Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Bendtsen, F.

Coenraad, M.J.

Porcher, R.

Leiden University Scholary Publications

JOURNAL OF HEPATOLOGYEditorialHepatic and cardiac hemodynamics and systemic inflammationin cirrhosis: It takes three to tangoM.J. Coenraad1,⇑, R. Porcher2, F. Bendtsen31Department of Gastroenterology-Hepatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands;2Centre de Recherche Epidémiologie et Statistique Sorbonne Paris Cité, UMR 1153, Inserm, Université Paris Descartes, Hopital Hôtel-Dieu,Paris, France; 3University of Copenhagen, Gastrounit, Medical Section, Hvidovre University Hospital, Copenhagen, DenmarkSee Article, pages 949–958In this issue, Turco et al.1 present a single center study whereinthey comprehensively assessed hepatic and cardiac haemody-namics and C-reactive protein (CRP) to analyse their interrela-tionship and to explore their prognostic relevance, in a cohortof cirrhotic patients. Cirrhosis has for many decades beenclassified into two main prognostic stages: compensated anddecompensated stage. Decompensation is characterized by thepresence of clinically evident decompensating events, withascites and complications, such as spontaneous bacterial peri-tonitis, hepatorenal syndrome and variceal haemorrhage beingthe most frequent events, while hepatic encephalopathy andjaundice occur less frequently.2 Development of decompensatedcirrhosis is a milestone, as median survival is significantly lowerin decompensated patients, especially in patientswithmore thanone decompensating event, irrespective of the type of event.2Portal hypertension is responsible for the majority of decom-pensating events. Hepatic venous pressure gradient (HVPG) val-ues >5 mmHg indicate postsinusoidal portal hypertension andthe relationship between HVPG and decompensating events, likevariceal haemorrhage has long been recognized.3 The term clin-ically significant portal hypertension (CSPH) was defined as ahepatic venous pressure gradient >10 mmHg in the most recentBaveno consensus workshop.4 Compensated cirrhosis was fur-ther divided in the recent AASLD guideline into those with mildPH (HVPG >5 but <10 mmHg); those with CSPHwithout gastroe-sophageal varices (GEV) and those with CSPH with GEV.5 Thissubstaging is prognostically important and the therapeuticapproach is different. However, in clinical practice, invasivemea-surement of HVPG, although a simple technique, is not availablein every center. Liver stiffness by transient elastography, which iswidely available nowadays, can be used to identify compensatedadvanced chronic liver disease,4 and in combinationwith plateletcount to identify up to 40% of patients with compensatedJournal of Hepatology 2Keywords: Cirrhosis; Hemodynamics; Portal hypertension; Inflammation; Hepaticdecompensation; Acute on chronic liver failure.Received 30 January 2018; received in revised form 12 February 2018; accepted 13February 2018qDOI of original article: http://dx.doi.org/10.1016/j.jhep.2017.12.027.⇑ Corresponding author. Address: Department of Gastroenterology- Hepatology,Leiden University Medical Center, PO Box 9600, Leiden, The Netherlands. Tel.: +31 715269111; fax: +31 71 5248115.E-mail address: m.j.coenraad@lumc.nl (M.J. Coenraad).cirrhosis, who can safely avoid screening endoscopy for gastroe-sophageal varices.6The ‘peripheral arterial vasodilation hypothesis’ was pro-posed in 1988 by Schrier et al.7 and is still accepted nowadays.8Peripheral and splanchnic arterial vasodilation occurs as earlyas the compensated stage and is progressive in the decompen-sated stage and in hepatorenal syndrome, where it is accompa-nied by activation of vasoconstrictor systems, such as therenin-angiotensin-aldosterone system, the vasopressin systemand the sympathetic nervous system. Renal sodium and waterretention occurs, because of decreased arterial vascular filling.Increased cardiac output (CO) is a common feature of cirrhosis.7Cardiac dysfunction in advanced cirrhosis may contribute to thedecreased effective circulating volume, especially when theheart fails to compensate for the arterial vasodilation.9 Thismay lead to a systolic dysfunction as reflected by a lower CO,which may precipitate development of hepatorenal syndromeand early death.Recently, it has become clear that bacterial translocation, aswell as a storm of pro-inflammatory cytokines, and reactiveoxygen and nitrogen species, in response to pathogen-associated molecular patterns, appear to be the primary event inthe pathogenesis of decompensated liver cirrhosis and associatedliver failure.10,11 Therefore the syndrome of decompensatedcirrhosis is not solely explained by the peripheral arterialvasodilation hypothesis, but is a complex interplay betweeninflammation and vasodilation, with systemic inflammationbeing the primary event in decompensated cirrhosis and associ-ated organ failure (Fig. 1).11,12 The concept of acute on chronicliver failure (ACLF) has recently been introduced with cleardiagnostic criteria.13 ACLF is a syndrome distinct from ‘mere’decompensated cirrhosis, as it is characterized by acute decom-pensation, the presence of organ failure and associated with avery high short-term mortality rate. Remarkably, previous epi-sodes of acute decompensation were absent in 23% of patientswith ACLF, which did not confirm the generally accepted para-digm that organ failure in cirrhosis is a terminal event thatdevelops at the latest phase in the course of cirrhosis.13 Inflam-matory markers, white blood cell count (WBC) and CRP weresignificantly higher in patients with ACLF than the group with-out ACLF, even when patients with infection were excludedfrom the analysis. Moreover, mortality in ACLF was related to018 vol. 68 j 887–889Portal hypertensionVasodilationInflammationBacterial translocationPAMPsPro-inflammatory cytokines↑↑  Reactive oxygen and nitrogenHypo-dynamic stateHypo/hyper-dynamic stateCardiac dysfunctionCompensated cirrhosisDecompensated cirrhosisAcute on chronic liver failureOrgan failure(s)???Fig. 1. The hypothesis of the roles of inflammation, portal hypertension and cardiodynamic state in the pathogenesis of compensated anddecompensated cirrhosis, and acute on chronic liver failure. Question marks represent areas of uncertainty which need further exploration. PAMPs,pathogen-associated molecular patterns.EditorialWBC.13 Systemic inflammation, which is already present inacute decompensation of cirrhosis, appears to be the primarydriver of ACLF and the course of systemic inflammation is asso-ciated with the course of ACLF.12Turco et al.1 integrate the acquired knowledge in a compre-hensive exploratory study of hepatic and systemic hemodynam-ics, and inflammation by CRP, in a cohort of 238 patients amongthe different substages of cirrhosis, assessing their interrelation-ship and prognostic relevance. The authors adhered to the clas-sical stages of compensated and decompensated cirrhosis,although these stages were subdivided into five substages,according to the recent guidelines, dependent on the presenceand severity of portal hypertension, presence of varices anddecompensation. The novelty of the study was that data wereanalysed using different cardiodynamic states defined as hyper-dynamic, normodynamic and hypodynamic. Thorough hepaticand cardiac hemodynamic investigations were performed inpatients and CRP was measured as a marker of inflammation.The main findings are that CRP and a relatively hypo- or hyper-dynamic circulatory state are, next to known prognostic factors,predictive of the development of decompensation in compen-sated cirrhosis and of death or liver transplantation in decom-pensated cirrhosis. This study contributes to the understandingof the heterogeneity of cirrhosis and the roles of hepatic and car-diocirculatory factors and inflammation at the different stages ofcirrhosis, as well as their prognostic relevance.Many eligibility criteria were applied, significantly impactingon the number of patients included and the generalisability ofthe results. For example, compensated patients who were trea-ted with non-selective beta-blockers and patients with ACLF oractive infections were excluded from the study. The effect ofdisease-modifying treatments, such as use of direct-actingantivirals, or liver transplantation were adequately accounted888 Journal of Hepatology 2for in the analysis. However, given the number of events pervariable in the study, there is still a risk that the proposed modelcould over-fit the data, as rightly discussed by the authors.Moreover, calibration plots showed some under/overestimationof the probability of event at the extreme, especially for com-pensated cirrhosis. Therefore, studies are needed to externallyvalidate the proposed prognostic models. The authors explainthat the results of their study do not provide insight to thesequential interaction between bacterial translocation, inflam-mation and hemodynamic alterations at different stages of cir-rhosis and that this should be further explored. Indeed, thereis a need for better understanding of the drivers of the differentstages of cirrhosis, in order to identify patients at higher risk ofpoor outcome or to predict the response to a given therapy andmove towards individualizing patient care in cirrhosis usingtherapies directly targeting the driver.Financial supportThe authors did not receive any financial support to write themanuscript.Conflict of interestMC and RP have nothing to disclose; FB Ferring PharmaceuticalsA/S, consultant.Please refer to the accompanying ICMJE disclosure forms forfurther details.Authors’ contributionsMC wrote the manuscript, RP and FB revised the manuscript.018 vol. 68 j 887–889JOURNAL OF HEPATOLOGYSupplementary dataSupplementary data associated with this article can be found, inthe online version, at https://doi.org/10.1016/j.jhep.2018.02.007.References[1] Turco L, Garcia-Tsao G, Magnani I, Bianchini M, Costetti M, Caporali C,et al. Cardiopulmonary hemodynamics and C-reactive protein asprognostic indicators in compensated and decompensated cirrhosis. JHepatol 2018;68:949–958.[2] D’Amico G, Pasta L, Morabito A, D’Amico M, Caltagirone M, Malizia G,et al. Competing risks and prognostic stages of cirrhosis: a 25-yearinception cohort study of 494 patients. Aliment Pharmacol Ther2014;39:1180–1193.[3] Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE,Glickman M. Portal pressure, presence of gastroesophageal varices andvariceal bleeding. Hepatology 1985;5:419–424.[4] De Franchis RBaveno VI Faculty. Expanding consensus in portal hyper-tension: Report of the Baveno VI Consensus Workshop: Stratifying riskand individualizing care for portal hypertension. J Hepatol2015;63:743–752.[5] Garcia-Tsao G, Abraldes J, Berzigotti A, Bosch J. Portal hypertensivebleeding in cirrhosis: risk stratification, diagnosis, and management:2016 practice guidance by the American Association for the Study ofLiver Diseases. Hepatology 2017;65:310–335.[6] Augustin S, Pons M, Maurice J, Bureau C, Stefanescu H, Ney M, et al.Expanding the Baveno VI criteria for the screening of varices in patientsJournal of Hepatology 2with compensated advanced chronic liver disease. Hepatology2017;66:1980–1988.[7] Schrier R, Arroyo V, Bernardi M, Epstein M, Henriksen J, Rodés J.Peripheral arterial vasodilation hypothesis: a proposal for the initiationof renal sodium and water retention in cirrhosis. Hepatology1988;8:1151–1157.[8] Møller S, Bendtsen F. The pathophysiology of arterial vasodilatation andhyperdynamic circulation in cirrhosis. Liver Int 2017 Sep 16. https://doi.org/10.1111/liv.13589.[9] Krag A, Bendtsen F, Henriksen J, Møller S. Low cardiac output predictsdevelopment of hepato-renal syndrome and survival in patients withcirrhosis and ascites. Gut 2010;59:105–110.[10] Bellot P, Frances R, Such J. Pathological bacterial translocation incirrhosis: pathophysiology, diagnosis and clinical implications. LiverInt 2013;33:31–39.[11] Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms ofdecompensation and organ failure in cirrhosis: From peripheral arterialvasodilation to systemic inflammation hypothesis. J Hepatol2015;63:1272–1284.[12] Clària J, Stauber R, Coenraad M, Moreau R, Jalan R, Pavesi M,et alCANONIC Study Investigators of the EASL-CLIF Consortium and theEuropean Foundation for the Study of Chronic Liver Failure (EF-CLIF).Systemic inflammation in decompensated cirrhosis: Characterizationand role in acute-on-chronic liver failure. Hepatology2016;64:1249–1264.[13] Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et alCANONICStudy Investigators of the EASL–CLIF Consortium. Acute-on-chronic liverfailure is a distinct syndrome that develops in patients with acutedecompensation of cirrhosis. Gastroenterology 2013;144:1426–1437.018 vol. 68 j 887–889 889

Hepatic and cardiac hemodynamics and systemic inflammation in cirrhosis: It takes three to tango

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Hepatic and cardiac hemodynamics and systemic inflammation in cirrhosis: It takes three to tango

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