diet. Feeding of wild‐type mice with the CDE diet markedly elevated CK19+Ki67+ proliferating LPCs and hepatic inflammation. Disruption of the IL‐17 gene or IL‐27 receptor, alpha subunit (WSX‐1) gene abolished CDE diet‐induced LPC expansion and inflammation. In vitro treatment with IL‐17 promoted proliferation of bipotential murine oval liver cells (a liver progenitor cell line) and markedly up‐regulated IL‐27 expression in macrophages. Treatment with IL‐27 favored the differentiation of bipotential murine oval liver cells and freshly isolated LPCs into hepatocytes. Conclusion: The current data provide evidence for a collaborative role between IL‐17 and IL‐27 in promoting LPC expansion and differentiation, respectively, thereby contributing to liver regeneration. (Hepatology Communications 2018;2:329‐343)