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Gunt C, Çekmen N. Perioperative Variation of Plasma Copeptin and Its Association With Vasopressor Need During Liver Transplantation. Transplant Proc 2025; 57:277-283. [PMID: 39848860 DOI: 10.1016/j.transproceed.2024.11.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/25/2024] [Accepted: 11/19/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Vasopressor usage during liver transplant is related to decreased hepatic flow, graft failure, and mortality. We measured plasma Copeptin levels in liver transplant patients based on vasopressor requirements. We hypothesize that preoperative plasma copeptin measurement helps predict the vasopressor infusion requirement during liver transplantation in preoperative evaluation. METHODS The plasma Copeptin of 40 patients was measured 5 times: before the operation, 15 minutes before and after reperfusion, and postoperative 12th and 24th hours. Patients were categorized into 2 groups based on vasopressor infusion for comparison. RESULTS There was a statistically significant rise in median serum Copeptin concentration between the preoperative phase and before reperfusion (11.2 [7.3-20.9] vs 178.5 [121.5-243.0], P < .001), as well as a statistically substantial decline between after reperfusion and postoperative 12th hours (190.6 [127-276.3] vs 74.7 [42.0-124.9], P < .001). The vasopressor-taking group had significantly higher plasma copeptin at postoperative 12th hours (96.6 [71.4-191.7] vs 55.0 [31.8-82.5], P = .030) and 24th (133.7 [72.2-175.5] vs 51.1 [24.8-85.8], P = .037). A tendency above 11.85 pmol/L of plasma Copeptine level was observed between increasing preoperative plasma Copeptin and the odds of vasopressor use. CONCLUSION High preoperative plasma Copeptin levels may be an indicator of vasopressor need during liver transplantation. Further studies with more samples, including a higher range of preoperative plasma Copeptin levels, are required to provide more generalizable findings and to determine thresholds applicable to LT candidates.
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Affiliation(s)
- Ceren Gunt
- Ankara Güven Hospital, Department of Anaesthesiology and Reanimation Çankaya/Ankara, Turkey.
| | - Nedim Çekmen
- Nişantaşı University Health Services Vocational School, Department of Anesthesia, Turkey
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Benken ST, Thomas R, Fraidenburg DR, Benken JJ. Angiotensin II as a Vasopressor for Perioperative Hypotension in Solid Organ Transplant. Biomedicines 2024; 12:1817. [PMID: 39200281 PMCID: PMC11351893 DOI: 10.3390/biomedicines12081817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 07/29/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
During the perioperative period of transplantation, patients experience hypotension secondary to the side effects of anesthesia, surgical stress, inflammatory triggering, and intraoperative fluid shifts, among others causes. Vasopressor support, in this context, must reverse systemic hypotension, but ideally, the agents used should benefit allograft function and avoid the adverse events commonly seen after transplantation. Traditional therapies to reverse hypotension include catecholamine vasopressors (norepinephrine, epinephrine, dopamine, and phenylephrine), but their utility is limited when considering allograft complications and adverse events such as arrhythmias with agents with beta-adrenergic properties. Synthetic angiotensin II (AT2S-[Giapreza]) is a novel vasopressor indicated for distributive shock with a unique mechanism of action as an angiotensin receptor agonist restoring balance to an often-disrupted renin angiotensin aldosterone system. Additionally, AT2S provides a balanced afferent and efferent arteriole vasoconstriction at the level of the kidney and could avoid the arrhythmic complications of a beta-adrenergic agonist. While the data, to date, are limited, AT2S has demonstrated safety in case reports, pilot studies, and small series in the kidney, liver, heart, and lung transplant populations. There are physiologic and hemodynamic reasons why AT2S could be a more utilized agent in these populations, but further investigation is warranted.
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Affiliation(s)
- Scott T. Benken
- Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, Chicago, IL 60612, USA; (R.T.); (J.J.B.)
| | - Riya Thomas
- Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, Chicago, IL 60612, USA; (R.T.); (J.J.B.)
| | - Dustin R. Fraidenburg
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois Chicago College of Medicine, Chicago, IL 60612, USA;
| | - Jamie J. Benken
- Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, Chicago, IL 60612, USA; (R.T.); (J.J.B.)
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McGrath MS, Wentworth BJ. The Renin-Angiotensin System in Liver Disease. Int J Mol Sci 2024; 25:5807. [PMID: 38891995 PMCID: PMC11172481 DOI: 10.3390/ijms25115807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
The renin-angiotensin system (RAS) is a complex homeostatic entity with multiorgan systemic and local effects. Traditionally, RAS works in conjunction with the kidney to control effective arterial circulation, systemic vascular resistance, and electrolyte balance. However, chronic hepatic injury and resulting splanchnic dilation may disrupt this delicate balance. The role of RAS in liver disease, however, is even more extensive, modulating hepatic fibrosis and portal hypertension. Recognition of an alternative RAS pathway in the past few decades has changed our understanding of RAS in liver disease, and the concept of opposing vs. "rebalanced" forces is an ongoing focus of research. Whether RAS inhibition is beneficial in patients with chronic liver disease appears to be context-dependent, but further study is needed to optimize clinical management and reduce organ-specific morbidity and mortality. This review presents the current understanding of RAS in liver disease, acknowledges areas of uncertainty, and describes potential areas of future investigation.
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Affiliation(s)
- Mary S. McGrath
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA;
| | - Brian J. Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
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Bokoch MP, Tran AT, Brinson EL, Marcus SG, Reddy M, Sun E, Roll GR, Pardo M, Fields S, Adelmann D, Kothari RP, Legrand M. Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial. BMJ Open 2023; 13:e078713. [PMID: 37984940 PMCID: PMC10660907 DOI: 10.1136/bmjopen-2023-078713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 10/24/2023] [Indexed: 11/22/2023] Open
Abstract
INTRODUCTION Catecholamine vasopressors such as norepinephrine are the standard drugs used to maintain mean arterial pressure during liver transplantation. At high doses, catecholamines may impair organ perfusion. Angiotensin II is a peptide vasoconstrictor that may improve renal perfusion pressure and glomerular filtration rate, a haemodynamic profile that could reduce acute kidney injury. Angiotensin II is approved for vasodilatory shock but has not been rigorously evaluated for treatment of hypotension during liver transplantation. The objective is to assess the efficacy of angiotensin II as a second-line vasopressor infusion during liver transplantation. This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure. Completion of this study will allow design of a follow-up, multicentre trial powered to detect a reduction of organ injury in liver transplantation. METHODS AND ANALYSIS This is a double-blind, randomised clinical trial. Eligible subjects are adults with a Model for End-Stage Liver Disease Sodium Score ≥25 undergoing deceased donor liver transplantation. Subjects are randomised 1:1 to receive angiotensin II or saline placebo as the second-line vasopressor infusion. The study drug infusion is initiated on reaching a norepinephrine dose of 0.05 µg kg-1 min-1 and titrated per protocol. The primary outcome is the dose of norepinephrine required to maintain a mean arterial pressure ≥65 mm Hg. Secondary outcomes include vasopressin or epinephrine requirement and duration of hypotension. Safety outcomes include incidence of thromboembolism within 48 hours of the end of surgery and severe hypertension. An intention-to-treat analysis will be performed for all randomised subjects receiving the study drug. The total dose of norepinephrine will be compared between the two arms by a one-tailed Mann-Whitney U test. ETHICS AND DISSEMINATION The trial protocol was approved by the local Institutional Review Board (#20-30948). Results will be posted on ClinicalTrials.gov and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER ClinicalTrials.govNCT04901169.
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Affiliation(s)
- Michael P Bokoch
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
| | - Amy T Tran
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
| | - Erika L Brinson
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
| | - Sivan G Marcus
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
| | - Meghana Reddy
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
| | - Elizabeth Sun
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
| | - Garrett R Roll
- Division of Transplant Surgery, University of California San Francisco, San Francisco, California, USA
| | - Manuel Pardo
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
| | - Scott Fields
- Investigational Drug Pharmacy, University of California San Francisco, San Francisco, California, USA
| | - Dieter Adelmann
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
| | - Rishi P Kothari
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
- Department of Anesthesiology and Perioperative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Matthieu Legrand
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA
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Ortiz C, Klein S, Reul WH, Magdaleno F, Gröschl S, Dietrich P, Schierwagen R, Uschner FE, Torres S, Hieber C, Meier C, Kraus N, Tyc O, Brol M, Zeuzem S, Welsch C, Poglitsch M, Hellerbrand C, Alfonso-Prieto M, Mira F, Keller UAD, Tetzner A, Moore A, Walther T, Trebicka J. Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1. Cell Rep 2023; 42:112059. [PMID: 36729833 PMCID: PMC9989826 DOI: 10.1016/j.celrep.2023.112059] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 11/17/2022] [Accepted: 01/18/2023] [Indexed: 02/03/2023] Open
Abstract
Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP deficiency (Nep-/-) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep-/- in addition to AT1R blocker (ARB) or ACE inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto, a combination of ARB and NEP inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension.
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Affiliation(s)
- Cristina Ortiz
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Sabine Klein
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany; Department of Internal Medicine B, University of Münster, Albert-Schweitzer Campus 1, 48149 Münster, Germany
| | - Winfried H Reul
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | - Stefanie Gröschl
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Peter Dietrich
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Department of Internal Medicine 1, FAU Erlangen-Nuremberg and Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany
| | - Robert Schierwagen
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Frank E Uschner
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Sandra Torres
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Christoph Hieber
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Caroline Meier
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Nico Kraus
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Olaf Tyc
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Maximilian Brol
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Christoph Welsch
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | | | - Claus Hellerbrand
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Mercedes Alfonso-Prieto
- Institute for Neuroscience and Medicine INM-9 and Institute for Advanced Simulations IAS-5, Forschungszentrum Jülich, Jülich, Germany; Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Fabio Mira
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Ulrich Auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Anja Tetzner
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - Andrew Moore
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - Thomas Walther
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland; Department of Pediatric Surgery, Centre for Fetal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany; Department of Obstetrics, Centre for Fetal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany; Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Institute for Bioengineering of Catalonia, Barcelona, Spain; Department of Internal Medicine B, University of Münster, Albert-Schweitzer Campus 1, 48149 Münster, Germany.
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6
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Kumar R, Kumar V, Arya R, Anand U, Priyadarshi RN. Association of COVID-19 with hepatic metabolic dysfunction. World J Virol 2022; 11:237-251. [PMID: 36188741 PMCID: PMC9523326 DOI: 10.5501/wjv.v11.i5.237] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/25/2022] [Accepted: 06/20/2022] [Indexed: 02/05/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic continues to be a global problem with over 438 million cases reported so far. Although it mostly affects the respiratory system, the involvement of extrapulmonary organs, including the liver, is not uncommon. Since the beginning of the pandemic, metabolic com-orbidities, such as obesity, diabetes, hypertension, and dyslipidemia, have been identified as poor prognostic indicators. Subsequent metabolic and lipidomic studies have identified several metabolic dysfunctions in patients with COVID-19. The metabolic alterations appear to be linked to the course of the disease and inflammatory reaction in the body. The liver is an important organ with high metabolic activity, and a significant proportion of COVID-19 patients have metabolic comorbidities; thus, this factor could play a key role in orchestrating systemic metabolic changes during infection. Evidence suggests that metabolic dysregulation in COVID-19 has both short- and long-term metabolic implications. Furthermore, COVID-19 has adverse associations with metabolic-associated fatty liver disease. Due to the ensuing effects on the renin-angiotensin-aldosterone system and ammonia metabolism, COVID-19 can have significant implications in patients with advanced chronic liver disease. A thorough understanding of COVID-19-associated metabolic dysfunction could lead to the identification of important plasma biomarkers and novel treatment targets. In this review, we discuss the current understanding of metabolic dysfunction in COVID-19, focusing on the liver and exploring the underlying mechanistic pathogenesis and clinical implications.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Vijay Kumar
- Department of Medicine, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Rahul Arya
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Utpal Anand
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Rajeev Nayan Priyadarshi
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
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Abstract
PURPOSE OF REVIEW The objective of this review is to examine the epidemiology and pathogenesis of liver injury in coronavirus disease 2019 (COVID-19) and the impact of COVID-19 on patients with chronic liver disease (CLD) and liver transplant recipients. RECENT FINDINGS Abnormal liver chemistries occur in up to 60% of COVID-19 patients and are typically mild. COVID-19- associated liver injury may be because of direct viral cytopathic effect, immune-mediated damage, hypoxia, drug-induced liver injury (DILI), or exacerbation of CLD. COVID-19 patients with CLD and who are liver transplant recipients are at risk for severe disease and mortality. COVID-19 precipitated hepatic decompensation in 20-46% of cirrhotic patients. Alcohol consumption and cases of acute alcohol- associated hepatitis increased during the COVID-19 pandemic. Corticosteroids and calcineurin inhibitors are well tolerated to use during COVID-19 but immunomodulators have been associated with mortality. Less than 50% of transplant recipients produce adequate antibody titers after COVID-19 vaccination. SUMMARY COVID-19 patients with CLD should be monitored for liver injury and hepatic decompensation. Patients with CLD and liver transplant recipients should be considered for targeted COVID-19 pharmacotherapeutics and advised vaccination against COVID-19, including a third booster dose. CLD treatments and immunosuppression in liver transplant recipients could generally continue without interruption during COVID-19 infection, with the possible exception of immunomodulators.
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Affiliation(s)
- James Philip Esteban
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Lindsay Sobotka
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Colmbus, Ohio
| | - Don C Rockey
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, South Carolina, Charleston, USA
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van der Graaff D, Chotkoe S, De Winter B, De Man J, Casteleyn C, Timmermans JP, Pintelon I, Vonghia L, Kwanten WJ, Francque S. Vasoconstrictor antagonism improves functional and structural vascular alterations and liver damage in rats with early NAFLD. JHEP Rep 2022; 4:100412. [PMID: 35036886 PMCID: PMC8749167 DOI: 10.1016/j.jhepr.2021.100412] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND & AIMS Intrahepatic vascular resistance is increased in early non-alcoholic fatty liver disease (NAFLD), potentially leading to tissue hypoxia and triggering disease progression. Hepatic vascular hyperreactivity to vasoconstrictors has been identified as an underlying mechanism. This study investigates vasoconstrictive agonism and antagonism in 2 models of early NAFLD and in non-alcoholic steatohepatitis (NASH). METHODS The effects of endothelin-1 (ET-1), angiotensin II (ATII) and thromboxane A2 (TxA2) agonism and antagonism were studied by in situ ex vivo liver perfusion and preventive/therapeutic treatment experiments in a methionine-choline-deficient diet model of steatosis. Furthermore, important results were validated in Zucker fatty rats after 4 or 8 weeks of high-fat high-fructose diet feeding. In vivo systemic and portal pressures, ex vivo transhepatic pressure gradients (THPG) and transaminase levels were measured. Liver tissue was harvested for structural and mRNA analysis. RESULTS The THPG and consequent portal pressure were significantly increased in both models of steatosis and in NASH. ET-1, ATII and TxA2 increased the THPG even further. Bosentan (ET-1 receptor antagonist), valsartan (ATII receptor blocker) and celecoxib (COX-2 inhibitor) attenuated or even normalised the increased THPG in steatosis. Simultaneously, bosentan and valsartan treatment improved transaminase levels. Moreover, bosentan was able to mitigate the degree of steatosis and restored the disrupted microvascular structure. Finally, beneficial vascular effects of bosentan endured in NASH. CONCLUSIONS Antagonism of vasoconstrictive mediators improves intrahepatic vascular function. Both ET-1 and ATII antagonists showed additional benefit and bosentan even mitigated steatosis and structural liver damage. In conclusion, vasoconstrictive antagonism is a potentially promising therapeutic option for the treatment of early NAFLD. LAY SUMMARY In non-alcoholic fatty liver disease (NAFLD), hepatic blood flow is impaired and the blood pressure in the liver blood vessels is increased as a result of an increased response of the liver vasculature to vasoconstrictors. Using drugs to block the constriction of the intrahepatic vasculature, the resistance of the liver blood vessels decreases and the increased portal pressure is reduced. Moreover, blocking the vasoconstrictive endothelin-1 pathway restored parenchymal architecture and reduced disease severity.
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Key Words
- ALT, alanine aminotransferase
- ARB, angiotensin receptor blocker
- AST, aspartate aminotransferase
- ATII, angiotensin II
- COX, cyclooxygenase
- ET, endothelin
- HFHFD, high-fat high-fructose diet
- IHVR, intrahepatic vascular resistance
- Jak2, Janus-kinase-2
- MCD, methionine-choline deficient diet
- Mx, methoxamine
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NO, nitric oxide
- PP, portal pressure
- PR, pulse rate
- SEM, scanning electron microscopy
- TBW, total body weight
- TEM, transmission electron microscopy
- TXAS, thromboxane synthase
- TxA2, thromboxane A2
- ZFR, Zucker fatty rats
- angiotensin II
- endothelin-1
- non-alcoholic fatty liver disease
- portal hypertension
- thromboxane A2
- transhepatic pressure gradient
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Affiliation(s)
- Denise van der Graaff
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Shivani Chotkoe
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Benedicte De Winter
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Joris De Man
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Christophe Casteleyn
- Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium
- Department of Applied Veterinary Morphology, Faculty of Veterinary Medicine, University of Antwerp, Antwerp, Belgium
| | - Jean-Pierre Timmermans
- Laboratory of Cell Biology and Histology, Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium
| | - Isabel Pintelon
- Laboratory of Cell Biology and Histology, Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium
| | - Luisa Vonghia
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Wilhelmus J. Kwanten
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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Liedtke C, Nevzorova YA, Luedde T, Zimmermann H, Kroy D, Strnad P, Berres ML, Bernhagen J, Tacke F, Nattermann J, Spengler U, Sauerbruch T, Wree A, Abdullah Z, Tolba RH, Trebicka J, Lammers T, Trautwein C, Weiskirchen R. Liver Fibrosis-From Mechanisms of Injury to Modulation of Disease. Front Med (Lausanne) 2022; 8:814496. [PMID: 35087852 PMCID: PMC8787129 DOI: 10.3389/fmed.2021.814496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
The Transregional Collaborative Research Center "Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease" (referred to as SFB/TRR57) was funded for 13 years (2009-2021) by the German Research Council (DFG). This consortium was hosted by the Medical Schools of the RWTH Aachen University and Bonn University in Germany. The SFB/TRR57 implemented combined basic and clinical research to achieve detailed knowledge in three selected key questions: (i) What are the relevant mechanisms and signal pathways required for initiating organ fibrosis? (ii) Which immunological mechanisms and molecules contribute to organ fibrosis? and (iii) How can organ fibrosis be modulated, e.g., by interventional strategies including imaging and pharmacological approaches? In this review we will summarize the liver-related key findings of this consortium gained within the last 12 years on these three aspects of liver fibrogenesis. We will highlight the role of cell death and cell cycle pathways as well as nutritional and iron-related mechanisms for liver fibrosis initiation. Moreover, we will define and characterize the major immune cell compartments relevant for liver fibrogenesis, and finally point to potential signaling pathways and pharmacological targets that turned out to be suitable to develop novel approaches for improved therapy and diagnosis of liver fibrosis. In summary, this review will provide a comprehensive overview about the knowledge on liver fibrogenesis and its potential therapy gained by the SFB/TRR57 consortium within the last decade. The kidney-related research results obtained by the same consortium are highlighted in an article published back-to-back in Frontiers in Medicine.
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Affiliation(s)
- Christian Liedtke
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Yulia A. Nevzorova
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Immunology, Ophthalmology and Otolaryngology, School of Medicine, Complutense University Madrid, Madrid, Spain
| | - Tom Luedde
- Medical Faculty, Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Henning Zimmermann
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Daniela Kroy
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Marie-Luise Berres
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Jürgen Bernhagen
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Tilman Sauerbruch
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Alexander Wree
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Zeinab Abdullah
- Institute for Molecular Medicine and Experimental Immunology, University Hospital of Bonn, Bonn, Germany
| | - René H. Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | - Twan Lammers
- Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital RWTH Aachen, Aachen, Germany
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10
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Reiterer C, Taschner A, Luf F, Hecking M, Tamandl D, Zotti O, Reiberger T, Starlinger P, Mandorfer M, Fleischmann E. Effect of liver resection-induced increases in hepatic venous pressure gradient on development of postoperative acute kidney injury. BMC Nephrol 2022; 23:21. [PMID: 34996372 PMCID: PMC8742325 DOI: 10.1186/s12882-021-02658-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 12/23/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The impact of changes in portal pressure before and after liver resection (defined as ΔHVPG) on postoperative kidney function remains unknown. Therefore, we investigated the effect of ΔHVPG on (i) the incidence of postoperative AKI and (ii) the renin-angiotensin system (RAAS) and sympathetic nervous system (SNS) activity. METHODS We included 30 patients undergoing partial liver resection. Our primary outcome was postoperative AKI according to KDIGO criteria. For our secondary outcome we assessed the plasma renin, aldosterone, noradrenaline, adrenaline, dopamine and vasopressin concentrations prior and 2 h after induction of anaesthesia, on the first and fifth postoperative day. HVPG was measured prior and immediately after liver resection. RESULTS ΔHVPG could be measured in 21 patients with 12 patients HVPG showing increases in HVPG (∆HVPG≥1 mmHg) while 9 patients remained stable. AKI developed in 7/12 of patients with increasing HVPG, but only in 2/9 of patients with stable ΔHVPG (p = 0.302). Noradrenalin levels were significantly higher in patients with increasing ΔHVPG than in patients with stable ΔHVPG. (p = 0.009). Biomarkers reflecting RAAS and SNS activity remained similar in patients with increasing vs. stable ΔHVPG. CONCLUSIONS Patients with increased HVPG had higher postoperative creatinine concentrations, however, the incidence of AKI was similar between patients with increased versus stable HVPG.
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Affiliation(s)
- Christian Reiterer
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria. .,Outcomes Research Consortium, Cleveland, OH, USA.
| | - Alexander Taschner
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Florian Luf
- Department of Anaesthesia and Intensive Care, Hanusch Krankenhaus, Vienna, Austria
| | - Manfred Hecking
- Division of Nephrology and Dialysis, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Dietmar Tamandl
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Oliver Zotti
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | | | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Edith Fleischmann
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.,Outcomes Research Consortium, Cleveland, OH, USA
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11
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Wang X, Lei J, Li Z, Yan L. Potential Effects of Coronaviruses on the Liver: An Update. Front Med (Lausanne) 2021; 8:651658. [PMID: 34646834 PMCID: PMC8502894 DOI: 10.3389/fmed.2021.651658] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
The coronaviruses that cause notable diseases, namely, severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS) and coronavirus disease 2019 (COVID-19), exhibit remarkable similarities in genomic components and pathogenetic mechanisms. Although coronaviruses have widely been studied as respiratory tract pathogens, their effects on the hepatobiliary system have seldom been reported. Overall, the manifestations of liver injury caused by coronaviruses typically involve decreased albumin and elevated aminotransferase and bilirubin levels. Several pathophysiological hypotheses have been proposed, including direct damage, immune-mediated injury, ischemia and hypoxia, thrombosis and drug hepatotoxicity. The interaction between pre-existing liver disease and coronavirus infection has been illustrated, whereby coronaviruses influence the occurrence, severity, prognosis and treatment of liver diseases. Drugs and vaccines used for treating and preventing coronavirus infection also have hepatotoxicity. Currently, the establishment of optimized therapy for coronavirus infection and liver disease comorbidity is of significance, warranting further safety tests, animal trials and clinical trials.
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Affiliation(s)
- Xinyi Wang
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Jianyong Lei
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Zhihui Li
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Lunan Yan
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
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12
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Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. Pharmaceuticals (Basel) 2021; 14:ph14080805. [PMID: 34451902 PMCID: PMC8398530 DOI: 10.3390/ph14080805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/02/2021] [Accepted: 08/11/2021] [Indexed: 12/14/2022] Open
Abstract
Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1–7) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1–7) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases.
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13
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Iwakiri Y, Trebicka J. Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy. JHEP Rep 2021; 3:100316. [PMID: 34337369 PMCID: PMC8318926 DOI: 10.1016/j.jhepr.2021.100316] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/19/2021] [Accepted: 05/12/2021] [Indexed: 12/14/2022] Open
Abstract
Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.
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Key Words
- ACE2, angiogenesis-converting enzyme 2
- ACLF, acute-on-chronic liver failure
- AT1R, angiotensin II type I receptor
- CCL2, chemokine (C-C motif) ligand 2
- CCl4, carbon tetrachloride
- CLD, chronic liver disease
- CSPH, clinically significant portal hypertension
- Dll4, delta like canonical Notch ligand 4
- ECM, extracellular matrix
- EUS, endoscopic ultrasound
- FXR
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- HRS, hepatorenal syndrome
- HSC
- HSCs, hepatic stellate cells
- HVPG, hepatic venous pressure gradient
- Hsp90, heat shock protein 90
- JAK2, Janus kinase 2
- KO, knockout
- LSEC
- LSEC, liver sinusoidal endothelial cells
- MLCP, myosin light-chain phosphatase
- NET, neutrophil extracellular trap
- NO
- NO, nitric oxide
- NSBB
- NSBBs, non-selective beta blockers
- PDE, phosphodiesterase
- PDGF, platelet-derived growth factor
- PIGF, placental growth factor
- PKG, cGMP-dependent protein kinase
- Rho-kinase
- TIPS
- TIPS, transjugular intrahepatic portosystemic shunt
- VCAM1, vascular cell adhesion molecule 1
- VEGF
- VEGF, vascular endothelial growth factor
- angiogenesis
- eNOS, endothelial nitric oxide synthase
- fibrosis
- liver stiffness
- statins
- β-Arr2, β-arrestin 2
- β1-AR, β1-adrenergic receptor
- β2-AR, β2-adrenergic receptor
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, University Clinic Frankfurt, Frankfurt, Germany
- European Foundation for the Study of Chronic Liver Failure-EF Clif, Barcelona, Spain
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14
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Sansoè G, Aragno M, Wong F. COVID-19 and Liver Cirrhosis: Focus on the Nonclassical Renin-Angiotensin System and Implications for Therapy. Hepatology 2021; 74:1074-1080. [PMID: 33524188 PMCID: PMC8013494 DOI: 10.1002/hep.31728] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/28/2020] [Accepted: 01/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Giovanni Sansoè
- Division of GastroenterologyHumanitas InstituteGradenigo HospitalTorinoItaly
| | - Manuela Aragno
- Department of Clinical and Biological SciencesUniversity of TorinoTorinoItaly
| | - Florence Wong
- Department of MedicineUniversity of TorontoToronto General HospitalTorontoOntarioCanada
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15
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Su HY, Hsu YC. Patients with cirrhosis during the COVID-19 pandemic: Current evidence and future perspectives. World J Clin Cases 2021; 9:2951-2968. [PMID: 33969082 PMCID: PMC8080735 DOI: 10.12998/wjcc.v9.i13.2951] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/05/2021] [Accepted: 03/25/2021] [Indexed: 02/06/2023] Open
Abstract
The outbreak of coronavirus disease-2019 (COVID-19) has resulted in a global public health emergency. Patients with cirrhosis were deemed more susceptible to viral infection because of their dysregulated immune response. Similar to the general population, cirrhotic patients exhibit various degrees of COVID-19-related liver injury, which could be attributed to direct virus cytotoxicity, systemic immune system activation, drug-related liver injury, reactivation of pre-existing liver disease, and hypoxic hepatitis. The clinical symptoms in patients with cirrhosis and COVID-19 were similar to those in the general population with COVID-19, with a lower proportion of patients with gastrointestinal symptoms. Although respiratory failure is the predominant cause of mortality in cirrhotic patients with COVID-19, a significant proportion of them lack initial respiratory symptoms. Most evidence has shown that cirrhotic patients have relatively higher rates of morbidity and mortality associated with COVID-19. Advanced cirrhosis was also proposed as an independent factor affecting a poor prognosis and the need to consider COVID-19 palliative care. General measures implemented to prevent the transmission of the virus are also essential for cirrhotic patients, and they should also receive standard cirrhosis care with minimal interruptions. The efficacy of the available COVID-19 vaccines in cirrhotic patients still needs investigation.
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Affiliation(s)
- Hung-Yuan Su
- Department of Emergency Medicine, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yin-Chou Hsu
- Department of Emergency Medicine, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
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16
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Gonzalez E, Azkargorta M, Garcia-Vallicrosa C, Prieto-Elordui J, Elortza F, Blanco-Sampascual S, Falcon-Perez JM. Could protein content of Urinary Extracellular Vesicles be useful to detect Cirrhosis in Alcoholic Liver Disease? Int J Biol Sci 2021; 17:1864-1877. [PMID: 34131392 PMCID: PMC8193259 DOI: 10.7150/ijbs.59725] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/10/2021] [Indexed: 12/13/2022] Open
Abstract
Alcohol abuse has a high impact on the mortality and morbidity related to a great number of diseases and is responsible for the development of alcoholic liver disease (ALD). It remains challenging to detect and evaluate its severity, which is crucial for prognosis. In this work, we studied if urinary EVs (uEVs) could serve in diagnose and evaluate cirrhosis in ALD. To this purpose, uEVs characterization by cryo-electron microscopy (Cryo-EM), Nanoparticle Tracking Analysis (NTA) and Western blotting (WB) was performed in a cohort of 21 controls and 21 cirrhotic patients. Then, proteomics of uEVs was carried out in a second cohort of 6 controls and 8 patients in order to identify new putative biomarkers for cirrhosis in ALD. Interestingly, uEVs concentration, size and protein composition were altered in cirrhotic patients. From a total of 1304 proteins identified in uEVs, 90 of them were found to be altered in cirrhotic patients. The results suggest that uEVs could be considered as a tool and a supplier of new biomarkers for cirrhosis in ALD, whose application would be especially relevant in chronic patients. Yet, further research is necessary to obtain more relevant result in clinical terms.
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Affiliation(s)
- Esperanza Gonzalez
- Exosomes Laboratory. Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Mikel Azkargorta
- Proteomics Platform. Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Clara Garcia-Vallicrosa
- Exosomes Laboratory. Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
| | | | - Felix Elortza
- Proteomics Platform. Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
| | | | - Juan Manuel Falcon-Perez
- Exosomes Laboratory. Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
- Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Madrid, Spain
- IKERBASQUE Basque Foundation for Science Bilbao Spain
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17
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Shigefuku R, Iwasa M, Eguchi A, Tamai Y, Yoshikawa K, Sugimoto R, Takei Y. Serum copeptin level is a biomarker associated with ascites retention and the formation of a portosystemic shunt in chronic liver disease. J Gastroenterol Hepatol 2021; 36:1006-1014. [PMID: 32790956 DOI: 10.1111/jgh.15215] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/12/2020] [Accepted: 08/09/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Copeptin is a stable cleavage product of the arginine vasopressin precursor and is equimolarly secreted with arginine vasopressin. We aimed to assess whether copeptin is the surrogate marker for complications related chronic liver disease (CLD) such as ascites, hepatic encephalopathy (HE), portosystemic shunts (PSSs), and all causes of mortality in CLD. METHODS Serum copeptin was measured in 170 CLD patients upon hospital admission. The association of copeptin levels with liver enzymes, liver functional reserve, and clinical parameters was investigated. Cox proportional hazard regression, logistic regression, and Kaplan-Meier analyses were performed to evaluate the associations of copeptin and ascites, HE and PSS formation, and prognostic factors with short-term (1 year) and long-term (4 years) mortality. RESULTS Serum copeptin levels were significantly correlated with liver and renal function, elevated in parallel with liver disease progression, and also associated with HE. Serum copeptin, albumin-bilirubin score and hepatocellular carcinoma were independent predictors of PSS formation and decreased rate of survival. Serum copeptin and albumin-bilirubin scores were independent predictors of ascites retention. The short-term and long-term cumulative mortality rate was significantly decreased in patients with serum copeptin >5.5 or >4.8 pmol/mL compared with patients in whom serum copeptin levels were <5.5 or <4.8 pmol/mL (P < 0.0001; P < 0.0001). CONCLUSIONS Serum copeptin level is a predictor for ascites retention and HE and PSS formation associated with portal hypertension. Moreover, serum copeptin level may be useful in predicting the rate of survival in patients with CLD.
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Affiliation(s)
- Ryuta Shigefuku
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Akiko Eguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Yasuyuki Tamai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Kyoko Yoshikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Ryosuke Sugimoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
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18
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Synowiec A, Szczepański A, Barreto-Duran E, Lie LK, Pyrc K. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): a Systemic Infection. Clin Microbiol Rev 2021; 34:e00133-20. [PMID: 33441314 PMCID: PMC7849242 DOI: 10.1128/cmr.00133-20] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
To date, seven identified coronaviruses (CoVs) have been found to infect humans; of these, three highly pathogenic variants have emerged in the 21st century. The newest member of this group, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected at the end of 2019 in Hubei province, China. Since then, this novel coronavirus has spread worldwide, causing a pandemic; the respiratory disease caused by the virus is called coronavirus disease 2019 (COVID-19). The clinical presentation ranges from asymptomatic to mild respiratory tract infections and influenza-like illness to severe disease with accompanying lung injury, multiorgan failure, and death. Although the lungs are believed to be the site at which SARS-CoV-2 replicates, infected patients often report other symptoms, suggesting the involvement of the gastrointestinal tract, heart, cardiovascular system, kidneys, and other organs; therefore, the following question arises: is COVID-19 a respiratory or systemic disease? This review aims to summarize existing data on the replication of SARS-CoV-2 in different tissues in both patients and ex vivo models.
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Affiliation(s)
- Aleksandra Synowiec
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Artur Szczepański
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
- Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Emilia Barreto-Duran
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Laurensius Kevin Lie
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Krzysztof Pyrc
- Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
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19
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Grace JA, Casey S, Burrell LM, Angus PW. Proposed mechanism for increased COVID-19 mortality in patients with decompensated cirrhosis. Hepatol Int 2020; 14:884-885. [PMID: 32886332 PMCID: PMC7471588 DOI: 10.1007/s12072-020-10084-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/17/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Josephine A Grace
- Department of Gastroenterology and Hepatology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia.
- Department of Medicine and Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia.
| | - Stephen Casey
- Department of Gastroenterology and Hepatology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia
- Department of Medicine and Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Louise M Burrell
- Department of Medicine and Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Peter W Angus
- Department of Gastroenterology and Hepatology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia
- Department of Medicine and Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia
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20
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Kulkarni AV, Kumar P, Tevethia HV, Premkumar M, Arab JP, Candia R, Talukdar R, Sharma M, Qi X, Rao PN, Reddy DN. Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19. Aliment Pharmacol Ther 2020; 52:584-599. [PMID: 32638436 PMCID: PMC7361465 DOI: 10.1111/apt.15916] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/22/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The incidence of elevated liver chemistries and the presence of pre-existing chronic liver disease (CLD) have been variably reported in COVID-19. AIMS To assess the prevalence of CLD, the incidence of elevated liver chemistries and the outcomes of patients with and without underlying CLD/elevated liver chemistries in COVID-19. METHODS A comprehensive search of electronic databases from 1 December 2019 to 24 April 2020 was done. We included studies reporting underlying CLD or elevated liver chemistries and patient outcomes in COVID-19. RESULTS 107 articles (n = 20 874 patients) were included for the systematic review. The pooled prevalence of underlying CLD was 3.6% (95% CI, 2.5-5.1) among the 15 407 COVID-19 patients. The pooled incidence of elevated liver chemistries in COVID-19 was 23.1% (19.3-27.3) at initial presentation. Additionally, 24.4% (13.5-40) developed elevated liver chemistries during the illness. The pooled incidence of drug-induced liver injury was 25.4% (14.2-41.4). The pooled prevalence of CLD among 1587 severely infected patients was 3.9% (3%-5.2%). The odds of developing severe COVID-19 in CLD patients was 0.81 (0.31-2.09; P = 0.67) compared to non-CLD patients. COVID-19 patients with elevated liver chemistries had increased risk of mortality (OR-3.46 [2.42-4.95, P < 0.001]) and severe disease (OR-2.87 [95% CI, 2.29-3.6, P < 0.001]) compared to patients without elevated liver chemistries. CONCLUSIONS Elevated liver chemistries are common at presentation and during COVID-19. The severity of elevated liver chemistries correlates with the outcome of COVID-19. The presence of CLD does not alter the outcome of COVID-19. Further studies are needed to analyse the outcomes of compensated and decompensated liver disease.
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Affiliation(s)
- Anand V. Kulkarni
- Department of HepatologyAsian Institute of GastroenterologyHyderabadIndia
| | - Pramod Kumar
- Department of HepatologyAsian Institute of GastroenterologyHyderabadIndia
| | | | | | - Juan Pablo Arab
- Departamento de GastroenterologiaEscuela de MedicinaPontificia Universidad Catolica de ChileSantiagoChile
| | - Roberto Candia
- Departamento de GastroenterologiaEscuela de MedicinaPontificia Universidad Catolica de ChileSantiagoChile
| | - Rupjyoti Talukdar
- Department of GastroenterologyAsian Institute of GastroenterologyHyderabadIndia
| | - Mithun Sharma
- Department of HepatologyAsian Institute of GastroenterologyHyderabadIndia
| | - Xiaolong Qi
- CHESS CenterInstitute of Portal HypertensionThe First Hospital of Lanzhou UniversityLanzhouChina
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Ali B, Salim A, Alam A, Zuberi BF, Ali Z, Azam Z, Kamani L, Farooqi JI, Salih M, Nawaz AA, Chaudhry AA, Hashmi ZY, Siddique M. HEP-Net opinion on the management of ascites and its complications in the setting of decompensated cirrhosis in the resource constrained environment of Pakistan. Pak J Med Sci 2020; 36:1117-1132. [PMID: 32704299 PMCID: PMC7372671 DOI: 10.12669/pjms.36.5.2407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 05/09/2020] [Accepted: 05/20/2020] [Indexed: 11/30/2022] Open
Abstract
Approximately one half of patients develop ascites within 10 years of diagnosis of compensated cirrhosis. It is a poor prognostic indicator, with only 50% surviving beyond two years. Mortality worsens significantly to 20% to 50% at one year if the ascites becomes refractory to medical therapy. Pakistan has one of the highest prevalence of viral hepatitis in the world and patients with ascites secondary to liver cirrhosis make a major percentage of both inpatient and outpatient burden. Studies indicate that over 80% of patients admitted with ascites have liver cirrhosis as the cause. This expert opinion suggests proper assessment of patients with ascites in the presence of underlying cirrhosis. This expert opinion includes appropriate diagnosis and management of uncomplicated ascites, refractory ascites and complicated ascites (including spontaneous bacterial peritonitis (SBP) ascites, hepatorenal syndrome (HRS) and hyponatremia. The purpose behind this expert opinion is to help consultants, postgraduate trainees, medical officers and primary care physicians optimally manage their patients with cirrhosis and ascites in a resource constrained setting as is often encountered in a developing country like Pakistan.
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Affiliation(s)
- Bushra Ali
- Bushra Ali, Fatima Memorial Medical and Dental College, Lahore, Pakistan
| | - Adnan Salim
- Adnan Salim, Shaikh Zayed Postgraduate Medical Institute, Lahore, Pakistan
| | - Altaf Alam
- Altaf Alam, Shaikh Zayed Postgraduate Medical Institute, Lahore, Pakistan
| | - Bader Faiyaz Zuberi
- Bader Faiyaz Zuberi, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Zeeshan Ali
- Zeeshan Ali, Jinnah Postgraduate Medical Centre, Karachi, Pakistan
| | - Zahid Azam
- Zahid Azam, NILGID, Dow University of Health Sciences, Karachi, Pakistan
| | - Lubna Kamani
- Lubna Kamani, Liaquat National Hospital, Karachi, Pakistan
| | | | - Muhammed Salih
- Muhammed Salih, Quaid e Azam International Hospital, Islamabad, Pakistan
| | - Arif Amir Nawaz
- Arif Amir Nawaz, Fatima Memorial Medical and Dental College, Lahore, Pakistan
| | | | | | - Masood Siddique
- Masood Siddique, Jinnah Memorial Hospital, Rawalpindi, Pakistan
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AlQudah M, Hale TM, Czubryt MP. Targeting the renin-angiotensin-aldosterone system in fibrosis. Matrix Biol 2020; 91-92:92-108. [PMID: 32422329 DOI: 10.1016/j.matbio.2020.04.005] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023]
Abstract
Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in the pathogenesis of fibrosis. The renin-angiotensin-aldosterone system (RAAS) interacts with the potent Transforming Growth Factor β (TGFβ) pro-fibrotic pathway to mediate fibrosis in many cell and tissue types. RAAS consists of both classical and alternative pathways, which act to potentiate or antagonize fibrotic signaling mechanisms, respectively. This review provides an overview of recent literature describing the roles of RAAS in the pathogenesis of fibrosis, particularly in the liver, heart, kidney and skin, and with a focus on RAAS interactions with TGFβ signaling. Targeting RAAS to combat fibrosis represents a promising therapeutic approach, particularly given the lack of strategies for treating fibrosis as its own entity, thus animal and clinical studies to examine the impact of natural and synthetic substances to alter RAAS signaling as a means to treat fibrosis are reviewed as well.
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Affiliation(s)
- Mohammad AlQudah
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Canada; Department of Physiology and Biochemistry, College of Medicine, Jordan University of Science and Technology, Jordan
| | - Taben M Hale
- Department of Basic Medical Sciences, University of Arizona College of Medicine Phoenix, United States
| | - Michael P Czubryt
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Canada.
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