Background and AimsImmunoregulatory checkpoint receptors (CR) contribute to the profound immunoparesis observed in alcohol-related liver disease (ALD) and in vitro neutralization of inhibitory-CRs TIM3/PD1 on anti-bacterial T-cells can rescue innate and adaptive anti-bacterial immunity. Recently described soluble-CR forms can modulate immunity in inflammatory conditions, but the contributions of soluble-TIM3 and soluble-PD1 and other soluble-CRs to immune derangements in ALD remain unclear.MethodsIn Alcoholic Hepatitis (AH; n = 19), alcohol-related cirrhosis (ARC; n = 53) and healthy control (HC; n = 27) subjects, we measured by Luminex technology (i) plasma levels of 16 soluble-CRs, 12 pro/anti-inflammatory cytokines and markers of gut bacterial translocation; (ii) pre-hepatic, post-hepatic and non-hepatic soluble-CR plasma levels in ARC patients undergoing TIPS; (iii) soluble-CRs production from ethanol-treated immunocompetent precision cut human liver slices (PCLS); (iv) whole-blood soluble-CR expression upon bacterial challenge. By FACS, we assessed the relationship between soluble-TIM3 and membrane-TIM3 and rescue of immunity in bacterial-challenged PBMCs.ResultsSoluble-TIM3 was the dominant plasma soluble-CR in ALD vs. HC (p = 0.00002) and multivariate analysis identified it as the main driver of differences between groups. Soluble-CRs were strongly correlated with pro-inflammatory cytokines, gut bacterial translocation markers and clinical indices of disease severity. Ethanol exposure or bacterial challenge did not induce soluble-TIM3 production from PCLS nor from whole-blood. Bacterial challenge prompted membrane-TIM3 hyperexpression on PBMCs from ALD patient’s vs. HC (p < 0.002) and was inversely correlated with plasma soluble-TIM3 levels in matched patients. TIM3 ligands soluble-Galectin-9 and soluble-CEACAM1 were elevated in ALD plasma (AH > ARC; p < 0.002). In vitro neutralization of Galectin-9 and soluble-CEACAM1 improved the defective anti-bacterial and anti-inflammatory cytokine production from E. coli-challenged PBMCs in ALD patients.ConclusionsAlcohol-related liver disease patients exhibit supra-physiological plasma levels of soluble-TIM3, particularly those with greater disease severity. This is also associated with increased levels of soluble TIM3-ligands and membrane-TIM3 expression on immune cells. Soluble-TIM3 can block the TIM3-ligand synapse and improve anti-bacterial immunity; however, the increased levels of soluble TIM3-binding ligands in patients with ALD negate any potential immunostimulatory effects. We believe that anti-TIM3 neutralizing antibodies currently in Phase I clinical trials or soluble-TIM3 should be investigated further for their ability to enhance anti-bacterial immunity. These agents could potentially represent an innovative immune-based supportive approach to rescue anti-bacterial defenses in ALD patients.

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patients with a diagnosis of AIH who required the addition of tacrolimus as a third line agent. Methods The tacrolimus database for the Regional Liver Unit, Royal Victoria Hospital was reviewed to identify all patients with AIH who had been treated with tacrolimus from Jan 2010 until August 2017. Records were cross referenced with the diagnostic coding department. Demographic details, indications for tacrolimus therapy, clinical and biochemical outcomes were recorded. Results 30 patients were identified (24 (80%) female, mean age 40.7 years, range 19-81 years). 27 of the 30 patients were initially treated with azathioprine of whom 21 (78%) discontinued treatment due to adverse effects including blood dyscrasias and 6 (22%) were switched to tacrolimus due treatment failure. Three of 30 patients were started on tacrolimus instead of azathioprine or mycophenolate. Two of these patients had previous episodes of pancytopenia at the time of commencing treatment for AIH and azathioprine/mycophenolate were excluded as a treatment option. One of the patients was commenced on prednisolone and tacrolimus without another steroid sparing agent trailed for other reasons. 26 (87%) of 30 patients remain on tacrolimus, of whom 11 (42%) had normalisation of transaminases and a further 12 (46%) had improvement of transaminases. Liver function tests in the 3 (11.5%) remaining patients were deranged but static. Of note all three had established cirrhosis at the time of AIH diagnosis. Of the four whose tacrolimus therapy was discontinued, two stopped due to side effects, 1 is deceased (not tacrolimus related) and one stopped due to commencing infliximab for IBD. Conclusions Tacrolimus is a safe and well tolerated treatment for AIH when first line therapy has failed. In the cohort observed, only 6% failed to tolerate tacrolimus and biochemical parameters were improved or normalised in 88% of patients who remained on tacrolimus therapy.

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apportioned telephone review to discuss Results and/or symptoms. As per NICE guidance annual Fibroscan was organised through a dedicated clinic. If any clinical and/or biochemical concerns arose a face-to-face review in clinic is arranged. Results Over this period 45 patients received 6-monthly virtual HBV clinic review. Bloods showed a median peak ALT 36 u/L (0-41 u/L), median viral load 62 iu/ml. and median AFP 2.7. Only 3/45 required face-to-face follow up due to a possible flare, with 2/45 eventually requiring an antiviral agent (Tenofovir). No patients required admission and/or access to other acute and/or community services due to their liver disease during this period. The cost savings were considerable. 6 monthly reviews in a face-to-face clinic over the 2.5 year period would have cost an estimated £27 636. The cost of running a virtual telephone clinic for the same period was £5,517; a saving of 501%. There were only 5 missed blood tests ahead of the clinic appointment. This compares to the 22% DNA rate in our general hepatology clinics. Conclusions A nurse-led virtual clinic provides high-quality, cost-effective care to patients and improves HBV monitoring. Better compliance allows for detection of flares which could require antiviral treatment. With the prospect of new treatments on the horizon it is important these patients remain under the care of a hepatology team and a virtual clinic model allows them to remain engaged with Liver services.