Publications by authors named "Constantine J Karvellas"

107 Publications

Optic Nerve Sheath Diameter in Acute Liver Failure: A Prospective Cohort Study.

GE Port J Gastroenterol 2021 Apr 2;28(3):170-178. Epub 2020 Dec 2.

Intensive Care Unit, Curry Cabral Hospital, Lisbon, Portugal.

Introduction: Acute liver failure (ALF) is a rare disease that may lead to cerebral edema and death. An increased optic nerve sheath diameter (ONSD) may reflect an early increase in intracranial pressure. We assessed the feasibility and safety of the ONSD measurement and its association with outcomes in patients with ALF.

Methods: This was an open-label prospective cohort study including adult patients with ALF admitted to a liver-specialized intensive care unit (ICU) in an academic center between October 2018 and February 2020 (among 24): 20 as intention-to-treat and 17 as per-protocol analyses. The ONSD measurement (primary exposure) used an ultrasound transducer (3 determinations on each eye per patient). The primary outcome was hospital mortality.

Results: Among the 20 patients, 11 (55.0%) were females and the mean age was 45 ± 16 years. On the day of ONSD measurement (median 32.4 h post-ICU admission; IQR 19.8-59.8): 8 patients (40.0%) were in a coma, the mean international normalized ratio (INR) was 3.3 ± 1.4, median bilirubin was 12.3 mg/dL (IQR 4.7-24.5), mean ammonia was 163 ± 101 µmol/L, and mean SOFA score was 11 ± 5. The mean bilateral ONSD was 5.6 ± 0.7 mm, with a very good correlation between right and left eyes (Pearson's = 0.90). Ten (50.0%) patients were transplanted and 13 (65.0%) patients survived the hospital stay (all with a 2-month extended Glasgow Outcome Scale of 8). The mean ONSD was significantly higher for hospital non-survivors than survivors both in the intention-to-treat (6.2 vs. 5.3 mm; = 0.004) and per-protocol (6.2 vs. 5.2 mm; = 0.004) analyses. No adverse effects from ONSD measurements were reported.

Conclusions: In patients with ALF, a higher ONSD was associated with higher hospital mortality. ONSD measurement is feasible and safe and may have prognostic value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000511646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138150PMC
April 2021

Post-Liver Transplant Acute Kidney Injury.

Liver Transpl 2021 May 8. Epub 2021 May 8.

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

Acute kidney injury (AKI) is a common condition following liver transplantation (LT). It negatively impacts patient outcomes by increasing the chances of developing chronic kidney disease (CKD) and reducing graft and patient survival. Multiple definitions of AKI have been proposed and utilized throughout the years with the International Club of Ascites (ICA) definition being the most widely used now for cirrhosis patients. Multiple factors are associated with development of post-LT AKI and can be categorized into pre-LT comorbidities, donor and recipient characteristics, operative factors, and post-LT factors. Many of these factors can be optimized in an attempt to minimize the risk of AKI occurring and to improve renal function if AKI is already present. A special consideration during the post-LT phase is need for immunosuppression as certain immunosuppressive medications can be nephrotoxic. The calcineurin inhibitor (CNI) tacrolimus is the mainstay of immunosuppression but can result in AKI. Several strategies including use of the monoclonoal antibody basilixamab to allow for delayed tacrolimus start and minimization or elimination of tacrolimus through combination with mycophenolate mofetil (MMF) or mammalian target of rapamycin (mTOR) inhibitors have been implemented to reverse and avoid AKI in the post-LT setting. Renal replacement therapy may ultimately be required to support patients until recovery of AKI post-LT. Overall by improving renal function in post-LT patients with AKI, outcomes can be improved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lt.26094DOI Listing
May 2021

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

J Hepatol 2021 Apr 12. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.03.013DOI Listing
April 2021

Hepatorenal Syndrome.

Crit Care Clin 2021 Apr 15;37(2):321-334. Epub 2020 Dec 15.

Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, 1520 San Pablo Street, Suite 4300, Los Angeles, CA 90033, USA. Electronic address:

Development of acute kidney injury in patients with chronic liver disease is common and portends a poor prognosis. Diagnosis remains challenging, as traditional markers, such as serum creatinine, are not reliable. Recent development of novel biomarkers may assist with this. Pathophysiology of this condition is multifactorial, relating to physiologic changes associated with portal hypertension, kidney factors, and systemic inflammatory response. Mainstay of treatment remains use of vasoconstrictors along with albumin. Recent guidelines streamline the selection of patients that will require simultaneous liver and kidney transplantation. Posttransplant kidney injury is common relating to multiple factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccc.2020.11.011DOI Listing
April 2021

Using technology to assess nutritional status and optimize nutrition therapy in critically ill patients.

Curr Opin Clin Nutr Metab Care 2021 Mar;24(2):189-194

Division of Gastroenterology (Liver Unit).

Purpose Of Review: Malnutrition is prevalent in critically ill patients and is linked to worse outcomes such as prolonged mechanical ventilation, length of intensive care unit (ICU) stay, and increased mortality. Therefore, nutritional therapy is important. However, it is often difficult to accurately identify those at high malnutrition risk and to optimize nutritional support. Different technological modalities have therefore been developed to identify patients at high nutritional risk and to guide nutritional support in an attempt to optimize outcomes.

Recent Findings: Computed tomography (CT), ultrasound (US), and bioelectrical impedance analysis are tools that allow assessment of lean body mass and detection of sarcopenia, which is a significant marker of poor nutrition. The use of indirect calorimetry allows the determination of resting energy expenditure to serve as a guide to providing optimal nutrition intake in ICU patients.

Summary: By using CT, US, or bioelectrical impedance analysis, detection of sarcopenia can be undertaken in patients admitted to the ICU. This allows for an accurate picture of underlying nutritional status to help clinicians focus on nutritional support for these patients. Subsequently, indirect calorimetry can be used to guide optimal nutrition therapy and caloric intake in critically ill patients. However, whether these methods result in improved outcomes in critically ill patients remains to be validated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCO.0000000000000721DOI Listing
March 2021

Liver Transplantation in Acute-on-Chronic Liver Failure.

Transplantation 2020 Nov 17. Epub 2020 Nov 17.

Liver transplantation (LT) has revolutionized outcomes for cirrhotic patients. Current liver allocation policies dictate patients with highest short-term mortality receive the highest priority, thus, several patients become increasingly ill on the waitlist. Given cirrhosis is a progressive disease, it can be complicated by the occurrence of acute-on-chronic liver failure (ACLF), a syndrome defined by an acute deterioration of liver function associated with extra-hepatic organ failures requiring intensive care support and a high short-term mortality. Successfully bridging to transplant includes accurate prognostication and prioritization of ACLF patients awaiting LT, optimizing intensive care (ICU) support pre-LT and tailoring immunosuppressive and anti-infective therapies post-LT. Furthermore, predicting futility (too sick to undergo LT) in ACLF is challenging. In this review, we summarize the role of LT in ACLF specifically highlighting a) current prognostic scores in ACLF, b) critical care management of the ACLF patient awaiting LT, c) donor issues to consider in transplant in ACLF and d) explore recent post-LT outcomes in ACLF and potential opportunities to improve outcomes including current care gaps and unmet research needs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003550DOI Listing
November 2020

Positive fluid balance was associated with mortality in patients with acute-on-chronic liver failure: A cohort study.

J Crit Care 2021 Jun 20;63:238-242. Epub 2020 Sep 20.

Division of Gastroenterology (Liver Unit) and Department of Critical Care, University of Alberta, Edmonton, Canada. Electronic address:

Purpose: We aimed to study the effect of FB in the outcomes of critically-ill patients with cirrhosis.

Materials: Retrospective analysis of all adult consecutive admissions of patients with cirrhosis and organ failures to the Intensive Care Unit (ICU) at Curry Cabral Hospital (Lisbon, Portugal) and University of Alberta Hospital (Edmonton, Canada) on 08/2013-08/2017. Primary exposure was FB at 3 and 7 days post ICU admission. Primary endpoint was hospital mortality.

Results: Amongst 333 patients, median age was 56 years and 67.6% were men. Median MELD, APACHEII, CLIF-SOFA, and CLIF-C-ACLF scores on ICU admission were 27, 28, 14, and 54, respectively. ICU and hospital mortality rates were 33.0% and 49.2%, respectively. While median FB at 3 days post ICU admission (+5.46 l vs. +6.62 l; P = 0.74) was not associated with hospital mortality, higher median FB at 7 days post ICU admission (+13.50 l vs. +6.90 l; P = 0.036) was associated with higher hospital mortality. This association remained significant (OR 95%CI = 1.04 [1.01;1.07] per each l) after adjustment for confounders (age, ascites, infection, lactate, and number of organ failures).

Conclusions: FB may be a therapeutic target that helps to improve the outcomes of patients with acute-on-chronic liver failure. This data may inform future clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcrc.2020.09.012DOI Listing
June 2021

Clinical and Neurologic Outcomes in Acetaminophen-Induced Acute Liver Failure: A 21-Year Multicenter Cohort Study.

Clin Gastroenterol Hepatol 2020 Sep 10. Epub 2020 Sep 10.

Liver Unit, Division of Gastroenterology, Department of Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background & Aims: Acetaminophen (APAP)-induced acute liver failure (ALF) is a rare disease associated with high mortality rates. This study aimed to evaluate changes in interventions, psychosocial profile, and clinical outcomes over a 21-year period using data from the ALF Study Group registry.

Methods: A retrospective review of this prospective, multicenter cohort study of all APAP-ALF patients enrolled during the study period (1998-2018) was completed. Primary outcomes evaluated were the 21-day transplant-free survival (TFS) and neurologic complications. Covariates evaluated included enrollment cohort (early, 1998-2007; recent, 2008-2018), intentionality, psychiatric comorbidity, and use of organ support including continuous renal replacement therapy (CRRT).

Results: Of 1190 APAP-ALF patients, recent cohort patients (n = 608) had significantly improved TFS (recent, 69.8% vs early, 61.7%; P = .005). Recent cohort patients were more likely to receive CRRT (22.2% vs 7.6%; P < .001), and less likely to develop intracranial hypertension (29.9% vs 51.5%; P < .001) or die by day 21 from cerebral edema (4.5% vs 11.6%; P < .001). Grouped by TFS status (non-TFS, n = 365 vs TFS, n = 704), there were no differences in psychiatric comorbidity (51.5% vs 55.0%; P = .28) or intentionality (intentional, 39.7% vs 41.6%; P = .58). On multivariable logistic regression adjusting for vasopressor support, development of grade 3/4 hepatic encephalopathy, King's College criteria, and MELD score, the use of CRRT (odds ratio, 1.62; P = .023) was associated with significantly increased TFS (c-statistic, 0.86). In a second model adjusting for the same covariates, recent enrollment was associated significantly with TFS (odds ratio, 1.42; P = .034; c-statistic, 0.86).

Conclusions: TFS in APAP-ALF has improved in recent years and rates of intracranial hypertension/cerebral edema have decreased, possibly related to increased CRRT use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2020.09.016DOI Listing
September 2020

The authors reply.

Crit Care Med 2020 09;48(9):e843

Department of Medicine, McMaster University, Hamilton, ON, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004485DOI Listing
September 2020

Acute-on-chronic liver failure: The challenge of PREDICTing who and when.

J Hepatol 2020 10 13;73(4):755-756. Epub 2020 Aug 13.

Department of Critical Care Medicine, University of Alberta, Edmonton, Canada; Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.07.029DOI Listing
October 2020

Patients with severe acute-on-chronic liver failure are disadvantaged by model for end-stage liver disease-based organ allocation policy.

Aliment Pharmacol Ther 2020 10 29;52(7):1204-1213. Epub 2020 Jul 29.

Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, London, UK.

Background: Mortality for patients with acute-on-chronic liver failure (ACLF) may be underestimated by the model for end-stage liver disease-sodium (MELD-Na) score.

Aim: To assess waitlist outcomes across varying grades of ACLF among a cohort of patients listed with a MELD-Na score ≥35, and therefore having similar priority for liver transplantation.

Methods: We analysed the United Network for Organ Sharing (UNOS) database, years 2010-2017. Waitlist outcomes were evaluated using Fine and Gray's competing risks regression.

Results: We identified 6342 candidates at listing with a MELD-Na score ≥35, of whom 3122 had ACLF-3. Extra-hepatic organ failures were present primarily in patients with four to six organ failures. Competing risks regression revealed that candidates listed with ACLF-3 had a significantly higher risk for 90-day waitlist mortality (Sub-hazard ratio (SHR) = 1.41; 95% confidence interval [CI] 1.12-1.78) relative to patients with lower ACLF grades. Subgroup analysis of ACLF-3 revealed that both the presence of three organ failures (SHR = 1.40, 95% CI 1.20-1.63) or four to six organ failures at listing (SHR = 3.01; 95% CI 2.54-3.58) was associated with increased waitlist mortality. Candidates with four to six organ failures also had the lowest likelihood of receiving liver transplantation (SHR = 0.61, 95% CI 0.54-0.68). The Share 35 rule was associated with reduced 90-day waitlist mortality among the full cohort of patients listed with ACLF-3 and MELD-Na score ≥35 (SHR = 0.59; 95% CI 0.49-0.70). However, Share 35 rule implementation was not associated with reduced waitlist mortality among patients with four to six organ failures (SHR = 0.76; 95% CI 0.58-1.02).

Conclusions: The MELD-Na score disadvantages patients with ACLF-3, both with and without extra-hepatic organ failures. Incorporation of organ failures into allocation policy warrants further exploration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.15988DOI Listing
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.15932DOI Listing
September 2020

Longterm Outcomes of Patients Undergoing Liver Transplantation for Acute-on-Chronic Liver Failure.

Liver Transpl 2020 12 25;26(12):1594-1602. Epub 2020 Aug 25.

Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom.

Recent data have demonstrated >80% 1-year survival probability after liver transplantation (LT) for patients with severe acute-on-chronic liver failure (ACLF). However, longterm outcomes and complications are still unknown for this population. Our aim was to compare longterm patient and graft survival among patients transplanted across all grades of ACLF. We analyzed the United Network for Organ Sharing database for the years 2004-2017. Patients with ACLF were identified using the European Association for the Study of the Liver-Chronic Liver Failure criteria. Kaplan-Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. A total of 56,801 patients underwent transplantation of which 31,024 (54.6%) had no ACLF, 8757 (15.4%) had ACLF grade 1, 9039 (15.9%) had ACLF grade 2, and 7891 (14.1%) had ACLF grade 3. The 5-year patient survival after LT was lower in the ACLF grade 3 patients compared with the other groups (67.7%; P < 0.001), although after year 1, the percentage decrease in survival was similar among all groups. Infection was the primary cause of death among all patient groups in the first year. Infection was the primary cause of death among all patient groups in the first year. After the first year, infection was the main cause of death in patients transplanted with ACLF grade 1 (32.1%), ACLF grade 2 (33.9%), and ACLF grade 3 (37.6%), whereas malignancy was the predominant cause of death in those transplanted with no ACLF (28.5%). In conclusion, patients transplanted with ACLF grade 3 had lower 5-year survival as compared with patients with ACLF grades 0-2, but mortality rates were not significantly different after the first year following LT. Graft survival was excellent across all ACLF groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lt.25831DOI Listing
December 2020

Management of the neurologically deceased organ donor: A Canadian clinical practice guideline.

CMAJ 2020 04;192(14):E361-E369

Departments of Medicine (Ball), Internal Medicine (Basmaji) and Surgery (Luke), Western University, London, Ont.; Children's Hospital of Eastern Ontario Research Institute (Hornby); Deceased Donation (Hornby, Shemie, Wilson), Canadian Blood Services, Ottawa, Ont.; Department of Medicine (Division of Critical Care) and Department of Health Research Methods, Evidence and Impact (Rochwerg, Meade), McMaster University, Hamilton, Ont.; Faculté de médecine (Weiss), Université Laval; Transplant Quebec (Weiss), Québec, Que.; Canadian Blood Services (Gillrie), Ottawa, Ont.; Department of Medicine and School of Public Health (Chassé), University of Montreal, Montréal, Que.; Department of Anesthesiology, Faculty of Medicine and Health Sciences (D'Aragon), University of Sherbrooke, Sherbrooke, Que.; Critical Care (Soliman), Queen's University, Kingston, Ont.; Latner Thoracic Surgery Research Laboratories, Institute of Medical Sciences (Ali), University of Toronto, Toronto, Ont.; Northern Ontario School of Medicine (Arora), Thunder Bay, Ont.; Department of Medicine (Neurology) and Critical Care, Centre for Neuroscience Studies (Boyd), Queen's University, Kingston, Ont.; Department of Medicine (Cantin), Université Laval, Québec, Que.; Gerald Bronfman Department of Oncology (Cantin), McGill University, Montréal, Que.; Departments of Surgery (Cypel) and Medicine (Singh), University of Toronto, Toronto, Ont.; Division of Cardiac Surgery (Freed), University of Alberta, Edmonton, Alta.; Faculty of Pharmacy (Frenette), University of Montreal, Montréal, Que.; Alberta Health Services (Hruska), Calgary, Alta.; Department of Critical Care Medicine (Karvellas), University of Alberta, Edmonton, Alta.; BC Transplant (Keenan), Vancouver, BC; Division of Critical Care (Keenan), University of British Columbia, Vancouver, BC; Departments of Critical Care Medicine and Clinical Neurosciences, Hotchkiss Brain Institute (Kramer), University of Calgary, Calgary, Alta.; Faculty of Medicine and Dentistry (Kutsogiannis), University of Alberta, Edmonton, Alta.; Department of Medicine (Lien), University of Alberta, Edmonton, Alta.; London Health Sciences Centre (Luke), London, Ont.; Department of Pediatrics (Mahoney), University of Calgary, Calgary, Alta.; Division of Infectious Diseases (Wright), University of British Columbia, Vancouver, BC; Division of Nephrology (Zaltzman), University of Toronto, Toronto, Ont.; Department of Pediatrics (Shemie), McGill University, Montréal, Que.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1503/cmaj.190631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145376PMC
April 2020

BiMM tree: A decision tree method for modeling clustered and longitudinal binary outcomes.

Commun Stat Simul Comput 2020 12;49(4):1004-1023. Epub 2018 Sep 12.

Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.

Clustered binary outcomes are frequently encountered in clinical research (e.g. longitudinal studies). Generalized linear mixed models (GLMMs) for clustered endpoints have challenges for some scenarios (e.g. data with multi-way interactions and nonlinear predictors unknown ). We develop an alternative, data-driven method called Binary Mixed Model (BiMM) tree, which combines decision tree and GLMM within a unified framework. Simulation studies show that BiMM tree achieves slightly higher or similar accuracy compared to standard methods. The method is applied to a real dataset from the Acute Liver Failure Study Group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03610918.2018.1490429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202553PMC
September 2018

Acute kidney injury: A critical care perspective for orthotopic liver transplantation.

Best Pract Res Clin Anaesthesiol 2020 Mar 17;34(1):69-78. Epub 2019 Dec 17.

Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada; Department of Critical Care Medicine, University of Alberta, Edmonton, Canada. Electronic address:

Acute kidney injury (AKI) is associated with high perioperative mortality in patients undergoing liver transplantation (LT). In the era of Model of End-stage Liver Disease score-based allocation, more patients with impaired renal function are receiving LT. The majority of preoperative AKI is secondary to azotemia, including hepatorenal syndrome - a progressive form of renal impairment unique to liver failure. Prompt recognition and initiation of cause-directed therapies are central to improving post-transplant survival. Given that, the healthcare providers must develop an expertise in liver failure-related renal complications, specifically their management and perioperative implications. Notably, AKI may complicate intraoperative course, exacerbating hemodynamic instability, metabolic acidosis, and electrolyte and coagulation abnormalities. Adjunctive intraoperative continuous renal replacement therapy has been employed; however, prospective studies remain necessary to validate potential benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpa.2019.12.002DOI Listing
March 2020

Elevated Serum Liver-Type Fatty Acid Binding Protein Levels in Non-acetaminophen Acute Liver Failure Patients with Organ Dysfunction.

Dig Dis Sci 2021 01 3;66(1):273-283. Epub 2020 Mar 3.

Hepato-neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada.

Background: Liver-type fatty acid binding protein (FABP1) has previously been demonstrated to improve prognostic discrimination in acetaminophen (APAP)-induced ALF but has not been investigated in other etiologies of ALF.

Aim: To determine whether FABP1 levels (early: admission or late: days 3-5) are associated with 21-day transplant-free survival in non-APAP ALF.

Methods: FABP1 was measured in serum samples from 384 ALF patients (n = 88 transplant-free survivors (TFS), n = 296 died/LT-NTFS) using solid-phase enzyme-linked immunosorbent assay and analyzed with US ALFSG registry data.

Results: Of 384 ALF patients (autoimmune hepatitis n = 125, drug-induced liver injury n = 141, Hepatitis B n = 118), 177 (46%) patients received LT. Early FABP1 levels were significantly higher in ALF patients requiring vasopressor support (203.4 vs. 76.3 ng/mL) and renal replacement therapy (203.4 vs. 78.8 ng/mL; p < 0.001 for both). Late FABP1 levels were significantly higher in patients requiring mechanical ventilation (77.5 vs. 53.3 ng/mL), vasopressor support (116.4 vs. 53.3 ng/mL) and in patients with grade 3/4 hepatic encephalopathy (71.4 vs. 51.4 ng/mL; p = 0.03 for all). Late FABP1 levels were significantly lower in TFS patients (TFS 54 vs. NTFS 66 ng/mL; p = 0.049) but not admission (TFS 96 vs. NTFS 87 ng/mL; p = 0.67). After adjusting for significant covariates, serum FABP1 did not discriminate significantly between TFS and patients who died/received LT at day 21 either on admission (p = 0.29) or late (days 3-5, p = 0.087) time points.

Conclusion: In this first report of FABP1 in non-APAP ALF, FABP1 levels at late time points (days 3-5) were significantly lower in ALF patients who were alive without transplant at day 21 but not after adjusting for covariates reflecting severity of illness. Higher FABP1 levels were associated with the presence of increased organ failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-020-06166-wDOI Listing
January 2021

Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary, and Renal Considerations.

Crit Care Med 2020 03;48(3):e173-e191

Department of Medicine, McMaster University, Hamilton, ON, Canada.

Objectives: To develop evidence-based recommendations for clinicians caring for adults with acute or acute on chronic liver failure in the ICU.

Design: The guideline panel comprised 29 members with expertise in aspects of care of the critically ill patient with liver failure and/or methodology. The Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy were followed throughout. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development.

Setting: The panel was divided into nine subgroups: cardiovascular, hematology, pulmonary, renal, endocrine and nutrition, gastrointestinal, infection, perioperative, and neurology.

Interventions: We developed and selected population, intervention, comparison, and outcomes questions according to importance to patients and practicing clinicians. For each population, intervention, comparison, and outcomes question, we conducted a systematic review aiming to identify the best available evidence, statistically summarized the evidence whenever applicable, and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements.

Measurements And Main Results: In this article, we report 29 recommendations (from 30 population, intervention, comparison, and outcomes questions) on the management acute or acute on chronic liver failure in the ICU, related to five groups (cardiovascular, hematology, pulmonary, renal, and endocrine). Overall, six were strong recommendations, 19 were conditional recommendations, four were best-practice statements, and in two instances, the panel did not issue a recommendation due to insufficient evidence.

Conclusions: Multidisciplinary international experts were able to formulate evidence-based recommendations for the management acute or acute on chronic liver failure in the ICU, acknowledging that most recommendations were based on low-quality indirect evidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004192DOI Listing
March 2020

Acute-on-chronic liver failure: Objective admission and support criteria in the intensive care unit.

JHEP Rep 2019 May 18;1(1):44-52. Epub 2019 Mar 18.

Division of Gastroenterology, University of Alberta, Edmonton, Canada.

Cirrhosis is a leading cause of morbidity and mortality throughout the world. Significant complications include variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, and infection. When these complications are severe, admission to the intensive care unit (ICU) is often required for organ support and management. Intensive care therapy can also serve as a bridge to liver transplantation. Along with decompensation of cirrhosis, the concept of acute-on-chronic liver failure (ACLF) has emerged. This involves an acute precipitating event, such as the development of infection in a patient with cirrhosis, which leads to acute deterioration of hepatic function and extrahepatic organ failure. Extrahepatic complications often include renal, cardiovascular, and respiratory failures. Patients with significant extrahepatic and hepatic failures need ICU admission for organ support. Again, in patients who are deemed suitable liver transplant candidates, intensive care management may allow bridging to liver transplantation. However, patients with a Chronic Liver Failure Consortium ACLF score greater than 70 at 48 to 72 hours post-ICU admission do not seem to benefit from ongoing intensive support and a palliative approach may be more appropriate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhepr.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001553PMC
May 2019

Serum osmolality, cerebrospinal fluid specific gravity and overt hepatic encephalopathy severity in patients with liver failure.

Liver Int 2020 08 12;40(8):1977-1986. Epub 2020 Feb 12.

Division of Stroke and Neurocritical Care, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.

Background And Aims: Hepatic encephalopathy (HE) is a leading contributor to morbidity in liver disease. While hyperammonaemia plays a key role, the mechanisms of cerebral toxicity are unclear. We hypothesized that serum hyperosmolality contributes to HE during acute (ALF) and acute-on-chronic liver failure (ACLF) through mechanisms that affect the water and solute composition of the cerebral environment.

Methods: We performed a retrospective analysis of serum osmolality, cerebral spinal fluid (CSF) solute density (specific gravity, determined from computed tomography attenuation) and clinical HE severity (Glasgow Coma Score [GCS]) at the time of intensive care admission in a prospectively identified cohort of liver failure patients with overt HE.

Results: Seventy-three patients (39 ALF and 34 ACLF) were included, of whom 28 (38%) were comatose. Serum osmolality (303.9 ± 15.4 mOsm/kg) was elevated despite normal serum sodium (136.6 ± 6.3 mEq/L). Increased osmolality was independently associated with more severe encephalopathy (ordinal adjusted OR 0.26 [95% CI 0.22, 0.31] for higher GCS per standard deviation increase in osmolality) and lower CSF-specific gravity (linear adjusted β = -0.039 [95% CI -0.069, -0.009] Hounsfield unit per 1 mOsm/kg).

Conclusions: In the context of related research, these data suggest that hyperosmolality increases brain exposure to metabolic toxins by blood-brain barrier alteration and may be a unique therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398828PMC
August 2020

Critical care considerations in the management of acute-on-chronic liver failure.

Curr Opin Crit Care 2020 04;26(2):171-179

Department of Critical Care Medicine.

Purpose Of Review: Patients with cirrhosis are frequently hospitalized with acute decompensation and organ system failure - a syndrome referred to as acute on chronic liver failure (ACLF). These patients often require critical care intervention and experience significant mortality; however, established diagnostic and prognostic criteria are lacking. Given this, it remains imperative for intensivists to develop an expertise in common ACLF complications and management.

Recent Findings: Liver transplantation serves as the definitive management strategy in ACLF. Traditional organ allocation procedures are based on the Model for Endstage Liver Disease score, which may not correlate with ACLF severity and the associated need for urgent liver transplantation. Recent studies have suggested favorable postliver transplantation outcomes in ACLF patients with multiorgan failure, emphasizing the need for further studies to elucidate optimal timing and candidacy for liver transplantation.

Summary: Cirrhosis is a chronic and progressive condition leaving patients vulnerable to acute decompensation necessitating the need for critical care intervention. Prompt recognition and implementation of targeted supportive therapies, together with consideration of urgent liver transplantation, are essential to combat the high short-term mortality of ACLF patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCC.0000000000000698DOI Listing
April 2020

Pathophysiology of Acute Liver Failure.

Nutr Clin Pract 2020 Feb 15;35(1):24-29. Epub 2019 Dec 15.

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

Acute liver failure (ALF) is a rare syndrome resulting from an acute insult to the liver in patients without known underlying chronic liver disease. It is characterized by loss of synthetic function in the form of jaundice and coagulopathy and development of hepatic encephalopathy. Multiorgan failure (MOF) eventually develops, leading to death. Many different etiologies have been identified, with acetaminophen (APAP) overdose and viral hepatitis being the most common causes worldwide. The pathophysiology of ALF can be divided into cause-specific liver injury pathophysiologies and pathophysiology related to occurrence of secondary MOF. In terms of liver injury pathophysiology, APAP toxicity is the most well known. Secondary MOF is often a result of the initial massive proinflammatory response generating a systemic inflammatory response syndrome followed by a compensatory anti-inflammatory response leading to immune cell dysfunction and sepsis. As the liver is a tremendously important metabolic organ involved in energy metabolism, protein synthesis, fat metabolism, and glycemic control, multiple aspects of nutrition also need to be considered as part of the overall pathophysiology of ALF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ncp.10459DOI Listing
February 2020

The Hepatokine TSK does not affect brown fat thermogenic capacity, body weight gain, and glucose homeostasis.

Mol Metab 2019 12 4;30:184-191. Epub 2019 Oct 4.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval (CRIUCPQ), Québec City, Québec, Canada; Département de Médecine de l'Université Laval, Université Laval, Québec City, Québec, Canada; Centre de Recherche sur le Cancer de l'Université Laval, Université Laval, Québec City, Québec, Canada. Electronic address:

Objectives: Hepatokines are proteins secreted by the liver that impact the functions of the liver and various tissues through autocrine, paracrine, and endocrine signaling. Recently, Tsukushi (TSK) was identified as a new hepatokine that is induced by obesity and cold exposure. It was proposed that TSK controls sympathetic innervation and thermogenesis in brown adipose tissue (BAT) and that loss of TSK protects against diet-induced obesity and improves glucose homeostasis. Here we report the impact of deleting and/or overexpressing TSK on BAT thermogenic capacity, body weight regulation, and glucose homeostasis.

Methods: We measured the expression of thermogenic genes and markers of BAT innervation and activation in TSK-null and TSK-overexpressing mice. Body weight, body temperature, and parameters of glucose homeostasis were also assessed in the context of TSK loss and overexpression.

Results: The loss of TSK did not affect the thermogenic activation of BAT. We found that TSK-null mice were not protected against the development of obesity and did not show improvement in glucose tolerance. The overexpression of TSK also failed to modulate thermogenesis, body weight gain, and glucose homeostasis in mice.

Conclusions: TSK is not a significant regulator of BAT thermogenesis and is unlikely to represent an effective target to prevent obesity and improve glucose homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2019.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889588PMC
December 2019

Effect of the clinical course of acute-on-chronic liver failure prior to liver transplantation on post-transplant survival.

J Hepatol 2020 03 25;72(3):481-488. Epub 2019 Oct 25.

Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, London, UK.

Background & Aims: Patients with acute-on-chronic liver failure (ACLF) can be listed for liver transplantation (LT) because LT is the only curative treatment option. We evaluated whether the clinical course of ACLF, particularly ACLF-3, between the time of listing and LT affects 1-year post-transplant survival.

Methods: We identified patients from the United Network for Organ Sharing database who were transplanted within 28 days of listing and categorized them by ACLF grade at waitlist registration and LT, according to the EASL-CLIF definition.

Results: A total of 3,636 patients listed with ACLF-3 underwent LT within 28 days. Among those transplanted, 892 (24.5%) recovered to no ACLF or ACLF grade 1 or 2 (ACLF 0-2) and 2,744 (75.5%) had ACLF-3 at transplantation. One-year survival was 82.0% among those transplanted with ACLF-3 vs. 88.2% among those improving to ACLF 0-2 (p <0.001). Conversely, the survival of patients listed with ACLF 0-2 who progressed to ACLF-3 at LT (n = 2,265) was significantly lower than that of recipients who remained at ACLF 0-2 (n = 17,631) at the time of LT (83.8% vs. 90.2%, p <0.001). Cox modeling demonstrated that recovery from ACLF-3 to ACLF 0-2 at LT was associated with reduced 1-year mortality after transplantation (hazard ratio0.65; 95% CI 0.53-0.78). Improvement in circulatory failure, brain failure, and removal from mechanical ventilation were also associated with reduced post-LT mortality. Among patients >60 years of age, 1-year survival was significantly higher among those who improved from ACLF-3 to ACLF 0-2 than among those who did not.

Conclusions: Improvement from ACLF-3 at listing to ACLF 0-2 at transplantation enhances post-LT survival, particularly in those who recovered from circulatory or brain failure, or were removed from the mechanical ventilator. The beneficial effect of improved ACLF on post-LT survival was also observed among patients >60 years of age.

Lay Summary: Liver transplantation (LT) for patients with acute-on-chronic liver failure grade 3 (ACLF-3) significantly improves survival, but 1-year survival probability after LT remains lower than the expected outcomes for transplant centers. Our study reveals that among patients transplanted within 28 days of waitlist registration, improvement of ACLF-3 at listing to a lower grade of ACLF at transplantation significantly enhances post-transplant survival, even among patients aged 60 years or older. Subgroup analysis further demonstrates that improvement in circulatory failure, brain failure, or removal from mechanical ventilation have the strongest impact on post-transplant survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183313PMC
March 2020

BiMM forest: A random forest method for modeling clustered and longitudinal binary outcomes.

Chemometr Intell Lab Syst 2019 Feb 11;185:122-134. Epub 2019 Jan 11.

Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.

Clustered binary outcomes and datasets with many predictor variables are frequently encountered in clinical research (e.g. longitudinal studies). Generalized linear mixed models (GLMMs) typically employed for clustered endpoints have challenges for some scenarios, particularly for complex datasets which contain many interactions among predictors and nonlinear predictors of outcome. We propose a new method called Binary Mixed Model (BiMM) forest, which combines random forest and GLMM methodology. BiMM forest offers a flexible and stable method which naturally models interactions among predictors and can be employed in the setting of clustered data. Simulation studies show that BiMM forest achieves similar or superior prediction accuracy compared to standard random forest, GLMMs and its tree counterpart (BiMM tree) for clustered binary outcomes. The method is applied to a real dataset from the Acute Liver Failure Study Group. BiMM forest offers an alternative method for modeling clustered binary outcomes which may be applied in myriad research settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chemolab.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813794PMC
February 2019

The impact of cirrhosis in patients undergoing cardiac surgery: a retrospective observational cohort study.

Can J Anaesth 2020 01 30;67(1):22-31. Epub 2019 Sep 30.

Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2X8, Canada.

Purpose: Patients with cirrhosis and concomitant coronary/valvular heart disease present a clinical dilemma. The therapeutic outcome of major cardiac surgery is significantly poorer in patients with cirrhosis compared with patients without cirrhosis. To address this, we aimed to identify associations between the severity of cirrhosis and post-cardiac surgical outcomes.

Methods: A historical cohort analysis of patients undergoing cardiac surgery at the University of Alberta Hospital from January 2004 to December 2014 was used to identify and propensity score-match 60 patients with cirrhosis to 310 patients without cirrhosis. The relationships between cirrhosis and i) mortality, ii) postoperative complications, and iii) requirement of healthcare resources were evaluated.

Results: Ten-year mortality was significantly higher in cirrhotic patients compared with propensity score-matched non-cirrhotic patients (40% vs 20%; relative risk [RR], 2.0; 95% confidence interval [CI], 1.3 to 2.9; P = 0.001). Cirrhotic patients had more complications (63% vs 48%; RR, 1.3; 95% CI, 1.05 to 1.7; P = 0.02), longer median [interquartile range (IQR)] intensive care unit stays (5 [3-11] vs 2 [1-4] days; P < 0.001), time on mechanical ventilation (median [IQR] 2 [1-5] vs 1 [0.5-1.2] days; P < 0.001) and more frequently required renal replacement therapy (15% vs 6%; RR, 2.5; 95% CI, 1.2 to 5.2; P = 0.02) postoperatively. After adjusting for other covariates, presence of cirrhosis (adjusted odds ratio, 2.2; 95% CI, 1.1 to 4.1) and intraoperative transfusion (adjusted odds ratio, 3.2; 95% CI, 1.6 to 6.3) were independently associated with increased mortality.

Conclusion: Despite having low median model for end-stage liver disease scores, this small series of cirrhotic patients undergoing cardiac surgery had significantly higher mortality rates and required more organ support postoperatively than propensity score-matched non-cirrhotic patients. Impact de la cirrhose chez les patients subissant une chirurgie cardiaque : une étude de cohorte observationnelle et rétrospective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12630-019-01493-7DOI Listing
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14268DOI Listing
March 2020

Metabolic support in the critically ill: a consensus of 19.

Crit Care 2019 09 18;23(1):318. Epub 2019 Sep 18.

Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, 1070, Brussels, Belgium.

Metabolic alterations in the critically ill have been studied for more than a century, but the heterogeneity of the critically ill patient population, the varying duration and severity of the acute phase of illness, and the many confounding factors have hindered progress in the field. These factors may explain why management of metabolic alterations and related conditions in critically ill patients has for many years been guided by recommendations based essentially on expert opinion. Over the last decade, a number of randomized controlled trials have been conducted, providing us with important population-level evidence that refutes several longstanding paradigms. However, between-patient variation means there is still substantial uncertainty when translating population-level evidence to individuals. A cornerstone of metabolic care is nutrition, for which there is a multifold of published guidelines that agree on many issues but disagree on others. Using a series of nine questions, we provide a review of the latest data in this field and a background to promote efforts to address the need for international consistency in recommendations related to the metabolic care of the critically ill patient. Our purpose is not to replace existing guidelines, but to comment on differences and add perspective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-019-2597-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751850PMC
September 2019

The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis.

JCI Insight 2019 08 8;4(15). Epub 2019 Aug 8.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval (CRIUCPQ), Québec City, Québec, Canada.

Nonalcoholic fatty liver disease (NAFLD) prevails in obesity and is linked to several health complications including dyslipidemia and atherosclerosis. How exactly NAFLD induces atherogenic dyslipidemia to promote cardiovascular diseases is still elusive. Here, we identify Tsukushi (TSK) as a hepatokine induced in response to NAFLD. We show that both endoplasmic reticulum stress and inflammation promote the expression and release of TSK in mice. In humans, hepatic TSK expression is also associated with steatosis, and its circulating levels are markedly increased in patients suffering from acetaminophen-induced acute liver failure (ALF), a condition linked to severe hepatic inflammation. In these patients, elevated blood TSK levels were associated with decreased transplant-free survival at hospital discharge, suggesting that TSK could have a prognostic significance. Gain- and loss-of-function studies in mice revealed that TSK impacts systemic cholesterol homeostasis. TSK reduces circulating HDL cholesterol, lowers cholesterol efflux capacity, and decreases cholesterol-to-bile acid conversion in the liver. Our data identify the hepatokine TSK as a blood biomarker of liver stress that could link NAFLD to the development of atherogenic dyslipidemia and atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.129492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693835PMC
August 2019