Cellular and Molecular Mechanisms in Perioperative Hepatic Protection: A Review of Current Interventions

Zahra Talebi, Hassan Peyvandi, َAli Dabbagh



Liver is one of the most important organs needing great concern during the perioperative period. There are a number of different mechanisms that interact with liver cells and might affect their integrity and cell live. Though these mechanisms are not all the same, there is a great common point: all affect the metabolic pathways of the liver. Ischemia, anesthetic drug effects and other perioperative insults may affect the liver. Disturbance in an organ’s blood flow is an inherent part of diverse surgical procedures, which leads to lack of oxygen and nutrient supply. These ischemic periods can be particularly long in case of liver surgeries, such as resection of large hepatic tumors, management of hepatic trauma and liver transplant. Once the blood flow and oxygen supply are restored, the interruption of blood flow affects the oxygen dependent cells in liver, which require mitochondrial oxidative phosphorylation for their metabolism. Molecular mechanisms such as Redox status, ionic interchange disturbances as well as different mediators and cells like KC, SEC, dendritic cells, leukocytes, and lymphocytes, are involved in the process ultimately leading to cell death by apoptosis and necrosis. This review provides an overview on the cellular and molecular mechanisms involved in liver injuries, categorizing these mechanisms in 3 different classes: preoperative mechanisms, intraoperative mechanisms and postoperative mechanisms. Each of them are discussed in a different part of the manuscript


Cellular and Molecular Mechanisms, Perioperative Hepatic Protection, Redox status, ionic interchange,KC, SEC, dendritic cells, leukocytes, lymphocytes

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Montalvo-Jave EE, Escalante-Tattersfield T, Ortega-Salgado JA, Piña E, Geller DA. Factors in the pathophysiology of the liver ischemia-reperfusion injury. J Surg Res. 2008;147(1):153–9.

Weigand K, Brost S, Steinebrunner N, Büchler M, Schemmer P, Müller M. Ischemia/Reperfusion injury in liver surgery and transplantation: pathophysiology. HPB Surg. 2012;2012.

Hide D, Ortega-Ribera M, Garcia-Pagan J-C, Peralta C, Bosch J, Gracia-Sancho J. Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy. Sci Rep. 2016;6.

Pine JK, Aldouri A, Young AL, Davies MH, Attia M, Toogood GJ, et al. Liver transplantation following donation after cardiac death: an analysis using matched pairs. Liver Transplant. 2009;15(9):1072–82.

Nastos C, Kalimeris K, Papoutsidakis N, Tasoulis M-K, Lykoudis PM, Theodoraki K, et al. Global consequences of liver ischemia/reperfusion injury. Oxid Med Cell Longev. 2014;2014.

Jarrar D, Chaudry IH, Wang P. Organ dysfunction following hemorrhage and sepsis: mechanisms and therapeutic approaches (Review). Int J Mol Med. 1999;4(6):575–83.

Beck C, Schwartges I, Picker O. Perioperative liver protection. Curr Opin Crit Care. 2010;16(2):142–7.

Picker O, Beck C, Pannen B. Liver protection in the perioperative setting. Best Pract Res Clin Anaesthesiol. 2008;22(1):209–24.

O’Glasser AY, Haranath SP, Enestvedt BK. Perioperative management of the patient with liver disease. WebMD emedicine. 2009;

Derosa G, Maffioli P. GLP-1 agonists exenatide and liraglutide: A review about their safety and efficacy. Curr Clin Pharmacol [Internet]. 2012;7(3):214–28. Available from: https://www.scopus.com/inward/record.uri?eid=2-s2.0-84862125514&partnerID=40&md5=59ab7934a558a2f20a212a78f6f8baaa

Estol CJ, Faris AA, Martinez AJ, Ahdab-Barmada M. Central pontine myelinolysis after liver transplantation. Neurology. 1989;39(4):493.

van Ginhoven TM, Mitchell JR, Verweij M, Hoeijmakers JHJ, IJzermans JNM, de Bruin RWF. The use of preoperative nutritional interventions to protect against hepatic ischemia‐reperfusion injury. Liver Transplant. 2009;15(10):1183–91.

Hanje AJ, Patel T. Preoperative evaluation of patients with liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4(5):266–76.

Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end‐stage liver disease. Hepatology. 2001;33(2):464–70.

Chalasani N, Kahi C, Francois F, Pinto A, Marathe A, Bini EJ, et al. Model for end‐stage liver disease (MELD) for predicting mortality in patients with acute variceal bleeding. Hepatology. 2002;35(5):1282–4.

Sheth M, Riggs M, Patel T. Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis of patients with alcoholic hepatitis. BMC Gastroenterol. 2002;2(1):1.

Vergani D, Mieli-Vergani G, Alberti A, Neuberger J, Eddleston ALWF, Davis M, et al. Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis. N Engl J Med. 1980;303(2):66–71.

Farrell G, Prendergast D, Murray M. Halothane hepatitis: detection of a constitutional susceptibility factor. N Engl J Med. 1985;313(21):1310–4.

Safari S, Motavaf M, Siamdoust SAS, Alavian SM. Hepatotoxicity of halogenated inhalational anesthetics. Iran Red Crescent Med J. 2014;16(9).

Christ DD, Kenna JG, Kammerer W, Satoh H, Pohl LR. Enflurane metabolism produces covalently bound liver adducts recognized by antibodies from patients with halothane hepatitis. Anesthesiology. 1988;69(6):833–8.

Gil F, Fiserova-Bergerova V, Altman NH. Hepatic protection from chemical injury by isoflurane. Anesth Analg. 1988;67(9):860–7.

Anderson JS, Rose NR, Martin JL, Eger EI, Njoku DB. Desflurane hepatitis associated with hapten and autoantigen-specific IgG4 antibodies. Anesth Analg. 2007;104(6):1452.

Eydi M, Golzari SEJ, Aghamohammadi D, Kolahdouzan K, Safari S, Ostadi Z. Postoperative Management of Shivering: A Comparison of Pethidine vs. Ketamine. Anesthesiol pain Med. 2014;4(2).

Hajiesmaeili MR, Motavaf M, Safari S. Regional analgesia in intensive care unit. Anesthesiol pain Med. 2013;3(2):263–5.

Mohseni M, Safari S, Alavian SM. Volatile anesthetics in ischemic liver injury: enemy or friend? Hepat Mon. 2014;14(6).

Dabbagh A, Rajaei S. Xenon: a solution for anesthesia in liver disease? Hepat Mon. 2012;12(11).

Richardson AJ, Laurence JM, Lam VWT. Portal triad clamping versus other methods of vascular control in liver resection: a systematic review and meta‐analysis. HPB. 2012;14(6):355–64.

Petrowsky H, McCormack L, Trujillo M, Selzner M, Jochum W, Clavien P-A. A prospective, randomized, controlled trial comparing intermittent portal triad clamping versus ischemic preconditioning with continuous clamping for major liver resection. Ann Surg. 2006;244(6):921–30.

Pandey CK, Nath SS, Pandey VK, Karna ST, Tandon M. Perioperative ischaemia-induced liver injury and protection strategies: An expanding horizon for anaesthesiologists. Indian J Anaesth. 2013;57(3):223.

Meier-Hellmann A, Reinhart K, Bredle DL, Specht M, Spies CD, Hannemann L. Epinephrine impairs splanchnic perfusion in septic shock. Crit Care Med. 1997;25(3):399–404.

Raddatz A, Kubulus D, Winning J, Bauer I, Pradarutti S, Wolf B, et al. Dobutamine improves liver function after hemorrhagic shock through induction of heme oxygenase-1. Am J Respir Crit Care Med. 2006;174(2):198–207.

Fink T, Heymann P, Taha-Melitz S, Taha A, Wolf B, Rensing H, et al. Dobutamine pretreatment improves survival, liver function, and hepatic microcirculation after polymicrobial sepsis in rat. Shock. 2013;40(2):129–35.

Sand Bown L, Ricksten S, Houltz E, Einarsson H, Söndergaard S, Rizell M, et al. Vasopressin‐induced changes in splanchnic blood flow and hepatic and portal venous pressures in liver resection. Acta Anaesthesiol Scand. 2016;

Tse I, Zhao H-L, Ma D-Q. Organoprotective effects of Dexmedetomidine: from bench to bedside. J Perioper Sci. 2014;1(3):1–15.

Iguchi K, Hatano E, Yamanaka K, Sato M, Yamamoto G, Kasai Y, et al. Hepatoprotective effect by pretreatment with olprinone in a swine partial hepatectomy model. Liver Transplant. 2014;20(7):838–49.

Genovés P, García D, Cejalvo D, Martin A, Zaragoza C, Toledo AH, et al. Pentoxifylline in liver ischemia and reperfusion. J Investig Surg. 2014;27(2):114–24.

Werner I, Brunner S, Meybohm P, Moritz A, Stock UA, Beiras-Fernandez A. Levosimendan Protect Human Hepatocytes from Ischemia/Reperfusion Injury: A Second Benefit for Patients with Acute Heart Failure? Thorac Cardiovasc Surg. 2015;63(S 01):ePP93.

Alvarez J, Baluja A, Selas S, Otero P, Rial M, Veiras S, et al. A comparison of dobutamine and levosimendan on hepatic blood flow in patients with a low cardiac output state after cardiac surgery: a randomised controlled study. Anaesth Intensive Care. 2013;41(6):719.

Grossini E, Pollesello P, Bellofatto K, Sigaudo L, Farruggio S, Origlia V, et al. Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats. Liver Transplant. 2014;20(3):361–75.

Onody P, Stangl R, Fulop A, Rosero O, Garbaisz D, Turoczi Z, et al. Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury? PLoS One. 2013;8(9):e73758.

Guan L-Y, Fu P-Y, Li P-D, Li Z-N, Liu H-Y, Xin M-G, et al. Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide. World J Gastrointest Surg. 2014;6(7):122–8.

Li H, Cen Y, Zhang Z. [Doxorubicin preconditioning instead of ischemic preconditioning in providing ischemic tolerance for rats abdomen island flaps]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi [Internet]. 2012;26(12):1501–4. Available from: http://europepmc.org/abstract/MED/23316646

Dabbagh A, Rajaei S. The role of anesthetic drugs in liver apoptosis. Hepat Mon. 2013;13(8).

Kaplan N, Yagmurdur H, Kilinc K, Baltaci B, Tezel S. The protective effects of intravenous anesthetics and verapamil in gut ischemia/reperfusion-induced liver injury. Anesth Analg. 2007;105(5):1371–8.

Ajamieh H, Merino N, Candelario-Jalil E, Menéndez S, Martinez-Sanchez G, Re L, et al. Similar protective effect of ischaemic and ozone oxidative preconditionings in liver ischaemia/reperfusion injury. Pharmacol Res. 2002;45(4):333–9.

Yang L-Q, Tao K-M, Liu Y-T, Cheung C-W, Irwin MG, Wong GTC, et al. Remifentanil preconditioning reduces hepatic ischemia-reperfusion injury in rats via inducible nitric oxide synthase expression. Anesthesiology. 2011 May;114(5):1036–47.

Bressan AK, Roberts DJ, Bhatti SU, Dixon E, Sutherland FR, Bathe OF, et al. Preoperative single-dose methylprednisolone versus placebo after major liver resection in adults: protocol for a randomised controlled trial. BMJ Open. 2015;5(10):e008948.

Akhtar MZ, Henderson T, Sutherland A, Vogel T, Friend PJ. Novel approaches to preventing ischemia-reperfusion injury during liver transplantation. In: Transplantation proceedings. Elsevier; 2013. p. 2083–92.

Pedemonte JC, Vargas R, Castillo V, Hodali T, Gutiérrez S, Tapia G, et al. A combined iron and thyroid hormone protocol suppresses ischemia–reperfusion injury in rat livers. RSC Adv. 2015;5(33):26209–17.

McKay A, Cassidy D, Sutherland F, Dixon E. Clinical results of N‐acetylcysteine after major hepatic surgery: a review. J Hepatobiliary Pancreat Surg. 2008;15(5):473–8.

Sarin S, Kaman L, Dahiya D, Behera A, Medhi B, Chawla Y. Effects of preoperative statin on liver reperfusion injury in major hepatic resection: a pilot study. Updates Surg. 2016;1–7.

Khonakdar-Tarsi A, Ghanaat K. Melatonin Protective Effects against Liver Ischemia/Reperfusion Injury. Res Mol Med. 2016;4(1):5–17.

Younis NN, Shaheen MA, Mahmoud MF. Silymarin preconditioning protected insulin resistant rats from liver ischemia-reperfusion injury: role of endogenous H 2 S. J Surg Res. 2016;

Farmer WD, Silverman DG. Potential effects of herbal medicinals on perioperative care. In: Seminars in Anesthesia, Perioperative Medicine and Pain. WB Saunders; 2001. p. 110–7.

Jaeschke H, Woolbright BL. Current strategies to minimize hepatic ischemia–reperfusion injury by targeting reactive oxygen species. Transplant Rev. 2012;26(2):103–14.

Fouad AA, Jresat I. Therapeutic potential of cannabidiol against ischemia/reperfusion liver injury in rats. Eur J Pharmacol. 2011;670(1):216–23.

Tao T, Chen F, Bo L, Xie Q, Yi W, Zou Y, et al. Ginsenoside Rg1 protects mouse liver against ischemia–reperfusion injury through anti-inflammatory and anti-apoptosis properties. J Surg Res. 2014;191(1):231–8.

Lee SC, Kim K, Kim O, Lee SK, Kim S. Activation of Autophagy by Everolimus Confers Hepatoprotection Against Ischemia–Reperfusion Injury. Am J Transplant. 2016;

Friedman LS. Surgery in the Patient with Liver Disease. Trans Am Clin Climatol Assoc [Internet]. 2010;121:192–205. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917124/

Thasler W, Bein T, Jauch K-W. Perioperative effects of hepatic resection surgery on hemodynamics, pulmonary fluid balance, and indocyanine green clearance. Langenbeck’s Arch Surg. 2002;387(7–8):271–5.

Beaussier M. The Anesthesiologist’s Expanding Role in Perioperative Liver Protection. J Am Soc Anesthesiol. 2011;114(5):1014–5.

DOI: https://doi.org/10.22037/jcma.v2i2.14839


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