Background/Aim: Liver size regulation is based on the balance between hepatic regeneration and atrophy. To achieve a better understanding of intrahepatic size regulation, we explored the size regulation of a portally deprived liver lobe on a liver subjected to concurrent portal vein ligation (PVL) and partial hepatectomy (PHx). Materials and Methods: Using a surgical rat model consisting of right PVL (rPVL) plus 70% PHx, we evaluated the size regulation of liver lobes 1, 2, 3, and 7 days after the operation in terms of liver weight and hepatocyte proliferation. Portal hyperperfusion was confirmed by measuring portal flow. The portal vascular tree was visualized by injection of a contrast agent followed by CT imaging of explanted livers. Control groups consisted of 70% PHx, rPVL, and sham operation. Results: The size of the ligated right lobe increased to 1.4-fold on postoperative day 7 when subjected to rPVL + 70% PHx. The right lobe increased to 3-fold when subjected to 70% PHx alone and decreased to 0.3-fold when subjected to rPVL only. The small but significant increase in liver weight after the combined procedure was accompanied by a low proliferative response. In contrast, hepatocyte proliferation was undetectable in the right lobe undergoing atrophy after PVL only. The caudate lobe in the rPVL + 70% PHx group increased to 4.6-fold, which is significantly more than in the other groups. This increase in liver weight was paralleled by persisting portal hyperperfusion and a prolonged proliferative phase of 3 days. Conclusions: A discontinued portal blood supply does not always result in atrophy of the ligated lobe. The concurrent regenerative stimulus induced by 70% PHx seemed to counteract the local atrophy after a simultaneously performed rPVL, leading to a low but prolonged regenerative response of the portally deprived liver lobe. This observation supports the conclusion that portal flow is not necessary for liver regeneration. The persisting portal hyperperfusion may be crucial for the specific kinetics of prolonged liver regeneration after rPVL + 70% PHx in the portally supplied caudate lobe. Both observations deserve more attention regarding the underlying mechanism in further studies.

Keywords:
Intrahepatic size regulation, Liver regeneration, Partial hepatectomy, Portal hyperperfusion, Right portal vein ligation
1.
Qiu J, Chen S, Pankaj P, Wu H: Portal vein arterialization as a bridge procedure against acute liver failure after extended hepatectomy for hilar cholangiocarcinoma. Surg Innov 2014;21:372-375.
2.
Rous P, Larimore LD: Relation of the portal blood to liver maintenance: a demonstration of liver atrophy conditional on compensation. J Exp Med 1920;31:609-632.
3.
Gock M, Eipel C, Linnebacher M, Klar E, Vollmar B: Impact of portal branch ligation on tissue regeneration, microcirculatory response and microarchitecture in portal blood-deprived and undeprived liver tissue. Microvasc Res 2011;81:274-280.
4.
Rozga J, Jeppsson B, Bengmark S: Portal branch ligation in the rat. Reevaluation of a model. Am J Pathol 1986;125:300-308.
5.
Schoen JM, Wang HH, Minuk GY, Lautt WW: Shear stress-induced nitric oxide release triggers the liver regeneration cascade. Nitric Oxide 2001;5:453-464.
6.
Hohmann N, Weiwei W, Dahmen U, Dirsch O, Deutsch A, Voss-Böhme A: How does a single cell know when the liver has reached its correct size? PLoS One 2014;9:e93207.
7.
Donati M, Stavrou GA, Oldhafer KJ: Current position of ALPPS in the surgical landscape of CRLM treatment proposals. World J Gastroenterol 2013;19:6548-6554.
8.
Dell RB, Holleran S, Ramakrishnan R: Sample size determination. ILAR J 2002;43:207-213.
9.
Madrahimov N, Dirsch O, Broelsch C, Dahmen U: Marginal hepatectomy in the rat: from anatomy to surgery. Ann Surg 2006;244:89-98.
10.
Wei W, Zhang T, Zafarnia S, Schenk A, Xie C, Kan C, Dirsch O, Settmacher U, Dahmen U: Establishment of a rat model: associating liver partition with portal vein ligation for staged hepatectomy. Surgery 2016;159:1299-1307.
11.
Homeyer A, Schenk A, Arlt J, Dahmen U, Dirsch O, Hahn HK: Fast and accurate identification of fat droplets in histological images. Comput Methods Programs Biomed 2015;121:59-65.
12.
Gremse F, Stärk M, Ehling J, Menzel JR, Lammers T, Kiessling F: Imalytics Preclinical: interactive analysis of biomedical volume data. Theranostics 2016;6:328-341.
13.
Mueller L, Grotelueschen R, Meyer J, Vashist YK, Abdulgawad A, Wilms C, Hillert C, Rogiers X, Broering DC: Sustained function in atrophying liver tissue after portal branch ligation in the rat. J Surg Res 2003;114:146-155.
14.
Furrer K, Tian Y, Pfammatter T, Jochum W, El Badry AM, Graf R, Clavien PA: Selective portal vein embolization and ligation trigger different regenerative responses in the rat liver. Hepatology 2008;47:1615-1623.
15.
Sato Y, Tsukada K, Hatakeyama K: Role of shear stress and immune responses in liver regeneration after a partial hepatectomy. Surg Today 1999;29:1-9.
16.
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.
17.
Abshagen K, Eipel C, Vollmar B: A critical appraisal of the hemodynamic signal driving liver regeneration. Langenbecks Arch Surg 2012;397:579-590.
18.
Michalopoulos GK: Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 2010;176:2-13.
19.
Fausto N, Campbell JS, Riehle KJ: Liver regeneration. Hepatology 2006;43:S45-S53.
20.
Sato Y, Koyama S, Tsukada K, Hatakeyama K: Acute portal hypertension reflecting shear stress as a trigger of liver regeneration following partial hepatectomy. Surg Today 1997;27:518-526.
21.
Li K, Qi X, Yang J, Gong J, Tan C, Xia Q, Long J, Wang Z: Losartan supports liver regrowth via distinct boost of portal vein pressure in rodents with 90% portal branch ligation. Dig Dis Sci 2013;58:2205-2211.
22.
Schleimer K, Stippel DL, Kasper HU, Tawadros S, Allwissner R, Gaudig C, Greiner T, Hölscher AH, Beckurts KT: Portal hyperperfusion causes disturbance of microcirculation and increased rate of hepatocellular apoptosis: investigations in heterotopic rat liver transplantation with portal vein arterialization. Transplant Proc 2006;38:725-729.
23.
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.
24.
Rocheleau B, Ethier C, Houle R, Huet PM, Bilodeau M: Hepatic artery buffer response following left portal vein ligation: its role in liver tissue homeostasis. Am J Physiol 1999;277:G1000-G1007.
25.
Ding X, Beier JI, Baldauf KJ, Jokinen JD, Zhong H, Arteel GE: Acute ethanol preexposure promotes liver regeneration after partial hepatectomy in mice by activating ALDH2. Am J Physiol Gastrointest Liver Physiol 2014;306:G37-G47.
26.
He Y, Long J, Zhong W, Fu Y, Li Y, Lin S: Sustained endoplasmic reticulum stress inhibits hepatocyte proliferation via downregulation of c-Met expression. Mol Cell Biochem 2014;389:151-158.
27.
Michalopoulos GK: Liver regeneration. J Cell Physiol 2007;213:286-300.
28.
Michalopoulos GK, DeFrances MC: Liver regeneration. Science 1997;276:60-66.
© 2016 S. Karger AG, Basel
2016
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.