Publications by authors named "Vishal C Patel"

28 Publications

  • Page 1 of 1

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

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

Hemostatic balance in acute-on-chronic liver failure.

J Thromb Haemost 2021 03;19(3):869-870

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

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http://dx.doi.org/10.1111/jth.15192DOI Listing
March 2021

Global hemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease.

J Thromb Haemost 2021 01 29;19(1):85-95. Epub 2020 Nov 29.

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

Essentials Liver diseases are associated with profound hemostatic changes proportional to severity of illness. Hemostatic changes in acute-on-chronic liver failure (ACLF) may in part reflect critical illness. Hemostatic changes in ACLF partly overlap with those in sepsis, with rebalanced hemostasis in both. Patients with sepsis had hyperfibrinogenemia, associated with a thrombogenic clot structure. ABSTRACT: Background Even the sickest patients with chronic liver disease (CLD), such as those with acute-on-chronic liver failure (ACLF) remain in hemostatic balance due to a concomitant decline in pro- and antihemostatic factors. Objectives We aimed to study whether the hemostatic status in ACLF is merely an exaggeration from the status in patients with compensated and acutely decompensated cirrhosis, or whether sepsis-associated hemostatic changes contribute. Methods We performed extensive hemostatic profiling in 31 adult patients with ACLF, 20 patients with sepsis without underlying CLD, and 40 healthy controls. Results We found similarly elevated plasma levels of the platelet adhesive protein von Willebrand factor (VWF) and decreased levels of the VWF-regulating protease ADAMTS13 in both groups compared to healthy controls. In vivo markers of activation of coagulation (thrombin-antithrombin III, D-dimer) were similarly elevated in both groups compared to controls, but ex vivo thrombin-generating capacity was similar between patients and controls, despite a much more profound international normalized ratio elevation in ACLF. Plasma fibrinogen levels were much higher in septics, which was accompanied by a decreased ex vivo clot permeability and an increase in ex vivo resistance to clot lysis. All hemostatic parameters were remarkably stable over the first 10 days after admission. Conclusions We have found hemostatic changes in ACLF to partially overlap with that of patients with sepsis, and evidence of preserved hemostatic capacity in both patient groups. The notable difference was a profound hyperfibrinogenemia, associated with a thrombogenic clot structure and a marked ex vivo resistance to fibrinolysis in patients with sepsis.
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http://dx.doi.org/10.1111/jth.15112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839476PMC
January 2021

Modulating the gut-liver axis and the pivotal role of the faecal microbiome in cirrhosis.

Clin Med (Lond) 2020 09;20(5):493-500

King's College Hospital NHS Foundation Trust, London, UK, honorary senior lecturer, King's College London, London, UK and principal investigator, Institute of Hepatology, Foundation for Liver Research, London, UK

Cirrhosis is associated with intestinal dysbiosis, with specific alterations in the gut microbiota linked to particular aetiologies and manifestations of the disease. We review the role of the gut microbiome and the importance of the intestinal barrier in cirrhosis, provide an overview of the terminology and techniques relevant to this emerging area, and discuss the latest developments in therapies targeting the gut-liver axis.
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http://dx.doi.org/10.7861/clinmed.2020-0676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539737PMC
September 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

Plasma levels of circulating DNA are associated with outcome, but not with activation of coagulation in decompensated cirrhosis and ACLF.

JHEP Rep 2019 Sep 28;1(3):179-187. Epub 2019 Jun 28.

Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Acute-on-chronic liver failure (ACLF) is a recently (re)defined syndrome of acute decompensation of cirrhosis that presents with extrahepatic organ failure(s) and poor outcome. Given the prominent role of inflammation and activation of coagulation in ACLF, we hypothesized that ACLF might be characterized by the generation of neutrophil extracellular traps (NETs), that could drive both activation of coagulation and progression of organ failure.

Methods: We measured markers of circulating DNA, activation of coagulation, inflammation, and oxidative stress in 52 patients with acute decompensation (AD) of cirrhosis and 57 patients with ACLF on admission, and compared levels with 40 healthy controls.

Results: All analytes were higher in patients compared to controls. Plasma levels of cell-free DNA, but not of the specific NET marker myeloperoxidase-DNA complexes were higher in patients with ACLF compared to AD cirrhosis. In addition, TAT complexes (coagulation), IL-6 (inflammation), and TBARS (oxidative stress) were higher in ACLF compared to AD. Markers for activation of coagulation were not associated with circulating DNA, IL-6, or TBARS. In contrast, levels of circulating DNA, IL-6, and TBARS were higher in patients with more severe disease, higher in patients with organ failure, and higher in patients that died within 30 days of admission. Importantly, myeloperoxidase-DNA levels did not differ between patients with complications and poor outcome.

Conclusions: Collectively, we show that cell-free DNA, inflammation, and oxidative stress are associated with outcomes in AD and ACLF, but not with activation of coagulation. Our data argue against a role of NETs in activation of coagulation and in progression of organ failure in patients with AD and ACLF.

Lay Summary: Acute-on-chronic liver failure is a devastating syndrome that can follow acute decompensation of chronic liver disease. Herein, we demonstrate that these patients accumulate DNA released from dying cells in their blood, and that the quantity of this DNA is related to the outcome of disease. We also show that outcome of disease is not related to recently described neutrophil extracellular traps, which have been shown in animal models to play vital roles in the progression of liver diseases.
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http://dx.doi.org/10.1016/j.jhepr.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001554PMC
September 2019

Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay.

J Thromb Haemost 2020 04 18;18(4):834-843. Epub 2020 Feb 18.

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

Background And Aims: Patients with cirrhosis have a rebalanced hemostasis, often with normal or elevated thrombin-generating (TG) capacity in plasma. Whole blood (WB) TG allows faster determination and, importantly, includes the influence of all circulating blood cells. We aimed to study the TG profile of patients with cirrhosis in WB and in platelet poor plasma.

Methods: Thrombin-generating capacity in WB and plasma were assessed with a near-patient WB-TG assay and the calibrated automated thrombinography assay, respectively. TG assays were tested in presence and absence of thrombomodulin. Conventional coagulation tests were also performed.

Results: Thirty-four patients with cirrhosis and twenty-two controls were analyzed. Compared with controls, patients had substantially deranged results in conventional coagulation tests. Comparable WB-TG capacity (endogenous thrombin potential until peak, ETPp) but significantly lower peak thrombin were found in patients, and these results persisted when thrombomodulin was present. TG of the patients was more resistant to thrombomodulin than controls in both WB and plasma, although the inhibitory effect of thrombomodulin was drastically weaker in WB than in plasma. The peak of WB-TG in patients correlated moderately with their hematocrit and platelet count. Significant correlations were found between TG results in WB and plasma.

Conclusions: The WB-TG assay shows a normal to hypocoagulable state in patients with cirrhosis with a decreased anticoagulant activity of TM compared to plasma-TG. The clinical value of this assay needs further validation.
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http://dx.doi.org/10.1111/jth.14751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186949PMC
April 2020

Antimicrobial resistance in chronic liver disease.

Hepatol Int 2020 Jan 3;14(1):24-34. Epub 2019 Dec 3.

The Institute of Hepatology London and Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK.

High levels of antimicrobial drug resistance deleteriously affecting the outcome of treatment with antibacterial agents are causing increasing concern worldwide. This is particularly worrying in patients with cirrhosis with a depressed immune system and heightened susceptibility to infection. Antibiotics have to be started early before results of microbiological culture are available. Current guidelines for the empirical choice of antibiotics in this situation are not very helpful, and embracing antimicrobial stewardship including rapid de-escalation of therapy are not sufficiently emphasised. Multi-drug resistant organism rates to quinolone drugs of up to 40% are recorded in patients with spontaneous bacterial peritonitis on prophylactic antibiotics, leading to a break-through recurrence of intra-peritoneal infection. Also considered in this review is the value of rifaximin-α, non-selective beta-blockers, and concerns around proton pump inhibitor drug use. Fecal microbial transplantation and other gut-targeting therapies in lessening gut bacterial translocation are a promising approach, and new molecular techniques for determining bacterial sensitivity will allow more specific targeted therapy.
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http://dx.doi.org/10.1007/s12072-019-10004-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994429PMC
January 2020

Mixed Fibrinolytic Phenotypes in Decompensated Cirrhosis and Acute-on-Chronic Liver Failure with Hypofibrinolysis in Those With Complications and Poor Survival.

Hepatology 2020 04 24;71(4):1381-1390. Epub 2019 Oct 24.

Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background And Aims: Patients with liver disease acquire complex changes in their hemostatic system, which results in a fragile rebalanced status. The status of the fibrinolytic system is controversial, as is the role of fibrinolytic dysfunction in bleeding and thrombosis in patients with cirrhosis. Here, we aimed to determine fibrinolytic status and its relationship with outcome in acutely ill patients with cirrhosis.

Approach And Results: We assessed plasma fibrinolytic potential in a large cohort of patients with acutely decompensated cirrhosis (AD, n = 52) or acute-on-chronic liver failure (ACLF, n = 57). Compared with 40 healthy volunteers, median clot lysis times (CLTs) were shorter in patients with AD but comparable to controls in patients with ACLF. However, the variability in CLTs in patients was much larger than in healthy controls, and in both patient groups, a proportion of patients had clearly prolonged or shortened CLTs. The variability in CLTs in patients was not readily explained by variations in plasma levels of key fibrinolytic proteins. However, CLTs were clearly related to clinical characteristics, with longer CLTs in patients with sepsis and patients with any organ failure (as defined by the European Foundation for the Study of Chronic Liver Disease organ failure scores). CLTs were not different between patients that did or did not experience bleeding or a thrombotic event during follow-up. Baseline CLTs were substantially longer in patients that died within 30 days of admission.

Conclusions: Our study demonstrates a mixed fibrinolytic phenotype in acutely ill patients with cirrhosis with baseline hypofibrinolysis associated with sepsis, organ failure, and short-term mortality. These associations may be explained by defective clearance of intraorgan microthrombi that have been proposed to drive organ failure.
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http://dx.doi.org/10.1002/hep.30915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187291PMC
April 2020

Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list.

Aliment Pharmacol Ther 2019 08 6;50(4):435-441. Epub 2019 Jun 6.

Institute of Liver Studies and Transplantation, King's College Hospital, London, UK.

Background: Rifaximin reduces the risk of overt hepatic encephalopathy (HE) and is associated with significant reductions in hospitalisations and 30-day readmissions.

Aim: To examine the outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug.

Methods: Patient records of those listed for liver transplantation over a 2-year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment.

Results: Of the 622 patients listed for transplantation, 101 had HE. Sixty-six patients were treated with rifaximin and 35 were naïve at listing. The use of concurrent lactulose was not significantly different between groups. Median MELD score was similar (15 [14-16)] rifaximin-treated and 16 [14-18] rifaximin-naïve). Patients on the waiting list treated with rifaximin had reduced all-cause admissions, episodes of spontaneous bacterial peritonitis and variceal bleeding. Mean length of stay was 9 days (95% CI 6-12) in the rifaximin-treated group vs 14 (95% CI 7-21) in the rifaximin-naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in average days to readmission (adjusted effect estimate 71, 95% CI 3-140 days) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89-0.93).

Conclusion: Rifaximin prescribed for HE in patients listed for liver transplantation improved outcomes with significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and variceal bleeding.
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http://dx.doi.org/10.1111/apt.15326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816014PMC
August 2019

PROFIT, a PROspective, randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation in cirrhosis: study protocol for a single-blinded trial.

BMJ Open 2019 02 15;9(2):e023518. Epub 2019 Feb 15.

James Black Centre, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Introduction: Patients with advanced cirrhosis have enteric bacterial dysbiosis and translocation of bacteria and their products across the gut epithelial barrier. This culminates in systemic inflammation and endotoxaemia, inducing innate immune dysfunction which predisposes to infection, and development of complications such as bleeding, sepsis and hepatic encephalopathy. This feasibility study aims to assess the safety of administering faecal microbiota transplantion to patients with cirrhosis and explore the effect of the intervention on their prognosis by achieving restoration of a healthy gut microbiome.

Methods And Analysis: A PROspective, randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation is a single-centre, randomised, single-blinded, placebo-controlled study evaluating faecal microbiota transplantation (FMT) against placebo. Patients with advanced but stable cirrhosis with a Model for End-Stage Liver Disease score between 10 and 16 will be recruited. Twenty-four patients will be randomised to FMT plus standard of care (as per our institutional practice) and eight patients to placebo in a ratio of 3:1. Patients will be evaluated at baseline before the study intervention is administered and at 7, 30 and 90 days post-intervention to assess safety and adverse events. FMT/placebo will be administered into the jejunum within 7 days of baseline. The primary outcome measure will be safety and feasibility as assessed by recruitment rates, tolerability and safety of FMT treatment. Results will be disseminated via peer-reviewed journals and international conferences. The recruitment of the first patient occurred on 23 May 2018.

Ethics And Dissemination: Research Ethics approval was given by the London South East Research Ethics committee (ref 17/LO/2081).

Trial Registration Number: NCT02862249 and EudraCT 2017-003629-13.
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http://dx.doi.org/10.1136/bmjopen-2018-023518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398649PMC
February 2019

Therapeutic plasma exchange as a novel treatment for severe intrahepatic cholestasis of pregnancy: Case series and mechanism of action.

J Clin Apher 2018 Dec 15;33(6):638-644. Epub 2018 Oct 15.

Department of Women and Children's Health, King's College London, London, United Kingdom.

Introduction: Intrahepatic cholestasis of pregnancy is characterised by pruritus and elevated serum bile acids. The pruritus can be severe, and pharmacological options achieve inconsistent symptomatic improvement. Raised bile acids are linearly associated with adverse fetal outcomes, with existing management of limited benefit. We hypothesised that therapeutic plasma exchange removes pruritogens and lowers total bile acid concentrations, and improves symptoms and biochemical abnormalities in severe cases that have not responded to other treatments.

Methods: Four women with severe pruritus and hypercholanemia were managed with therapeutic plasma exchange. Serial blood biochemistry and visual analogue scores of itch severity were obtained. Blood and waste plasma samples were collected before and after exchange; individual bile acids and sulfated progesterone metabolites were measured with HPLC-MS, autotaxin activity and cytokine profiles with enzymatic methods. Results were analysed using segmental linear regression to describe longitudinal trends, and ratio t tests.

Results: Total bile acids and visual analogue itch scores demonstrated trends to transiently improve following plasma exchange, with temporary symptomatic benefit reported. Individual bile acids (excluding the drug ursodeoxycholic acid), and the sulfated metabolites of progesterone reduced following exchange (P = .03 and P = .04, respectively), whilst analysis of waste plasma demonstrated removal of autotaxin and cytokines.

Conclusions: Therapeutic plasma exchange can lower potentially harmful bile acids and improve itch, likely secondary to the demonstrated removal of pruritogens. However, the limited current experience and potential complications, along with minimal sustained symptomatic benefit, restrict its current use to women with the most severe disease for whom other treatment options have been exhausted.
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http://dx.doi.org/10.1002/jca.21654DOI Listing
December 2018

In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis.

Liver Int 2018 11 30;38(11):1988-1996. Epub 2018 May 30.

Liver Intensive Care Unit, Institute of Liver Studies, King College Hospital, London, UK.

Background & Aims: A simultaneous decline in pro- and anticoagulant drivers in patients with liver diseases results in a "rebalanced" haemostatic system, even in acutely ill patients. Nevertheless, both bleeding and thrombotic events are common. Here, we explored efficacy of pro- and antihaemostatic strategies in compensated and acutely ill cirrhotics which may be unpredictable given the profound haemostatic changes.

Methods: We tested the effects in vitro of the addition of clinically relevant doses of commonly used pro- and antihaemostatic strategies in plasma from healthy individuals (n = 30) and patients with compensated (n = 18) and acutely decompensated cirrhosis (n = 18), and acute-on-chronic liver failure (n = 10). We used thrombin generation tests and fibrin clot permeability assays to assess potency of various approaches.

Results: Fresh frozen plasma and recombinant factor VIIa modestly increased thrombin generation (10%-20%). Prothrombin complex concentrate increased thrombin generation two-fold in controls and 2-4-fold in patients. Clot permeability decreased after addition of fibrinogen concentrate by 51% in controls and by 50%-60% in patients. Low molecular weight heparin decreased thrombin generation by 18% in controls and by 23%-54% in patients. Similarly, dabigatran decreased thrombin generation by 33% in controls and by 47%-100% in patients. In contrast, rivaroxaban decreased thrombin generation by 55% in controls, but only by 11%-38% in patients.

Conclusions: These in vitro data suggest little prohaemostatic effect of fresh frozen plasma and recombinant factor VIIa in acutely ill cirrhotics, whereas prothrombin complex concentrate and fibrinogen concentrate clearly improved haemostasis. Furthermore, our data suggest the requirement for dose adjustments of commonly used anticoagulants in these patients.
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http://dx.doi.org/10.1111/liv.13882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220788PMC
November 2018

Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure.

J Crit Care 2018 Feb 17;43:54-60. Epub 2017 Aug 17.

Liver Intensive Care Unit, Institute of Liver Studies, King College Hospital, London, United Kingdom. Electronic address:

Background: Cirrhotic patients have complex haemostatic abnormalities. Current evidence suggests stable cirrhotic (SC) patients have a "re-balanced" haemostatic state. However, limited data exists in acute decompensated (AD) or acute on chronic liver failure (ACLF) patients.

Methods: We utilised thrombin generation analysis, fibrinolysis assessment, and evaluation of haemostatic parameters to assess haemostasis in liver disease of progressive severity.

Results: The study cohorts were comprised of: SC, n=8; AD n=44; ACLF, n=17; and Healthy Control (HC), n=35. There was a progressive increase across the cohorts in INR (p=0.0001), Factor VIII (p=0.0001) and VWF levels (p=0.0001) and a correspondingly decrease in anti-thrombin (p=0.0001), ADAMTS-13 (p=0.01) and fibrinogen levels (p=0.0001). In the presence of thrombomodulin, thrombin generation was equivalent or significantly higher in all the cohorts compared to HC (p=0.0001). Compared to AD, ACLF had a lower ETP (p=0.002) and thrombin peak (p=0.0001). There was no significant difference across the cohorts in clot lysis time (p=0.07), although compared to HC, AD had a significantly shorter lysis time (p=0.001).

Conclusions: Our cohorts, despite significant differences in haemostatic parameters, displayed intact thrombin generation but progressive hypo-functional clot stability and potentially but not universal hyper-functional haemostasis.
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http://dx.doi.org/10.1016/j.jcrc.2017.07.053DOI Listing
February 2018

CD14 CD15 HLA-DR myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.

Gut 2018 06 7;67(6):1155-1167. Epub 2017 Jun 7.

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

Objective: Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14HLA-DR myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses.

Design: Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14CD15CD11bHLA-DR cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques.

Results: Circulating CD14CD15CD11bHLA-DR M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo.

Conclusion: Immunosuppressive CD14HLA-DR M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.
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http://dx.doi.org/10.1136/gutjnl-2017-314184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969362PMC
June 2018

MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure.

Gut 2018 02 27;67(2):333-347. Epub 2017 Apr 27.

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

Objective: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response.

Design: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice.

Results: We demonstrate a significant expansion of resolution-like MerTK+HLA-DR cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCII macrophages during the resolution phase in ALF, APAP-treated Mer mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DR phenotype which promotes neutrophil apoptosis and their subsequent clearance.

Conclusions: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
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http://dx.doi.org/10.1136/gutjnl-2016-313615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868289PMC
February 2018

High-Speed Quantitative UPLC-MS Analysis of Multiple Amines in Human Plasma and Serum via Precolumn Derivatization with 6-Aminoquinolyl-N-hydroxysuccinimidyl Carbamate: Application to Acetaminophen-Induced Liver Failure.

Anal Chem 2017 02 7;89(4):2478-2487. Epub 2017 Feb 7.

Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , South Kensington, London SW7 2AZ, United Kingdom.

A targeted reversed-phase gradient UPLC-MS/MS assay has been developed for the quantification /monitoring of 66 amino acids and amino-containing compounds in human plasma and serum using precolumn derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AccQTag Ultra). Derivatization of the target amines required minimal sample preparation and resulted in analytes with excellent chromatographic and mass spectrometric detection properties. The resulting method, which requires only 10 μL of sample, provides the reproducible and robust separation of 66 analytes in 7.5 min, including baseline resolution of isomers such as leucine and isoleucine. The assay has been validated for the quantification of 33 amino compounds (predominantly amino acids) over a concentration range from 2 to 20 and 800 μM. Intra- and interday accuracy of between 0.05 and 15.6 and 0.78-13.7% and precision between 0.91 and 16.9% and 2.12-15.9% were obtained. A further 33 biogenic amines can be monitored in samples for relative changes in concentration rather than quantification. Application of the assay to samples derived from healthy controls and patients suffering from acetaminophen (APAP, paracetamol)-induced acute liver failure (ALF) showed significant differences in the amounts of aromatic and branched chain amino acids between the groups as well as a number of other analytes, including the novel observation of increased concentrations of sarcosine in ALF patients. The properties of the developed assay, including short analysis time, make it suitable for high-throughput targeted UPLC-ESI-MS/MS metabonomic analysis in clinical and epidemiological environments.
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http://dx.doi.org/10.1021/acs.analchem.6b04623DOI Listing
February 2017

Adaptive reorganization of retinogeniculate axon terminals in dorsal lateral geniculate nucleus following experimental mild traumatic brain injury.

Exp Neurol 2017 03 28;289:85-95. Epub 2016 Dec 28.

Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, USA. Electronic address:

The pathologic process in traumatic brain injury marked by delayed axonal loss, known as diffuse axonal injury (DAI), leads to partial deafferentation of neurons downstream of injured axons. This process is linked to persistent visual dysfunction following mild traumatic brain injury (mTBI), however, examination of deafferentation in humans is impossible with current technology. To investigate potential reorganization in the visual system following mTBI, we utilized the central fluid percussion injury (cFPI) mouse model of mTBI. We report that in the optic nerve of adult male C57BL/6J mice, axonal projections of retinal ganglion cells (RGCs) to their downstream thalamic target, dorsal lateral geniculate nucleus (dLGN), undergo DAI followed by scattered, widespread axon terminals loss within the dLGN at 4days post-injury. However, at 10days post-injury, significant reorganization of RGC axon terminals was found, suggestive of an adaptive neuroplastic response. While these changes persisted at 20days post-injury, the RGC axon terminal distribution did not recovery fully to sham-injury levels. Our studies also revealed that following DAI, the segregation of axon terminals from ipsilateral and contralateral eye projections remained consistent with normal adult mouse distribution. Lastly, our examination of the shell and core of dLGN suggested that different RGC subpopulations may vary in their susceptibility to injury or in their contribution to reorganization following injury. Collectively, these findings support the premise that subcortical axon terminal reorganization may contribute to recovery following mTBI, and that different neural phenotypes may vary in their contribution to this reorganization despite exposure to the same injury.
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http://dx.doi.org/10.1016/j.expneurol.2016.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5285456PMC
March 2017

Clinical science workshop: targeting the gut-liver-brain axis.

Metab Brain Dis 2016 12 8;31(6):1327-1337. Epub 2015 Oct 8.

Institute of Liver Studies, King's College London School of Medicine, King's College Hospital, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.

A clinical science workshop was held at the ISHEN meeting in London on Friday 11th September 2014 with the aim of thrashing out how we might translate what we know about the central role of the gut-liver-brain axis into targets which we can use in the treatment of hepatic encephalopathy (HE). This review summarises the integral role that inter-organ ammonia metabolism plays in the pathogenesis of HE with specific discussion of the roles that the small and large intestine, liver, brain, kidney and muscle assume in ammonia and glutamine metabolism. Most recently, the salivary and gut microbiome have been shown to underpin the pathophysiological changes which culminate in HE and patients with advanced cirrhosis present with enteric dysbiosis with small bowel bacterial overgrowth and translocation of bacteria and their products across a leaky gut epithelial barrier. Resident macrophages within the liver are able to sense bacterial degradation products initiating a pro-inflammatory response within the hepatic parenchyma and release of cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-8 into the systemic circulation. The endotoxemia and systemic inflammatory response that are generated predispose both to the development of infection as well as the manifestation of covert and overt HE. Co-morbidities such as diabetes and insulin resistance, which commonly accompany cirrhosis, may promote slow gut transit, promote bacterial overgrowth and increase glutaminase activity and may need to be acknowledged in HE risk stratification assessments and therapeutic regimens. Therapies are discussed which target ammonia production, utilisation or excretion at an individual organ level, or which reduce systemic inflammation and endotoxemia which are known to exacerbate the cerebral effects of ammonia in HE. The ideal therapeutic strategy would be to use an agent that can reduce hyperammonemia and reduce systemic inflammation or perhaps to adopt a combination of therapies that can address both.
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http://dx.doi.org/10.1007/s11011-015-9743-4DOI Listing
December 2016

Bile acid profiling and quantification in biofluids using ultra-performance liquid chromatography tandem mass spectrometry.

Anal Chem 2015 Oct 30;87(19):9662-70. Epub 2015 Sep 30.

Imperial College of London , Division of Computational Systems Medicine, Department of Surgery and Cancer, Sir Alexander Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.

Bile acids are important end products of cholesterol metabolism. While they have been identified as key factors in lipid emulsification and absorption due to their detergent properties, bile acids have also been shown to act as signaling molecules and intermediates between the host and the gut microbiota. To further the investigation of bile acid functions in humans, an advanced platform for high throughput analysis is essential. Herein, we describe the development and application of a 15 min UPLC procedure for the separation of bile acid species from human biofluid samples requiring minimal sample preparation. High resolution time-of-flight mass spectrometry was applied for profiling applications, elucidating rich bile acid profiles in both normal and disease state plasma. In parallel, a second mode of detection was developed utilizing tandem mass spectrometry for sensitive and quantitative targeted analysis of 145 bile acid (BA) species including primary, secondary, and tertiary bile acids. The latter system was validated by testing the linearity (lower limit of quantification, LLOQ, 0.25-10 nM and upper limit of quantification, ULOQ, 2.5-5 μM), precision (≈6.5%), and accuracy (81.2-118.9%) on inter- and intraday analysis achieving good recovery of bile acids (serum/plasma 88% and urine 93%). The ultra performance liquid chromatography-mass spectrometry (UPLC-MS)/MS targeted method was successfully applied to plasma, serum, and urine samples in order to compare the bile acid pool compositional difference between preprandial and postprandial states, demonstrating the utility of such analysis on human biofluids.
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http://dx.doi.org/10.1021/acs.analchem.5b01556DOI Listing
October 2015

High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.

J Hepatol 2016 Jan 29;64(1):69-78. Epub 2015 Aug 29.

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

Background & Aims: Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters.

Methods: In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken.

Results: For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (p<0.001).

Conclusions: Treatment with HVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction.
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http://dx.doi.org/10.1016/j.jhep.2015.08.018DOI Listing
January 2016

Immunotherapy in the treatment and prevention of infection in acute-on-chronic liver failure.

Immunotherapy 2015 12;7(6):641-54. Epub 2015 Jun 12.

Institute of Liver Studies, King's College Hospital, King's College London, London SE5 9RS, UK.

Chronic liver disease, depicted by gradual destruction and fibrosis of the liver, is a condition with high and probably increasing prevalence worldwide. Its deterioration, acute-on-chronic liver failure (ACLF), is characterized by an in-hospital mortality of up to 65%. Infectious complications are the main precipitants eliciting ACLF and concurrently the main cause of death from ACLF. Patients have a marked susceptibility to bacterial infections, which is thought to arise a consequence of an inadequate immune response to microbial challenge, termed immuneparesis. The pathophysiologic mechanisms remain poorly understood. Treatments aimed at restoring the patients' immune function may prevent onset of ACLF and death from secondary infections. A number of drugs approved for patients with liver disease bear immunomodulatory potential such as albumin, glucocorticoids, N-acetylcysteine. Specific targets have been defined that may lead to development of new immunotherapeutic agents. Here, we summarize the pathophysiology of immuneparesis in ACLF and drug candidates to restore immune function and improve survival in the future.
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http://dx.doi.org/10.2217/imt.15.27DOI Listing
April 2016

Salivary microbiota-immune profiling in cirrhosis: could this be the noninvasive strategy that will revolutionize prognostication in hepatology?

Hepatology 2015 Oct 19;62(4):1001-3. Epub 2015 Jun 19.

Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, London, United Kingdom.

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http://dx.doi.org/10.1002/hep.27870DOI Listing
October 2015

Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK.

Gastroenterology 2015 Mar 3;148(3):603-615.e14. Epub 2014 Dec 3.

Institute of Liver Studies, King's College Hospital, King's College London, United Kingdom; Centre for Liver Research and National Institute for Health Research, Biomedical Research Unit, University of Birmingham, United Kingdom; Section of Hepatology, St. Mary's Hospital, Imperial College London, United Kingdom. Electronic address:

Background & Aims: Characteristics of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) include susceptibility to infection, immuneparesis, and monocyte dysfunction. MER receptor tyrosine kinase (MERTK) is expressed by monocytes and macrophages and contributes to down-regulation of innate immune responses. We investigated whether MERTK expression is altered on monocytes from patients with liver failure.

Methods: We analyzed blood and liver samples collected from patients admitted to the liver intensive therapy unit at King's College Hospital in London from December 2012 through July 2014. Patients had either ACLF (n = 41), acute decompensation of cirrhosis without ACLF (n = 9), cirrhosis without decompensation (n = 17), or acute liver failure (n = 23). We also analyzed samples from healthy individuals (controls, n = 29). We used flow cytometry to determine the level of innate immune function, and associated the findings with disease severity. We developed an assay to measure recruitment and migration of immune cells from the tissue parenchyma. Immunohistochemistry and confocal microscopy were used to determine levels of MERTK in bone marrow, liver, and lymph node tissues. We performed immunophenotype analyses and measured the production of tumor necrosis factor and interleukin 6 and intracellular killing of Escherichia coli by monocytes and peritoneal macrophages incubated with lipopolysaccharide, with or without an inhibitor of MERTK (UNC569).

Results: The number of monocytes and macrophages that expressed MERTK was greatly increased in the circulation, livers, and lymph nodes of patients with ACLF, compared with patients with stable cirrhosis and controls. MERTK expression (mean fluorescence intensity) correlated with the severity of hepatic and extrahepatic disease and systemic inflammatory responses. Based on immunophenotype, migration, and functional analyses, MERTK-expressing monocytes migrate across the endothelia to localize into tissue sites and regional lymph nodes. Expression of MERTK reduced the response of cultured monocytes to lipopolysaccharide; the addition of UNC569 restored production of inflammatory cytokines in response to lipopolysaccharide.

Conclusions: Patients with ACLF have increased numbers of immunoregulatory monocytes and macrophages that express MERTK and suppress the innate immune response to microbes. The number of these cells correlates with disease severity and the inflammatory response. MERTK inhibitors restore production of inflammatory cytokines by immune cells from patients with ACLF, and might be developed to increase the innate immune response in these patients.
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http://dx.doi.org/10.1053/j.gastro.2014.11.045DOI Listing
March 2015

Lateral transpsoas fusion: indications and outcomes.

ScientificWorldJournal 2012 6;2012:893608. Epub 2012 Nov 6.

Department of Orthopaedic Surgery, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, MI 48073, USA.

Spinal fusion historically has been used extensively, and, recently, the lateral transpsoas approach to the thoracic and lumbar spine has become an increasingly common method to achieve fusion. Recent literature on this approach has elucidated its advantage over more traditional anterior and posterior approaches, which include a smaller tissue dissection, potentially lower blood loss, no need for an access surgeon, and a shorter hospital stay. Indications for the procedure have now expanded to include degenerative disc disease, spinal stenosis, degenerative scoliosis, nonunion, trauma, infection, and low-grade spondylolisthesis. Lateral interbody fusion has a similar if not lower rate of complications compared to traditional anterior and posterior approaches to interbody fusion. However, lateral interbody fusion has unique complications that include transient neurologic symptoms, motor deficits, and neural injuries that range from 1 to 60% in the literature. Additional studies are required to further evaluate and monitor the short- and long-term safety, efficacy, outcomes, and complications of lateral transpsoas procedures.
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http://dx.doi.org/10.1100/2012/893608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504425PMC
June 2013

Immediate weight bearing after modified percutaneous Achilles tendon repair.

Foot Ankle Int 2012 Dec;33(12):1093-7

Background: Controversy exists regarding postoperative treatment of Achilles tendon repair. The purpose of this study was to evaluate the results of immediate weight bearing following modified percutaneous Achilles tendon repair using readily available materials.

Methods: Fifty-two patients who were treated at a single center from 2000 to 2009 underwent percutaneous Achilles tendon repair by a single surgeon and were allowed immediate weight bearing. They were followed for on average of 2 years postoperatively and evaluated with functional and subjective outcomes.

Results: The average American Orthopaedic Foot and Ankle Society ankle-hindfoot scale was 96 points (range, 81 to 100), with 95% confidence interval ranging from 89.1 to 102.9. Subjective evaluation demonstrated that 47 patients (90%) were able to return to a desired level of activity, with an overall complication rate of 11.5%.

Conclusion: Immediate weight bearing after percutaneous Achilles tendon repair had a low overall complication rate with good clinical and functional outcomes.
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http://dx.doi.org/10.3113/FAI.2012.1093DOI Listing
December 2012

Bilateral simultaneous femoral diaphyseal fractures in a patient with long-term ibandronate use.

Orthopedics 2010 Oct 11;33(10):775. Epub 2010 Oct 11.

Westchester Medical Center, Macy Pavilion 008, 95 Grasslands Dr, Valhalla, NY 10595, USA. [email protected] gmail.com

Bisphosphonates are the most common medication used to treat patients with documented osteoporosis. Recently, reports have associated long-term bisphosphonate use with low-energy femur fractures. While no definitive mechanism has been associated, bisphosphonate use has been strongly implicated. This article presents the case of a 65-year-old woman with a 2-year history of ibandronate use presenting with simultaneous low-energy femoral shaft fractures. The patient reported prodromal bilateral thigh pain and was seen by a spine surgeon. A review of the literature implicates long-term ibandronate use in low-energy femur fractures. With most of the basic science studies demonstrating suppressed bone turnover after 5 years of treatment with alendronate, the significance of the present case also lies in the relatively short duration of time the patient was on ibandronate before suffering the bilateral femoral shaft fractures. Possible pathophysiology for the fractures includes suppressed bone turnover that may allow microcracks to propagate in cortical bone, which can weaken the bone and possibly predispose it to fractures. Patients who have been on bisphosphonates long term should be questioned about thigh pain and have radiographs of their femurs obtained if pain exists. Furthermore, if a patient presents with a single subtrochanteric or diaphyseal low-energy femur fracture after long-term bisphosphonate use, a radiograph of the contralateral femur should be obtained to assess for a cortical stress reaction.
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http://dx.doi.org/10.3928/01477447-20100826-31DOI Listing
October 2010
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