Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 5/2012

01-10-2012 | Review

Clinical review: The liver in sepsis

Authors: Nicolas Nesseler, Yoann Launey, Caroline Aninat, Fabrice Morel, Yannick Mallédant, Philippe Seguin

Published in: Critical Care | Issue 5/2012

Login to get access

Abstract

During sepsis, the liver plays a key role. It is implicated in the host response, participating in the clearance of the infectious agents/products. Sepsis also induces liver damage through hemodynamic alterations or through direct or indirect assault on the hepatocytes or through both. Accordingly, liver dysfunction induced by sepsis is recognized as one of the components that contribute to the severity of the disease. Nevertheless, the incidence of liver dysfunction remains imprecise, probably because current diagnostic tools are lacking, notably those that can detect the early liver insult. In this review, we discuss the epidemiology, diagnostic tools, and impact on outcome as well as the pathophysiological aspects, including the cellular events and clinical picture leading to liver dysfunction. Finally, therapeutic considerations with regard to the weakness of the pertinent specific approach are examined.
Appendix
Available only for authorised users
Literature
1.
Blanco J, Muriel-Bombín A, Sagredo V, Taboada F, Gandía F, Tamayo L, Collado J, García-Labattut A, Carriedo D, Valledor M, De Frutos M, López M, Caballero A, Guerra J, Alvarez B, Mayo A, Villar J: Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit Care. 2008, 12: R158-10.1186/cc7157.PubMedCentralCrossRefPubMed
2.
Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003, 348: 1546-1554. 10.1056/NEJMoa022139.CrossRefPubMed
3.
Dhainaut JF, Marin N, Mignon A, Vinsonneau C: Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med. 2001, 29: S42-47.CrossRefPubMed
4.
Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, Parsonnet J, Panzer R, Orav EJ, Snydman DR, Black E, Schwartz JS, Moore R, Johnson BLJ, Platt R: Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA. 1997, 278: 234-240. 10.1001/jama.1997.03550030074038.CrossRefPubMed
5.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001, 29: 1303-1310. 10.1097/00003246-200107000-00002.CrossRefPubMed
6.
Bakker J, Grover R, McLuckie A, Holzapfel L, Andersson J, Lodato R, Watson D, Grossman S, Donaldson J, Takala J: Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, doubleblind, placebo-controlled multicenter study (study no. 144-002). Crit Care Med. 2004, 32: 1-12. 10.1097/01.CCM.0000105118.66983.19.CrossRefPubMed
7.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent J, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003, 31: 1250-1256. 10.1097/01.CCM.0000050454.01978.3B.CrossRefPubMed
8.
Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M, Bojic A, Schellongowski P, Angermayr B, Kitzberger R, Warszawska J, Holzinger U, Schenk P, Madl C: Hypoxic hepatitis: underlying conditions and risk factors for mortality in critically ill patients. Intensive Care Med. 2009, 35: 1397-1405. 10.1007/s00134-009-1508-2.CrossRefPubMed
9.
Brun-Buisson C, Meshaka P, Pinton P, Vallet B: EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004, 30: 580-588.CrossRefPubMed
10.
Vincent JL, Angus DC, Artigas A, Kalil A, Basson BR, Jamal HH, Johnson G, Bernard GR, for the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group: Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med. 2003, 31: 834-840. 10.1097/01.CCM.0000051515.56179.E1.CrossRefPubMed
11.
Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ: Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995, 23: 1638-1652. 10.1097/00003246-199510000-00007.CrossRefPubMed
12.
Sakka SG: Assessing liver function. Curr Opin Crit Care. 2007, 13: 207-214. 10.1097/MCC.0b013e328012b268.CrossRefPubMed
13.
Kimura S, Yoshioka T, Shibuya M, Sakano T, Tanaka R, Matsuyama S: Indocyanine green elimination rate detects hepatocellular dysfunction early in septic shock and correlates with survival. Crit Care Med. 2001, 29: 1159-1163. 10.1097/00003246-200106000-00014.CrossRefPubMed
14.
Kortgen A, Paxian M, Werth M, Recknagel P, Rauchfuss F, Lupp A, Krenn CG, Müller D, Claus RA, Reinhart K, Settmacher U, Bauer M: Prospective assessment of hepatic function and mechanisms of dysfunction in the critically ill. Shock. 2009, 32: 358-365. 10.1097/SHK.0b013e31819d8204.CrossRefPubMed
15.
Stehr A, Ploner F, Traeger K, Theisen M, Zuelke C, Radermacher P, Matejovic M: Plasma disappearance of indocyanine green: a marker for excretory liver function?. Intensive Care Med. 2005, 31: 1719-1722. 10.1007/s00134-005-2826-7.CrossRefPubMed
16.
Hebert PC, Drummond AJ, Singer J, Bernard GR, Russell JA: A simple multiple system organ failure scoring system predicts mortality of patients who have sepsis syndrome. Chest. 1993, 104: 230-235. 10.1378/chest.104.1.230.CrossRefPubMed
17.
Abraham E, Laterre P, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005, 353: 1332-1341. 10.1056/NEJMoa050935.CrossRefPubMed
18.
Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008, 358: 877-887. 10.1056/NEJMoa067373.CrossRefPubMed
19.
Lautt WW: Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol. 1985, 249: G549-556.PubMed
20.
Vary TC, Kimball SR: Regulation of hepatic protein synthesis in chronic inflammation and sepsis. Am J Physiol. 1992, 262: C445-452.PubMed
21.
Casteleijn E, Kuiper J, Van Rooij HC, Kamps JA, Koster JF, Van Berkel TJ: Endotoxin stimulates glycogenolysis in the liver by means of intercellular communication. J Biol Chem. 1988, 263: 6953-6955.PubMed
22.
Meinz H, Lacy DB, Ejiofor J, McGuinness OP: Alterations in hepatic gluconeogenic amino acid uptake and gluconeogenesis in the endotoxin treated conscious dog. Shock. 1998, 9: 296-303. 10.1097/00024382-199804000-00010.CrossRefPubMed
23.
Harbrecht BG, Frye RF, Zenati MS, Branch RA, Peitzman AB: Cytochrome P-450 activity is differentially altered in severely injured patients. Crit Care Med. 2005, 33: 541-546. 10.1097/01.CCM.0000155989.54344.E0.CrossRefPubMed
24.
25.
Katz S, Jimenez MA, Lehmkuhler WE, Grosfeld JL: Liver bacterial clearance following hepatic artery ligation and portacaval shunt. J Surg Res. 1991, 51: 267-270. 10.1016/0022-4804(91)90105-U.CrossRefPubMed
26.
Nakatani Y, Fukui H, Kitano H, Nagamoto I, Tsujimoto T, Kuriyama S, Kikuchi E, Hoppou K, Tsujii T: Endotoxin clearance and its relation to hepatic and renal disturbances in rats with liver cirrhosis. Liver. 2001, 21: 64-70. 10.1034/j.1600-0676.2001.210110.x.CrossRefPubMed
27.
Fong YM, Marano MA, Moldawer LL, Wei H, Calvano SE, Kenney JS, Allison AC, Cerami A, Shires GT, Lowry SF: The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. J Clin Invest. 1990, 85: 1896-1904. 10.1172/JCI114651.PubMedCentralCrossRefPubMed
28.
Migita K, Abiru S, Nakamura M, Komori A, Yoshida Y, Yokoyama T, Daikoku M, Ueki T, Takii Y, Yano K, Yastuhashi H, Eguchi K, Ishibashi H: Lipopolysaccharide signaling induces serum amyloid A (SAA) synthesis in human hepatocytes in vitro. FEBS Lett. 2004, 569: 235-239. 10.1016/j.febslet.2004.05.072.CrossRefPubMed
29.
Aninat C, Seguin P, Descheemaeker P, Morel F, Malledant Y, Guillouzo A: Catecholamines induce an inflammatory response in human hepatocytes. Crit Care Med. 2008, 36: 848-854. 10.1097/CCM.0B013E31816532BE.CrossRefPubMed
30.
Ring A, Stremmel W: The hepatic microvascular responses to sepsis. Semin Thromb Hemost. 2000, 26: 589-594. 10.1055/s-2000-13215.CrossRefPubMed
31.
Koo DJ, Chaudry IH, Wang P: Kupffer cells are responsible for producing inflammatory cytokines and hepatocellular dysfunction during early sepsis. J Surg Res. 1999, 83: 151-157. 10.1006/jsre.1999.5584.CrossRefPubMed
32.
Knolle PA, Löser E, Protzer U, Duchmann R, Schmitt E, zum Büschenfelde KH, Rose-John S, Gerken G: Regulation of endotoxin-induced IL-6 production in liver sinusoidal endothelial cells and Kupffer cells by IL-10. Clin Exp Immunol. 1997, 107: 555-561. 10.1046/j.1365-2249.1997.d01-959.x.PubMedCentralCrossRefPubMed
33.
Ayala A, Knotts JB, Ertèl W, Perrin MM, Morrison MH, Chaudry IH: Role of interleukin 6 and transforming growth factor-beta in the induction of depressed splenocyte responses following sepsis. Arch Surg. 1993, 128: 89-94. 10.1001/archsurg.1993.01420130101015. discussion 94-95CrossRefPubMed
34.
De Domenico I, Zhang TY, Koening CL, Branch RW, London N, Lo E, Daynes RA, Kushner JP, Li D, Ward DM, Kaplan J: Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J Clin Invest. 2010, 120: 2395-2405. 10.1172/JCI42011.PubMedCentralCrossRefPubMed
35.
Huang Y, Yang Y, Tiao M, Kuo H, Huang L, Chuang J: Hepcidin protects against lipopolysaccharide-induced liver injury in a mouse model of obstructive jaundice. Peptides. 2012, 35: 212-217. 10.1016/j.peptides.2012.03.032.CrossRefPubMed
36.
Tsutsui H, Matsui K, Kawada N, Hyodo Y, Hayashi N, Okamura H, Higashino K, Nakanishi K: IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice. J Immunol. 1997, 159: 3961-3967.PubMed
37.
Bosisio D, Polentarutti N, Sironi M, Bernasconi S, Miyake K, Webb GR, Martin MU, Mantovani A, Muzio M: Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma: a molecular basis for priming and synergism with bacterial lipopolysaccharide. Blood. 2002, 99: 3427-3431. 10.1182/blood.V99.9.3427.CrossRefPubMed
38.
Wong JM, Billiar TR: Regulation and function of inducible nitric oxide synthase during sepsis and acute inflammation. Adv Pharmacol. 1995, 34: 155-170.CrossRefPubMed
39.
Pastor CM, Losser MR, Payen D: Nitric oxide donor prevents hepatic and systemic perfusion decrease induced by endotoxin in anesthetized rabbits. Hepatology. 1995, 22: 1547-1553.PubMed
40.
Sakamoto M, Ueno T, Kin M, Ohira H, Torimura T, Inuzuka S, Sata M, Tanikawa K: Ito cell contraction in response to endothelin-1 and substance P. Hepatology. 1993, 18: 978-983. 10.1002/hep.1840180432.CrossRefPubMed
41.
Wang JH, Redmond HP, Watson RW, Condron C, Bouchier-Hayes D: Induction of heat shock protein 72 prevents neutrophil-mediated human endothelial cell necrosis. Arch Surg. 1995, 130: 1260-1265. 10.1001/archsurg.1995.01430120014002.CrossRefPubMed
42.
Bauer M, Zhang JX, Bauer I, Clemens MG: ET-1 induced alterations of hepatic microcirculation: sinusoidal and extrasinusoidal sites of action. Am J Physiol. 1994, 267: G143-149.PubMed
43.
Miksa M, Das P, Zhou M, Wu R, Dong W, Ji Y, Goyert SM, Ravikumar TS, Wang P: Pivotal role of the alpha(2A)-adrenoceptor in producing inflammation and organ injury in a rat model of sepsis. PLoS ONE. 2009, 4: e5504-10.1371/journal.pone.0005504.PubMedCentralCrossRefPubMed
44.
Zhang F, Wu R, Qiang X, Zhou M, Wang P: Antagonism of alpha2Aadrenoceptor: a novel approach to inhibit inflammatory responses in sepsis. J Mol Med. 2010, 88: 289-296. 10.1007/s00109-009-0555-z.PubMedCentralCrossRefPubMed
45.
Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR: Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases. Medicine (Baltimore). 2003, 82: 392-406. 10.1097/01.md.0000101573.54295.bd.CrossRef
46.
Dahn MS, Lange P, Lobdell K, Hans B, Jacobs LA, Mitchell RA: Splanchnic and total body oxygen consumption differences in septic and injured patients. Surgery. 1987, 101: 69-80.PubMed
47.
Henrion J: Hypoxic hepatitis. Liver Int. 2011
48.
Raurich JM, Llompart-Pou JA, Ferreruela M, Colomar A, Molina M, Royo C, Ayestarán I, Ibáñez J: Hypoxic hepatitis in critically ill patients: incidence, etiology and risk factors for mortality. J Anesth. 2011, 25: 50-56. 10.1007/s00540-010-1058-3.CrossRefPubMed
49.
50.
51.
Kramer L, Jordan B, Druml W, Bauer P, Metnitz PGH: Incidence and prognosis of early hepatic dysfunction in critically ill patients--a prospective multicenter study. Crit Care Med. 2007, 35: 1099-1104. 10.1097/01.CCM.0000259462.97164.A0.CrossRefPubMed
52.
Moreno R, Vincent JL, Matos R, Mendonça A, Cantraine F, Thijs L, Takala J, Sprung C, Antonelli M, Bruining H, Willatts S: The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care. Results of a prospective, multicentre study. Working Group on Sepsis related Problems of the ESICM. Intensive Care Med. 1999, 25: 686-696. 10.1007/s001340050931.CrossRefPubMed
53.
54.
Assimakopoulos SF, Scopa CD, Vagianos CE: Pathophysiology of increased intestinal permeability in obstructive jaundice. World J Gastroenterol. 2007, 13: 6458-6464. 10.3748/wjg.13.6458.PubMedCentralCrossRefPubMed
55.
Trauner M, Meier PJ, Boyer JL: Molecular pathogenesis of cholestasis. N Engl J Med. 1998, 339: 1217-1227. 10.1056/NEJM199810223391707.CrossRefPubMed
56.
Fuchs M, Sanyal AJ: Sepsis and cholestasis. Clin Liver Dis. 2008, 12: 151-172. 10.1016/j.cld.2007.11.002. ixCrossRefPubMed
57.
Deeley RG, Westlake C, Cole SPC: Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev. 2006, 86: 849-899. 10.1152/physrev.00035.2005.CrossRefPubMed
58.
Spirlì C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, Larusso NF, Sonzogni A, Okolicsanyi L, Strazzabosco M: Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology. 2003, 124: 737-753. 10.1053/gast.2003.50100.CrossRefPubMed
59.
Kamiya S, Nagino M, Kanazawa H, Komatsu S, Mayumi T, Takagi K, Asahara T, Nomoto K, Tanaka R, Nimura Y: The value of bile replacement during external biliary drainage: an analysis of intestinal permeability, integrity, and microflora. Ann Surg. 2004, 239: 510-517. 10.1097/01.sla.0000118594.23874.89.PubMedCentralCrossRefPubMed
60.
Padillo FJ, Muntane J, Montero JL, Briceño J, Miño G, Solorzano G, Sitges-Serra A, Pera-Madrazo C: Effect of internal biliary drainage on plasma levels of endotoxin, cytokines, and C-reactive protein in patients with obstructive jaundice. World J Surg. 2002, 26: 1328-1332. 10.1007/s00268-002-6232-9.CrossRefPubMed
61.
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008, 36: 296-327. 10.1097/01.CCM.0000298158.12101.41.CrossRefPubMed
62.
Kubitz R, Wettstein M, Warskulat U, Häussinger D: Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone. Gastroenterology. 1999, 116: 401-410. 10.1016/S0016-5085(99)70138-1.CrossRefPubMed
63.
Moreno R, Sprung CL, Annane D, Chevret S, Briegel J, Keh D, Singer M, Weiss YG, Payen D, Cuthbertson BH, Vincent J: Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study. Intensive Care Med. 2011, 37: 1765-1772. 10.1007/s00134-011-2334-x.CrossRefPubMed
64.
McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B, Ochoa JB, Napolitano L, Cresci G: Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2009, 33: 277-316. 10.1177/0148607109335234.CrossRefPubMed
65.
Braga M, Gianotti L, Gentilini O, Parisi V, Salis C, Di Carlo V: Early postoperative enteral nutrition improves gut oxygenation and reduces costs compared with total parenteral nutrition. Crit Care Med. 2001, 29: 242-248. 10.1097/00003246-200102000-00003.CrossRefPubMed
66.
67.
Hegazi RA, Wischmeyer PE: Clinical review: optimizing enteral nutrition for critically ill patients - a simple data-driven formula. Crit Care. 2011, 15: 234-10.1186/cc10430.PubMedCentralCrossRefPubMed
68.
de Vree JM, Romijn JA, Mok KS, Mathus-Vliegen LM, Stoutenbeek CP, Ostrow JD, Tytgat GN, Sauerwein HP, Oude Elferink RP, Groen AK: Lack of enteral nutrition during critical illness is associated with profound decrements in biliary lipid concentrations. Am J Clin Nutr. 1999, 70: 70-77.PubMed
69.
Han MK, Hyzy R: Advances in critical care management of hepatic failure and insufficiency. Crit Care Med. 2006, 34: S225-231. 10.1097/01.CCM.0000231882.85350.71.CrossRefPubMed
70.
Hawker F: Liver dysfunction in critical illness. Anaesth Intensive Care. 1991, 19: 165-181.PubMed
71.
Moyer AM, Fridley BL, Jenkins GD, Batzler AJ, Pelleymounter LL, Kalari KR, Ji Y, Chai Y, Nordgren KKS, Weinshilboum RM: Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011, 120: 33-41. 10.1093/toxsci/kfq375.PubMedCentralCrossRefPubMed
72.
Roma MG, Toledo FD, Boaglio AC, Basiglio CL, Crocenzi FA, Sánchez Pozzi EJ: Ursodeoxycholic acid in cholestasis: linking action mechanisms to therapeutic applications. Clin Sci. 2011, 121: 523-544. 10.1042/CS20110184.CrossRefPubMed
Metadata
Title
Clinical review: The liver in sepsis
Authors
Nicolas Nesseler
Yoann Launey
Caroline Aninat
Fabrice Morel
Yannick Mallédant
Philippe Seguin
Publication date
01-10-2012
Publisher
BioMed Central
Published in
Critical Care / Issue 5/2012
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc11381

Other articles of this Issue 5/2012

Critical Care 5/2012 Go to the issue

Research

Metformin overdose causes platelet mitochondrial dysfunction in humans

Letter

Potential for overuse of corticosteroids and vasopressin in septic shock

Research

The estimation of cardiac output by the Nexfin device is of poor reliability for tracking the effects of a fluid challenge

Research

Angiogenic factors and their soluble receptors predict organ dysfunction and mortality in post-cardiac arrest syndrome

Research

The relationship between serum sodium and intracranial pressure when using hypertonic saline to target mild hypernatremia in patients with head trauma

Erratum

Erratum to: Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study