Publications by authors named "Mark McPhail"

93 Publications

Systematic review and meta-analysis of tumour microsatellite-instability status as a predictor of response to fluorouracil-based adjuvant chemotherapy in colorectal cancer.

Int J Colorectal Dis 2021 Oct 22. Epub 2021 Oct 22.

Imperial College London, London, United Kingdom.

Purpose: Colorectal cancer (CRC) can be classified according to the chromosomal-instability pathway (a microsatellite-stable (MSS) pathway) and the microsatellite-instability (MSI) pathway. Adjuvant therapy after surgery in advanced CRC is usually based on fluoropyrimidine 5-fluorouracil (5-FU) alone or combined with other agents. Controversy however remains on the use of 5-FU-based regimens in treating MSI-related tumours.

Aims: To systematically investigate the relationship between tumour microsatellite profile and 5-year overall survival in patients with CRC treated with 5-FU.

Methods: A systematic literature review of PubMed and Embase databases was conducted. Pre-specified criteria determined study inclusion/exclusion. The PRISMA and QUADAS-2 criteria were used to assess study suitability and quality respectively. Patients were categorised as having either MSI or MSS CRC. Overall 5-year survival was estimated from Kaplan-Meier curves. Publication bias was assessed using funnel-plots and Egger's test.

Results: 1807 studies were identified, with meta-analysis performed using nine studies. 5-FU treated individuals with CRC who died at 5 years were found to be 0.31 times less likely to have MSI than those who were alive, although this was not statistically significant. There was an insufficient number of studies to enable subgroup analysis by stage.

Conclusions: In this meta-analysis, MSI status does not alter 5-year survival of patients with CRC patients treated with adjuvant 5-FU, however there is significant heterogeneity in the design of individual studies in the data synthesis. More studies are necessary to clarify whether CRC patients with MSI CRC, in particular early stage, should be offered 5-FU based adjuvant chemotherapy.
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http://dx.doi.org/10.1007/s00384-021-04046-xDOI Listing
October 2021

Prevalence of bleeding and thrombosis in critically ill patients with chronic liver disease.

Thromb Haemost 2021 Oct 12. Epub 2021 Oct 12.

Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom of Great Britain and Northern Ireland.

Introduction: Haemorrhage and venous thromboembolism (VTE) are recognised complications of chronic liver disease (CLD), but their prevalence and risk factors in critically ill patients is uncertain.

Patients And Methods: We studied a retrospective cohort of patients with CLD non-electively admitted to a specialist intensive care unit determining the prevalence and timing of major bleeding and VTE (early, present on admission/diagnosed within 48h; later diagnosed >48h post ICU admission). Associations with baseline clinical and laboratory characteristics, multi-organ failure (MOF), blood product administration and mortality were explored. Odds ratios (OR) and 95% CIs were calculated using logistic regression.

Results: Of 623 patients with median age 52, bleeding (>48 hours after admission) occurred in 87 (14%) patients. Bleeding was associated with greater illness severity and increased mortality. Gastrointestinal bleeding accounted for 72% of events, secondary to portal hypertension in >90%. Procedure-related bleeding was uncommon. VTE occurred in 125 (20%) patients: Early VTE in 80 (13%) and involving the portal vein (PVT) in 85%. Later VTE affected 45 (7.2%) patients. Hepatocellular Carcinoma (HCC) and non-alcoholic liver disease were independently associated with early VTE (OR 2.79, (95% CI 1.5 -5.2) and 2.32, (1.4 -3.9) respectively), and HCC, sepsis and cryoprecipitate use with late VTE (OR 2.45, (1.11-5.43), 2.26 (1.2-4.3) and 2.60 (1.3-5.1).

Conclusion: VTE was prevalent on admission to critical care and less commonly developed later. Bleeding was associated with MOF and increased mortality. Severe MOF was not associated with an increased rate of VTE which was linked with HCC, and specific etiologies of CLD.
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http://dx.doi.org/10.1055/a-1667-7293DOI Listing
October 2021

Aberrant hepatic trafficking of gut-derived T-cells is not specific to primary sclerosing cholangitis.

Hepatology 2021 Oct 11. Epub 2021 Oct 11.

Department of Gastroenterology, King's College Hospital, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.

Background & Aims: The 'gut-homing' hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T-cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here we examine 'the gut-homing theory' in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases.

Methods: Expression of MAdCAM-1, CCL25 and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from CLD patients undergoing orthotopic liver transplantation and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T-cells was assessed using flow cytometry.

Results: Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was upregulated in all CLDs compared to normal liver. There were no differences between disease groups. Frequencies of α4β7, αEβ7, CCR9 and GPR15 expressing hepatic T-cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. β7 expressing hepatic T-cells displayed an increased inflammatory phenotype compared with β7 negative cells, though this inflammatory cytokine profile was present in both the inflamed and normal liver.

Conclusions: These findings refute the widely accepted 'gut-homing' hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T-cells is not unique to PSC, but is a pan-aetiological feature of CLD.
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http://dx.doi.org/10.1002/hep.32193DOI Listing
October 2021

Rifaximin reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial.

J Hepatol 2021 Sep 24. Epub 2021 Sep 24.

Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK; Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK. Electronic address:

Background: Rifaximin is efficacious in the prevention of recurrent hepatic encephalopathy (HE) but its mechanism of action remains unclear. We postulated that rifaximin reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE.

Design: A randomised placebo-controlled double-blind mechanistic study of rifaximin versus placebo was performed in cirrhotic patients with HE. Rifaximin-α 550mg (TARGAXAN) twice daily (n=19) or placebo (n=19) was administered for 90-days.

Primary Outcome: 50% reduction in neutrophil oxidative burst (OB) at 30-days.

Secondary Outcomes: Psychometric Hepatic Encephalopathy Scale (PHES), shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolome, blood bacterial DNA, neutrophil toll-like receptor (TLR)-2/4/9 and interleukin-8 expression, and plasma and faecal cytokine analysis.

Results: Patients were well-matched: median MELD [11 rifaximin-α versus 10 placebo]. Day 30 HE grade normalised on rifaximin-α but not placebo (p=0.014) with an improvement in PHES score; p=0.009. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day-30 (p=0.021) with a reduction in plasma tumour necrosis factor-α (TNF-α); p<0.001. Rifaximin-α suppressed oralisation of the gut, reducing the mucin-degrading sialidase-rich species Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α and IL-17E enriched intestinal microenvironment augmenting anti-bacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection [odds ratio 0.21(0.05-0.96)].

Conclusion: Rifaximin-treated patients were less likely to develop infection with resolution of overt and covert HE. Rifaximin-α reduced oralisation of the gut with mucin-degrading species attenuating systemic inflammation. These data link rifaximin-α as having a role in gut barrier repair as a mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis.

Lay Summary: This clinical trial examined the underlying mechanism of action of an antibiotic called rifaximin which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). It shows that rifaximin suppresses gut bacteria that translocate from the mouth to the intestine which causes the intestinal wall to become leaky by breaking down the protective mucus barrier. This resolves encephalopathy and reduces inflammation in the blood preventing the development of infection.

Clinical Trial Number: ClinicalTrials.gov NCT02019784.
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http://dx.doi.org/10.1016/j.jhep.2021.09.010DOI Listing
September 2021

Suppressor CD4 T cells expressing HLA-G are expanded in the peripheral blood from patients with acute decompensation of cirrhosis.

Gut 2021 Aug 3. Epub 2021 Aug 3.

Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK.

Objective: Identifying components of immuneparesis, a hallmark of chronic liver failure, is crucial for our understanding of complications in cirrhosis. Various suppressor CD4 T cells have been established as potent inhibitors of systemic immune activation. Here, we establish the presence, regulation and mechanism of action of a suppressive CD4 T cell subset expressing human leucocyte antigen G (HLA-G) in patients with acute decompensation of cirrhosis (AD).

Design: Flow cytometry was used to determine the proportion and immunophenotype of CD4HLA-G T cells from peripheral blood of 20 healthy controls (HCs) and 98 patients with cirrhosis (28 with stable cirrhosis (SC), 20 with chronic decompensated cirrhosis (CD) and 50 with AD). Transcriptional and functional signatures of cell-sorted CD4HLA-G cells were delineated by NanoString technology and suppression assays, respectively. The role of immunosuppressive cytokine interleukin (IL)-35 in inducing this population was investigated through in vitro blockade experiments. Immunohistochemistry (IHC) and cultures of primary human Kupffer cells (KCs) were performed to assess cellular sources of IL-35. HLA-G-mediated T cell suppression was explored using neutralising antibodies targeting co-inhibitory pathways.

Results: Patients with AD were distinguished by an expansion of a CD4HLA-GCTLA-4IL-35 immunosuppressive population associated with disease severity, clinical course of AD, infectious complications and poor outcome. Transcriptomic analyses excluded the possibility that these were thymic-derived regulatory T cells. IHC analyses and in vitro cultures demonstrate that KCs represent a potent source of IL-35 which can induce the observed HLA-G phenotype. These exert cytotoxic T lymphocyte antigen-4-mediated impaired responses in T cells paralleled by an HLA-G-driven downregulation of T helper 17-related cytokines.

Conclusion: We have identified a cytokine-driven peripherally derived suppressive population that may contribute to immuneparesis in AD.
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http://dx.doi.org/10.1136/gutjnl-2021-324071DOI Listing
August 2021

SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care.

Nat Commun 2021 06 7;12(1):3406. Epub 2021 Jun 7.

Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK.

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.
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http://dx.doi.org/10.1038/s41467-021-23494-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184784PMC
June 2021

Margin ACcentuation for resectable Pancreatic cancer using Irreversible Electroporation - Results from the MACPIE-I study.

Eur J Surg Oncol 2021 Oct 19;47(10):2571-2578. Epub 2021 May 19.

Institute of Liver Studies, King's College Hospital, London, SE5 9RS, United Kingdom. Electronic address:

Introduction: Margin accentuation (MA) using Irreversible electroporation (IRE) offers an unique opportunity to reduce the R1 resections in resectable pancreatic cancer (RPC). This study aims to assess the rate of margin positivity using IRE for MA during pancreaticoduodenectomy (PD) for resectable pancreatic head tumours.

Materials And Methods: Following ethical approval, MA using IRE was carried out in 20 consecutive patients to posterior and superior mesenteric vein (SMV) margin, and the pancreatic neck, prior to the PD resection. The control group (non-IRE; n = 91) underwent PD without MA over the study period, March 2018 to March 2020.

Results: There was no difference between the two groups in terms of patients' age, gender, pre-op biliary drainage, site of malignancy or pre-operative TNM stage. The overall margin positive rate for IRE group was lesser (35.0%) when compared to non-IRE group (51.6%; p = 0.177), with significantly less posterior pancreatic margin positivity (5.0% vs. 25.3%; p = 0.046). When only treated margins (SMA margin excluded) were compared, the IRE group had significantly lower margin positive rates (20.0% vs. 51.6%; p = 0.013). There was no difference between the two groups in terms of intra- or post-operative complications. With a median follow-up of 15.6 months, the median DFS and OS for IRE and non-IRE groups were 17 and 18 months (p = 0.306) and 19 and 22 months (p = 0.227) respectively.

Conclusion: Our pilot study confirms the safety of MA using IRE for RPC, with reduction in margin positivity. These results as a proof of concept are promising and need further validation with a randomised controlled trial.
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http://dx.doi.org/10.1016/j.ejso.2021.05.024DOI Listing
October 2021

Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry.

Hepatology 2021 Oct 21;74(4):2032-2046. Epub 2021 Jun 21.

Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.

Background And Aims: Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, -04, -07, or -13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD.

Approach And Results: We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups.

Conclusions: Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course.
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http://dx.doi.org/10.1002/hep.31893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463472PMC
October 2021

Dysregulation of the Lysophosphatidylcholine/Autotaxin/Lysophosphatidic Acid Axis in Acute-on-Chronic Liver Failure Is Associated With Mortality and Systemic Inflammation by Lysophosphatidic Acid-Dependent Monocyte Activation.

Hepatology 2021 Aug 15;74(2):907-925. Epub 2021 Jun 15.

Department of Inflammation Biology, School of Immunity and Microbial Sciences, Kings College London, UK.

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study.

Approaches & Results: Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14 monocytes were cultured with LPC, or its autotaxin (ATX)-derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P < 0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure-Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNF-α, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14 cells without increasing phagocytic capacity.

Conclusions: ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF.
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http://dx.doi.org/10.1002/hep.31738DOI Listing
August 2021

A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure.

J Hepatol 2021 08 12;75(2):424-434. Epub 2021 Apr 12.

Institute of Liver Studies, King's College Hospital, London, UK. Electronic address:

Background & Aims: Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF.

Methods: We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method.

Results: Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score.

Conclusions: Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation.

Lay Summary: While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.
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http://dx.doi.org/10.1016/j.jhep.2021.03.013DOI Listing
August 2021

Acute liver failure.

J Hepatol 2021 06 10;74(6):1489-1490. Epub 2021 Apr 10.

Liver Intensive Therapy Unit, Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.

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http://dx.doi.org/10.1016/j.jhep.2021.01.037DOI Listing
June 2021

Patterns and prediction of liver injury with persistent cholestasis in survivors of severe SARS-CoV-2 infection.

J Infect 2021 06 4;82(6):e11-e13. Epub 2021 Apr 4.

Institute of Liver Studies, King's College Hospital, London, United Kingdom; Department of Inflammation Biology, King's College London, United Kingdom.

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http://dx.doi.org/10.1016/j.jinf.2021.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019401PMC
June 2021

Mitochondrial dysfunction as a mechanistic biomarker in patients with non-alcoholic fatty liver disease (NAFLD).

Mitochondrion 2021 03 31;57:119-130. Epub 2020 Dec 31.

Institute of Liver Studies, Kings College Hospital, London, United Kingdom.

Background: Dysfunctional metabolism lies at the centre of the pathogenesis for Non-Alcoholic Fatty Liver Disease (NAFLD) and involves mitochondrial dysfunction, lipid dysmetabolism and oxidative stress. This study, for the first time, explores real-time energy changes in peripheral blood and corresponding metabolite changes, to investigate whether mitochondria-related immunometabolic biomarkers can predict progression in NAFLD.

Methods: Thirty subjects divided into 3 groups were assessed: NAFLD with biopsy-proven mild fibrosis (n = 10), severe fibrosis (n = 10) and healthy controls (HC, n = 10). Mitochondrial functional analysis was performed in a Seahorse XFp analyzer in live peripheral blood mononuclear cells (PBMCs). Global metabolomics quantified a broad range of human plasma metabolites. Mitochondrial carbamoyl phosphate synthase 1(CPS-1), Ornithine transcarbamoylase (OTC), Fibroblast growth factor-21 (FGF-21) and a range of cytokines in plasma were measured by ELISA.

Results: NAFLD patients with severe fibrosis demonstrated reduced maximal respiration (106 ± 25 versus 242 ± 62, p < 0.05) and reserve capacity (56 ± 16 versus 184 ± 42, p = 0.006) compared to mild/moderate fibrosis. Comparing mild/moderate vs severe liver fibrosis in patients with NAFLD, 14 out of 493 quantified metabolites were significantly changed (p < 0.05). Most of the amino acids modulated were the urea cycle (UC) components which included citrulline/ornithine ratio, arginine and glutamate. Plasma levels of CPS-1 and FGF-21 were significantly higher mild versus severe fibrosis in NAFLD patients. This novel panel generated an area under the ROC of 0.95, sensitivity of 100% and specificity 80% and p = 0.0007 (F1-F2 versus F3-F4).

Conclusion: Progression in NAFLD is associated with mitochondrial dysfunction and changes in metabolites associated with the urea cycle. We demonstrate a unique panel of mitochondrial-based, signatures which differentiate between stages of NAFLD.

Lay Summary: Mitochondrial dysfunction in peripheral cells along with alterations in metabolites of urea cycle act as a sensor of hepatocyte mitochondrial damage. These changes can be measured in blood and together represent a unique panel of biomarkers for progression of fibrosis in NAFLD.
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http://dx.doi.org/10.1016/j.mito.2020.12.010DOI Listing
March 2021

PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury.

J Clin Invest 2021 02;131(4)

Department of Metabolism, Digestion and Reproduction, Section of Hepatology and Gastroenterology, and.

Patients with acute liver failure (ALF) have systemic innate immune suppression and increased susceptibility to infections. Programmed cell death 1 (PD-1) expression by macrophages has been associated with immune suppression during sepsis and cancer. We therefore examined the role of the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in regulating Kupffer cell (KC) inflammatory and antimicrobial responses in acetaminophen-induced (APAP-induced) acute liver injury. Using intravital imaging and flow cytometry, we found impaired KC bacterial clearance and systemic bacterial dissemination in mice with liver injury. We detected increased PD-1 and PD-L1 expression in KCs and lymphocyte subsets, respectively, during injury resolution. Gene expression profiling of PD-1+ KCs revealed an immune-suppressive profile and reduced pathogen responses. Compared with WT mice, PD-1-deficient mice and anti-PD-1-treated mice with liver injury showed improved KC bacterial clearance, a reduced tissue bacterial load, and protection from sepsis. Blood samples from patients with ALF revealed enhanced PD-1 and PD-L1 expression by monocytes and lymphocytes, respectively, and that soluble PD-L1 plasma levels could predict outcomes and sepsis. PD-1 in vitro blockade restored monocyte functionality. Our study describes a role for the PD-1/PD-L1 axis in suppressing KC and monocyte antimicrobial responses after liver injury and identifies anti-PD-1 immunotherapy as a strategy to reduce infection susceptibility in ALF.
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http://dx.doi.org/10.1172/JCI140196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880414PMC
February 2021

Mitochondrial metabolic manipulation by SARS-CoV-2 in peripheral blood mononuclear cells of patients with COVID-19.

Am J Physiol Cell Physiol 2021 01 5;320(1):C57-C65. Epub 2020 Nov 5.

Institute of Liver Studies, Kings College Hospital, London, United Kingdom.

The COVID-19 pandemic has been the primary global health issue since its outbreak in December 2019. Patients with metabolic syndrome suffer from severe complications and a higher mortality rate due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We recently proposed that SARS-CoV-2 can hijack host mitochondrial function and manipulate metabolic pathways for their own advantage. The aim of the current study was to investigate functional mitochondrial changes in live peripheral blood mononuclear cells (PBMCs) from patients with COVID-19 and to decipher the pathways of substrate utilization in these cells and corresponding changes in the inflammatory pathways. We demonstrate mitochondrial dysfunction, metabolic alterations with an increase in glycolysis, and high levels of mitokine in PBMCs from patients with COVID-19. Interestingly, we found that levels of fibroblast growth factor 21 mitokine correlate with COVID-19 disease severity and mortality. These data suggest that patients with COVID-19 have a compromised mitochondrial function and an energy deficit that is compensated by a metabolic switch to glycolysis. This metabolic manipulation by SARS-CoV-2 triggers an enhanced inflammatory response that contributes to the severity of symptoms in COVID-19. Targeting mitochondrial metabolic pathway(s) can help define novel strategies for COVID-19.
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http://dx.doi.org/10.1152/ajpcell.00426.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816428PMC
January 2021

Microcirculatory, Endothelial, and Inflammatory Responses in Critically Ill Patients With COVID-19 Are Distinct From Those Seen in Septic Shock: A Case Control Study.

Shock 2021 06;55(6):752-758

Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.

Abstract: Critically ill patients with COVID-19 infection frequently exhibit a hyperinflammatory response and develop organ failures; however, the underlying mechanisms are unclear. We investigated the microcirculatory, endothelial, and inflammatory responses in critically ill COVID-19 patients and compared them to a group of patients with septic shock in a prospective observational case control study. Thirty critically ill patients with COVID-19 were compared to 33 patients with septic shock.Measurements of sublingual microcirculatory flow using Incident Dark Field video-microscopy and serial measurements of IL-6 and Syndecan-1 levels were performed. COVID-19 patients had significantly less vasoactive drug requirement and lower plasma lactate than those with septic shock. Microcirculatory flow was significantly worse in septic patients than those with COVID-19 (MFI 2.6 vs 2.9 p 0.02, PPV 88 vs 97% P < 0.001). IL-6 was higher in patients with septic shock than COVID-19 (1653 vs 253 pg/mL, P 0.03). IL-6 levels in COVID 19 patients were not elevated compared to healthy controls except on the day of ICU admission. Syndecan-1 levels were not different between the two pathological groups. Compared to patients with undifferentiated septic shock an overt shock state with tissue hypoperfusion does not appear typical of COVID-19 infection. There was no evidence of significant sublingual microcirculatory impairment, widespread endothelial injury or marked inflammatory cytokine release in this group of critically ill COVID-19 patients.
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http://dx.doi.org/10.1097/SHK.0000000000001672DOI Listing
June 2021

Editorial: outcome prediction in patients with cirrhosis and acute-on-chronic liver failure-authors' reply.

Aliment Pharmacol Ther 2020 10;52(7):1227-1228

Liver Intensive Therapy Unit, Kings College Hospital, King's College, London, UK.

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http://dx.doi.org/10.1111/apt.16053DOI Listing
October 2020

Faecal cytokine profiling as a marker of intestinal inflammation in acutely decompensated cirrhosis.

JHEP Rep 2020 Dec 30;2(6):100151. Epub 2020 Jul 30.

Institute of Hepatology London, Foundation for Liver Research, London, UK.

Background & Aims: Gut dysbiosis and inflammation perpetuate loss of gut barrier integrity (GBI) and pathological bacterial translocation (BT) in cirrhosis, contributing to infection risk. Little is known about gut inflammation in cirrhosis and how this differs in acute decompensation (AD). We developed a novel approach to characterise intestinal immunopathology by quantifying faecal cytokines (FCs) and GBI markers.

Methods: Faeces and plasma were obtained from patients with stable cirrhosis (SC; n = 16), AD (n = 47), and healthy controls (HCs; n = 31). A panel of 15 cytokines and GBI markers, including intestinal fatty-acid-binding protein-2 (FABP2), d-lactate, and faecal calprotectin (FCAL), were quantified by electrochemiluminescence/ELISA. Correlations between analytes and clinical metadata with univariate and multivariate analyses were performed.

Results: Faecal (F) IL-1β, interferon gamma, tumour necrosis factor alpha, IL-21, IL-17A/F, and IL-22 were significantly elevated in AD SC ( <0.01). F-IL-23 was significantly elevated in AD HC ( = 0.0007). FABP2/d-lactate were significantly increased in faeces in AD SC and AD HC ( <0.0001) and in plasma ( = 0.0004;  = 0.011). F-FABP2 correlated most strongly with disease severity (Spearman's rho: Child-Pugh 0.466; <0.0001; model for end-stage liver disease 0.488; <0.0001). FCAL correlated with plasma IL-21, IL-1β, and IL-17F only and none of the faecal analytes. F-cytokines and F-GBI markers were more accurate than plasma in discriminating AD from SC.

Conclusions: FC profiling represents an innovative approach to investigating the localised intestinal cytokine micro-environment in cirrhosis. These data reveal that AD is associated with a highly inflamed and permeable gut barrier. FC profiles are very different from the classical innate-like features of systemic inflammation. There is non-specific upregulation of T1/T17 effector cytokines and those known to mediate intestinal barrier damage. This prevents mucosal healing in AD and further propagates BT and systemic inflammation.

Lay Summary: The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.
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http://dx.doi.org/10.1016/j.jhepr.2020.100151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391986PMC
December 2020

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.

JAMA 2020 09;324(11):1048-1057

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.

Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.

Design, Setting, And Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.

Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.

Main Outcomes And Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.

Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.

Conclusions And Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.

Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.
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http://dx.doi.org/10.1001/jama.2020.16349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442954PMC
September 2020

Leucocyte ratios are biomarkers of mortality in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.

Aliment Pharmacol Ther 2020 09 19;52(5):855-865. Epub 2020 Jul 19.

Liver Intensive Therapy Unit, Kings College Hospital, King's College, London, UK.

Background: In patients with cirrhosis, progression to acute decompensation (AD) and acute-on-chronic liver failure (ACLF) has been associated with poor prognosis. Differential leucocyte ratios might predict mortality in systemic inflammatory conditions.

Aim: To evaluate differential leucocyte ratios as prognostic biomarkers in patients with cirrhosis.

Methods: Patients with AD and ACLF were recruited from four centres in three countries. Peripheral blood differential leucocytes were measured (three centres using flow cytometry) on hospital admission and at 48 hours. Ratios were correlated to model for end-stage liver disease (MELD), chronic liver failure-sequential organ failure (CLIF-SOFA), suspected/culture-positive bacterial infection and survival.

Results: Nine hundred twenty-six patients (562 (61%) male, median age 55 (25-94) years) were studied. Overall, 350 (37%) did not survive to hospital discharge. Neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR) were elevated in patients with AD and ACLF who died during their hospital stay. On multivariate analysis NLR retained statistical significance independently of CLIF-SOFA or MELD. NLR >30 was associated with an 80% 90-day mortality in patients with ACLF but not AD. On sensitivity analysis for subgroups (alcohol-related liver disease and suspected sepsis), NLR and MLR retained statistically robust accuracy for the prediction of mortality. Significant predictive accuracy was only observed in centres using flow cytometry.

Conclusion: Leucocyte ratios are simple and robust biomarkers of outcome in ACLF, which are comparable to CLIF-SOFA score but dependent on leucocyte quantification method. NLR and MLR may be used as screening tools for mortality prediction in patients with acutely deteriorating cirrhosis.
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http://dx.doi.org/10.1111/apt.15932DOI Listing
September 2020

Metabolomics to discriminate between acute decompensation and acute-on-chronic liver failure in cirrhosis.

J Hepatol 2020 09 14;73(3):730-732. Epub 2020 Jul 14.

Department of Metabolism, Digestion and Reproduction, Imperial College, London, United Kingdom; Oncology Safety, Clinical Pharmacology & Safety Sciences, R&D, Astra Zeneca, Cambridge, United Kingdom.

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http://dx.doi.org/10.1016/j.jhep.2020.03.021DOI Listing
September 2020

Serum MicroRNA Signatures in Recovery From Acute and Chronic Liver Injury and Selection for Liver Transplantation.

Liver Transpl 2020 06;26(6):811-822

Institute of Liver Studies, King's College Hospital, London, United Kingdom.

We previously demonstrated a distinct hepatic microRNA (miRNA) signature (down-regulation of miRNA-23a, -150, - 200b, -503, and -663 and up-regulation of miRNA-20a) is associated with successful regeneration in auxiliary liver transplantation (ALT). This study aimed to evaluate whether the serum expression of this regeneration-linked miRNA signature is associated with clinical outcomes in acute and chronic liver disease. These were represented by patients with acetaminophen-induced acute liver failure (ALF; n = 18) and patients with hepatitis C virus (HCV) undergoing treatment with direct-acting antivirals (n = 56), respectively. Patients were grouped depending on their clinical outcome. Global serum miRNA expression was analyzed using polymerase chain reaction (PCR) arrays and selected miRNA expression using targeted PCR. We demonstrate that specific regeneration-linked miRNAs discriminate outcomes in both clinical scenarios. We further show that miRNA-20a, -23a, -150, -200b, -503, and -663 undergo concordant changes in expression in 3 distinct clinical settings: liver regeneration accompanying successful ALT, clinical recovery after ALF, and clinical recompensation after cure of HCV. This miRNA signature represents a potentially novel biomarker to predict outcome and optimize patient selection for liver transplantation in both acute and chronic liver disease.
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http://dx.doi.org/10.1002/lt.25781DOI Listing
June 2020

2-Hydroxyglutarate Metabolism Is Altered in an Model of LPS Induced Endotoxemia.

Front Physiol 2020 3;11:147. Epub 2020 Mar 3.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.

The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration , and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect. To determine the role of supplementation with 2HG, we carried out co-administration of LPS and 2HG. This co-administration in mice modulates a number of aspects of physiological responses to LPS, and in particular, protects against LPS-induced hypothermia. Our results identify a novel role for 2HG in endotoxemia pathophysiology, and suggest that this metabolite may be a critical diagnostic and therapeutic target for sepsis.
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http://dx.doi.org/10.3389/fphys.2020.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063103PMC
March 2020

Sequential Cohort Analysis After Liver Transplantation Shows de Novo Extended Release Tacrolimus Is Safe, Efficacious, and Minimizes Renal Dysfunction.

Transplant Direct 2020 Feb 17;6(2):e528. Epub 2020 Jan 17.

Institute of Liver Studies, King's College Hospital, Denmark Hill, London, United Kingdom.

The use of once-daily extended-release tacrolimus (ERT) is associated with improved long-term graft and patient survival when compared with twice-daily tacrolimus (BDT), but the underlying reasons for differential survival are unclear. The aim of the study was to compare clinical outcomes known to impact on posttransplant survival for de novo BDT and ERT in liver transplantation (LT) recipients.

Methods: We conducted a single-center, prospective sequential cohort analysis of adult patients undergoing LT during a change in protocol from de novo BDT to ERT, with a 6-month post-LT follow-up.

Results: A total of 160 transplanted patients were evaluated; 82 were in the BDT group and 78 were in the ERT group. The cohorts were matched for standard variables and a similar proportion in each group received induction interleukin-2 receptor antibody (36% and 31%). There were no significant differences in the measured outcomes of patient and graft survival, biopsy-proven acute rejection episodes, post LT diabetes, and toxicity. A significantly lower number of patients developed chronic kidney disease Stage3-4 in the ERT cohort compared with BDT cohort. In patients with pre-LT renal dysfunction who received antibody induction, estimated glomerular filtration rate decreased significantly in the BDT but not the ERT group.

Conclusions: We show that once-daily ERT is as safe and efficacious as BDT in de novo LT but optimally conserves renal function post-LT.
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http://dx.doi.org/10.1097/TXD.0000000000000970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004634PMC
February 2020

Assessing the Time-Dependent Impact of Performance Status on Outcomes After Liver Transplantation.

Hepatology 2020 10 30;72(4):1341-1352. Epub 2020 Jun 30.

Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom.

Background And Aims: Identifying how the prognostic impact of performance status (PS) differs according to indication, era, and time period ("epoch") after liver transplantation (LT) could have implications for selection and treatment of patients on the waitlist. We used national data from the United Kingdom and Ireland to assess impact of PS on mortality separately for HCC and non-HCC recipients.

Approach And Results: We assessed pre-LT PS using the 5-point modified Eastern Cooperative Oncology Group scale and used Cox regression methods to estimate hazard ratios (HRs) that compared posttransplantation mortality in different epochs of follow-up (0-90 days and 90 days to 1 year) and in different eras of transplantation (1995-2005 and 2006-2016). 2107 HCC and 10,693 non-HCC patients were included. One-year survival decreased with worsening PS in non-HCC recipients where 1-year survival was 91.9% (95% confidence interval [CI], 88.3-94.4) in those able to carry out normal activity (PS1) compared to 78.7% (95% CI, 76.7-80.5) in those completely reliant on care (PS5). For HCC patients, these estimates were 89.9% (95% CI, 85.4-93.2) and 83.1% (95% CI, 61.0-93.3), respectively. Reduction in survival in non-HCC patients with poorer PS was in the first 90 days after transplant, with no major effect observed between 90 days and 1 year. Adjustment for donor and recipient characteristics did not change the findings. Comparing era, post-LT mortality improved for HCC (adjusted HR, 0.55; 95% CI, 0.40-0.74) and non-HCC recipients (0.48; 95% CI, 0.42-0.55), but this did not differ according to PS score (P = 0.39 and 0.61, respectively).

Conclusions: Impact on mortality of the recipient's pretransplant PS is principally limited to the first 3 months after LT. Over time, mortality has improved for both HCC and non-HCC recipients and across the full range of PS.
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http://dx.doi.org/10.1002/hep.31124DOI Listing
October 2020

A 'real-world' analysis of risk factors for post liver transplant delirium and the effect on length of stay.

Eur J Gastroenterol Hepatol 2020 10;32(10):1373-1380

Institute of Liver Studies, King's College Hospital, Denmark Hill, London, UK.

Background: The development of delirium has been previously demonstrated to be associated with an increased risk of mortality and length of stay post liver transplant (LTx) with multiple risk factors being identified in previous studies. In this study, we have aimed to identify the most important variables associated with the onset of post-LTx delirium and understand the effect on length of stay (LOS).

Methods: All liver transplants for chronic liver disease between 1 August 2012 and 1 August 2017 were included (n = 793). Data were collected for analysis retrospectively from electronic patient records.

Results: Delirium is associated with an overall increased hospital and ICU LOS but not one-year mortality. The risk of developing post-LTx delirium was the greatest among patients: with post-LTx sepsis, who required renal sparing immunosuppression, who received donation after cardiac death (DCD) grafts and who were older. Patients with autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis seemed to be at lower risk of post-LTx delirium. However, global patient LOS was only prolonged in patients with sepsis and renal failure.

Conclusion: Many of the risk factors previously described to be associated with the development of post-LTx delirium were not demonstrated to be significant in this study. Sepsis, renal failure, older age and DCD use are associated with delirium post-LTx. It is unclear if this syndrome is an independent risk factor for increased LOS or if it is a symptom of well established syndromes associated with increased LOS. The role for prophylactic strategies to reduce the incidence of post-LTx delirium is therefore unclear.
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http://dx.doi.org/10.1097/MEG.0000000000001661DOI Listing
October 2020

Significant lung injury and its prognostic significance in acute liver failure: A cohort analysis.

Liver Int 2020 03 13;40(3):654-663. Epub 2019 Oct 13.

Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada.

Background And Aims: Respiratory failure complicating acute liver failure (ALF) may preclude liver transplantation (LT). We evaluated the association between significant lung injury (SLI) and important clinical outcomes.

Methods: Retrospective cohort study of 947 ALF patients with chest radiograph (CXR) and arterial blood gas (ABG) data enrolled in the US Acute Liver Failure Study Group (US-ALFSG) from January 1998 to December 2016. SLI was defined by moderate hypoxaemia (Berlin classification; PaO /FiO  < 200 mm Hg) and abnormalities on CXR. Primary outcomes were 21-day transplant-free survival (TFS) and overall survival.

Results: Of 947 ALF patients, 370 (39%) had evidence of SLI. ALF patients with SLI (ALF-SLI) had significantly worse oxygenation than controls on admission (median PF ratio 120 vs 300 mm Hg, P < .0001) and higher lactate (6.1 vs 4.6 mmol/l, P = .0008). ALF-SLI patients had higher rates of tracheal (19% vs 14%) and bloodstream (17% vs 11%, P < .005 for both) infections and were more likely to receive transfusions (red cells 55% vs 43%; FFP 74% vs 66%; P < .009 for both). ALF-SLI patients were less likely to receive LT (18% vs 25%, P = .02) and had significantly decreased 21-day TFS (34% vs 42%) and overall survival (49% vs 64%, P < .007 for both). After adjusting for significant covariates (INR, bilirubin, acetaminophen aetiology), the development of SLI was independently associated with decreased 21-day TFS (OR 0.71, P = .03) in ALF patients (C-index 0.78). The incorporation of SLI improved discriminatory ability of the King's College Criteria (P = .0061) but not the ALFSG prognostic index (P = .34).

Conclusion: Significant lung injury is a common complication in ALF patients that adversely affects patient outcomes.
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http://dx.doi.org/10.1111/liv.14268DOI Listing
March 2020

Modern Outcomes Following Treatment of Hepatocellular Carcinoma in Hereditary Hemochromatosis: A Matched Cohort Study.

Am J Clin Oncol 2019 12;42(12):918-923

Institute of Liver Studies.

Objective: Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival.

Materials And Methods: Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality.

Results: A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) μg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival.

Conclusions: Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.
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http://dx.doi.org/10.1097/COC.0000000000000583DOI Listing
December 2019

Lactate and number of organ failures predict intensive care unit mortality in patients with acute-on-chronic liver failure.

Liver Int 2019 07 19;39(7):1271-1280. Epub 2019 Mar 19.

Gastroenterology Division (Liver Unit), University of Alberta Hospital, Edmonton, AB, Canada.

Background And Aims: Patients with acute-on-chronic liver failure (ACLF) have high mortality rates. Most prognostic scores were not developed for the intensive care unit (ICU) setting. We aimed to improve risk stratification for patients with ACLF in the ICU.

Methods: A training set with 240 patients with cirrhosis and organ failures (Chronic Liver Failure Sequential Organ Failure Assessment score [CLIF-SOFA]) from Curry Cabral Hospital (Portugal) and University of Alberta Hospital (Canada) in 2010-2016 was used to derive a prognostic model for ICU mortality. A validation set with 237 patients with cirrhosis and organ failures from Vancouver General Hospital (Canada) in 2000-2011 was used to evaluate its performance.

Results: Amongst patients in the training set, ICU and hospital mortality rates were 39.2% and 54.6% respectively. Median lactate (4.4 vs 2.5 mmol/L) and number of organ failures (3 vs 2) on admission to ICU were associated with higher likelihood of ICU mortality (P < 0.001 for both). The lactate and organ failures predictive model (LacOF) was derived to predict ICU mortality: -2.420 + 0.072 × lactate + 0.569 × number of organ failures (area under-the-curve [AUC], 0.76). In the validation set, the LacOF model discriminative ability (AUC, 0.85) outperformed the CLIF-SOFA (AUC, 0.79), Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure (AUC, 0.73), Model for End-stage Liver Disease score (AUC, 0.78) and Acute Physiology and Chronic Health Evaluation II scores (AUC, 0.74; P < 0.05 for all). The LacOF model calibration was good up to the 25% likelihood of ICU mortality.

Conclusions: In patients with ACLF, lactate and number of organ failures on admission to ICU are useful to predict ICU mortality. This early prognostic evaluation may help to better stratify the risk of ICU mortality and thus optimize organ support strategies.
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http://dx.doi.org/10.1111/liv.14083DOI Listing
July 2019

L-Ornithine L-Aspartate (LOLA) for Hepatic Encephalopathy in Cirrhosis: Results of Randomized Controlled Trials and Meta-Analyses.

Drugs 2019 Feb;79(Suppl 1):31-37

Liver Intensive Therapy Unit, Institute of Liver Sciences, School of Immunology and Microbial Sciences, Kings College London, London, UK.

This manuscript represents an appraisal of the evidence in support of L-ornithine-L-aspartate (LOLA) for the management and treatment of hepatic encephalopathy (HE) in cirrhosis. Meta-analyses of randomized controlled trials (RCTs) conducted over the last two decades generally reveal evidence of benefit of LOLA in a range of clinical presentations. This included improvement of mental state grade in overt HE (OHE) assessed by West Haven criteria as well as in minimal HE (MHE) assessed by psychometric testing where the oral formulation of LOLA was determined to be particularly effective. However, concerns over study quality were noted in one meta-analysis. Nevertheless, the concomitant lowering of fasting blood ammonia was reported in all RCTs using this endpoint. Network meta-analyses showed that LOLA appears to be comparable (or superior) in efficacy to non-absorbable disaccharides or probiotics. Emerging evidence from single RCTs show efficacy of LOLA for the treatment of post-transjugular intrahepatic portosystemic shunt (TIPSS) HE as well as for secondary HE prophylaxis. These findings provide support for the use of LOLA in the treatment of HE and future trials should focus on the use of LOLA for prophylaxis.
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http://dx.doi.org/10.1007/s40265-018-1024-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416237PMC
February 2019
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