Background: The hepatic volume gain following resection is essential for clinical recovery. Previous studies have focused on cellular regeneration. This study aims to explore the rate of hepatic regeneration of the porcine liver following major resection, highlighting estimates of the early microarchitectural changes that occur during the cellular regeneration. Methods: Nineteen large white pigs had 75% resection with serial measurements of the hepatic volume, density, blood flow, and architectural changes. Results: The growth rate initially was 45% per day, then rapidly decreased and was accompanied by a similar pattern of hepatic fat deposition. The architectural changes showed a significant increase in the Ki67 expression (p < 0.0001) in the days following resection with a peak on the 2nd day and nearly normalized on day 7. The expression of CD31 increased significantly on the 2nd and 3rd days compared to the pre-resection samples (p = 0.03). Hepatic artery flow per liver volume remained at baseline ranges during regeneration. Portal flow per liver volume increased after liver resection (p < 0.001), was still elevated on the 1st postoperative day, then decreased. Correlations were significantly negative between the hepatic volume increase on day 3 and the hepatic oxygen consumption and the net lactate production at the end of the procedure (r = –0.82, p = 0.01, and r = –0.70, p = 0.03). Conclusion: The volume increase in the first days – a fast process – is not explained by cellular proliferation alone. The liver/body weight ratio is back to 50% of the preoperative value after 3 days to close to 100% volume regain on days 10–15.

Kishi Y, Abdalla EK, Chun YS, Zorzi D, Madoff DC, Wallace MJ, et al: Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg 2009; 250: 540–548.
Ding B-S, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, et al: Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 2010; 468: 310–315.
Niiya T, Murakami M, Aoki T, Murai N, Shimizu Y, Kusano M: Immediate increase of portal pressure, reflecting sinusoidal shear stress, induced liver regeneration after partial hepatectomy. J Hepatobiliary Pancreat Surg 1999; 6: 275–280.
Ninomiya M, Shirabe K, Terashi T, Ijichi H, Yonemura Y, Harada N, et al: Deceleration of regenerative response improves the outcome of rat with massive hepatectomy. Am J Transplant 2010; 10: 1580–1587.
Lin X-J, Yang J, Chen X-B, Zhang M, Xu M-Q: The critical value of remnant liver volume-to-body weight ratio to estimate posthepatectomy liver failure in cirrhotic patients. J Surg Res 2014; 188: 489–495.
Abulkhir A, Limongelli P, Healey AJ, Damrah O, Tait P, Jackson J, et al: Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg 2008; 247: 49–57.
Sparrelid E, Jonas E, Tzortzakakis A, Dahlén U, Murquist G, Brismar T, et al: Dynamic Evaluation of Liver Volume and Function in Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy. J Gastrointest Surg 2017; 21: 967–974.
Bekheit M, Bucur PO, Wartenberg M, Vibert E: Computerized tomography-based anatomic description of the porcine liver. J Surg Res 2017; 210: 223—230.
Bucur P, Bekheit M, Audebert C, Vignon-Clementel I, Vibert E: Simplified technique for 75% and 90% hepatic resection with hemodynamic monitoring in a large white swine model. J Surg Res 2016; 209: 122–130.
Iida T, Yagi S, Taniguchi K, Hori T, Uemoto S: Improvement of morphological changes after 70% hepatectomy with portocaval shunt: preclinical study in porcine model. J Surg Res 2007; 143: 238–246.
Bucur PO, Bekheit M, Audebert C, Othman A, Hammad S, Sebagh M, et al: Modulating Portal Hemodynamics With Vascular Ring Allows Efficient Regeneration After Partial Hepatectomy in a Porcine Model. Ann Surg 2018; 268: 134–142.
Court FG, Wemyss-Holden SA, Morrison CP, Teague BD, Laws PE, Kew J, et al: Segmental nature of the porcine liver and its potential as a model for experimental partial hepatectomy. Br J Surg 2003; 90: 440–444.
Hammad S, Hoehme S, Friebel A, von Recklinghausen I, Othman A, Begher-Tibbe B, et al: Protocols for staining of bile canalicular and sinusoidal networks of human, mouse and pig livers, three-dimensional reconstruction and quantification of tissue microarchitecture by image processing and analysis. Arch Toxicol 2014; 88: 1161–1183.
Wang D, Stockard CR, Harkins L, Lott P, Salih C, Yuan K, et al: Immunohistochemistry in the evaluation of neovascularization in tumor xenografts. Biotech Histochem 2008; 83: 179–189.
Demetris AJ, Kelly DM, Eghtesad B, Fontes P, Wallis Marsh J, Tom K, et al: Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am J Surg Pathol 2006; 30: 986–993.
Bekheit M, Bucur P, Vibert E, Andres C, others: The reference values for hepatic oxygen consumption and net lactate production, blood gasses, hemogram, major electrolytes, and kidney and liver profiles in anesthetized large white swine model. Transl Surg 2016; 1: 95–100.
Monolix version 2016R1. Antony, Lixoft SAS, 2016.
Kuhn E, Lavielle M: Maximum likelihood estimation in nonlinear mixed effects models. Comput Stat Data Anal Elsevier 2005; 49: 1020–1038.
Liska V, Treska V, Mirka H, Benes J, Vycital O, Bruha J, et al: Immediately preoperative use of biological therapy does not influence liver regeneration after large resection-porcine experimental model with monoclonal antibody against epidermal growth factor. In Vivo 2012; 26: 683–691.
Ding B-S, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, et al: Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 2014; 505: 97–102.
Audebert C, Bekheit M, Bucur P, Vibert E, Vignon-Clementel IE: Partial hepatectomy hemodynamics changes: experimental data explained by closed-loop lumped modeling. J Biomech 2017; 50: 202–208.
Lauber DT, Tihanyi DK, Czigány Z, Kovács T, Budai A, Drozgyik D, et al: Liver regeneration after different degrees of portal vein ligation. J Surg Res 2016; 203: 451–458.
Stolz DB, Ross MA, Ikeda A, Tomiyama K, Kaizu T, Geller DA, et al: Sinusoidal endothelial cell repopulation following ischemia/reperfusion injury in rat liver transplantation. Hepatology 2007; 46: 1464–1475.
Sato T, El-Assal ON, Ono T, Yamanoi A, Dhar DK, Nagasue N: Sinusoidal endothelial cell proliferation and expression of angiopoietin/Tie family in regenerating rat liver. J Hepatol 2001; 34: 690–698.
Morales-Navarrete H, Segovia-Miranda F, Klukowski P, Meyer K, Nonaka H, Marsico G, et al: A versatile pipeline for the multi-scale digital reconstruction and quantitative analysis of 3D tissue architecture. eLife 2015; 4:e11214.
Lautt WW: Regulatory processes interacting to maintain hepatic blood flow constancy: vascular compliance, hepatic arterial buffer response, hepatorenal reflex, liver regeneration, escape from vasoconstriction. Hepatol Res 2007; 37: 891–903.
Asencio JM, García-Sabrido JL, López-Baena JA, Olmedilla L, Peligros I, Lozano P, et al: Preconditioning by portal vein embolization modulates hepatic hemodynamics and improves liver function in pigs with extended hepatectomy. Surgery 2017; 161: 1489–1501.
Brasaemle DL: Cell biology. A metabolic push to proliferate. Science 2006; 313: 1581–1582.
Thevananther S: Adipose to the rescue: peripheral fat fuels liver regeneration. Hepatology 2010; 52: 1875–1876.
Tani K, Shindoh J, Takamoto T, Shibahara J, Nishioka Y, Hashimoto T, et al: Kinetic changes in liver parenchyma after preoperative chemotherapy for patients with colorectal liver metastases. J Gastrointest Surg 2017; 21: 813–821.
Zou Y, Bao Q, Kumar S, Hu M, Wang G-Y, Dai G: Four waves of hepatocyte proliferation linked with three waves of hepatic fat accumulation during partial hepatectomy-induced liver regeneration. PLoS One 2012; 7:e30675.
Ulicná O, Istvánová B, Valachová A, Brixová E: Oxidative phosphorylation in liver mitochondria after injury with carbon tetrachloride and during regeneration. Bratisl Lek Listy 1994; 95: 402–407.
Vibert E, Boleslawski E, Cosse C, Adam R, Castaing D, Cherqui D, et al: Arterial lactate concentration at the end of an elective hepatectomy is an early predictor of the postoperative course and a potential surrogate of intraoperative events. Ann Surg 2015; 262: 787–793.
Ozdogan M, Ersoy E, Dundar K, Albayrak L, Devay S, Gundogdu H: Beneficial effect of hyperbaric oxygenation on liver regeneration in cirrhosis. J Surg Res 2005; 129: 260–264.
Donadon M, Molinari AF, Corazzi F, Rocchi L, Zito P, Cimino M, et al: Pharmacological modulation of ischemic-reperfusion injury during Pringle maneuver in hepatic surgery. A prospective randomized pilot study. World J Surg 2016; 40: 2202–2212.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.