Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Nov 18, 2017; 9(32): 1227-1238
Published online Nov 18, 2017. doi: 10.4254/wjh.v9.i32.1227
Liver atrophy after percutaneous transhepatic portal embolization occurs in two histological phases: Hepatocellular atrophy followed by apoptosis
Yasuhito Iwao, Hidenori Ojima, Tatsushi Kobayashi, Yoji Kishi, Satoshi Nara, Minoru Esaki, Kazuaki Shimada, Nobuyoshi Hiraoka, Minoru Tanabe, Yae Kanai
Yasuhito Iwao, Hidenori Ojima, Nobuyoshi Hiraoka, Yae Kanai, Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
Yasuhito Iwao, Yoji Kishi, Satoshi Nara, Minoru Esaki, Kazuaki Shimada, Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo 104-0045, Japan
Yasuhito Iwao, Minoru Tanabe, Hepatobiliary and Pancreatic Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Hidenori Ojima, Yae Kanai, Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
Tatsushi Kobayashi, Diagnostic Radiology Division, National Cancer Center Hospital East, Chiba 277-8577, Japan
Author contributions: Iwao Y and Ojima H performed the experiments, analyzed the data and wrote the paper; Kobayashi T obtained the pig specimens; Kishi Y, Nara S, Esaki M and Shimada K obtained the human surgical liver specimens and determined the clinical data; Hiraoka N, Tanabe M and Kanai Y coordinated the research.
Supported by National Cancer Center Research and Development Fund (23-A-35).
Institutional review board statement: All patients gave written informed consent for inclusion in this study (2007-022).
Institutional animal care and use committee statement: All animal experiment protocols were approved by the Committee for Ethics in Animal Experimentation and were conducted in accordance with the Guidelines for Animal Experiments of our institution (K03-004).
Conflict-of-interest statement: The authors have no conflict of interest to disclose.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hidenori Ojima, MD, PhD, Division of Molecular Pathology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. hojima@ncc.go.jp
Telephone: +81-3-53633764 Fax: +81-3-3353-3290
Received: August 7, 2017
Peer-review started: August 7, 2017
First decision: September 13, 2017
Revised: October 9, 2017
Accepted: October 30, 2017
Article in press: October 30, 2017
Published online: November 18, 2017
Processing time: 101 Days and 0 Hours
Abstract
AIM

To clarify the histological changes associated with liver atrophy after percutaneous transhepatic portal embolization (PTPE) in pigs and humans.

METHODS

As a preliminary study, we performed pathological examinations of liver specimens from five pigs that had undergone PTPE in a time-dependent model of liver atrophy. In specimens from embolized lobes (EMB) and nonembolized lobes (controls), we measured the portal vein to central vein distance (PV-CV), the area and number of hepatocytes per lobule, and apoptotic activity using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Immunohistochemical reactivities were evaluated for light chain 3 (LC3) and lysosomal-associated membrane protein 2 (LAMP2) as autophagy markers and for glutamine synthetase and cytochrome P450 2E1 (CYP2E1) as metabolic zonation markers. Samples from ten human livers taken 20-36 d after PTPE were similarly examined.

RESULTS

PV-CVs and lobule areas did not differ between EMB and controls at day 0, but were lower in EMB than in controls at weeks 2, 4, and 6 (P ≤ 0.001). Hepatocyte numbers were not significantly reduced in EMB at day 0 and week 2 but were reduced at weeks 4 and 6 (P ≤ 0.05). Apoptotic activity was higher in EMB than in controls at day 0 and week 4. LC3 and LAMP2 staining peaked in EMB at week 2, with no significant difference between EMB and controls at weeks 4 and 6. Glutamine synthetase and CYP2E1 zonation in EMB at weeks 2, 4, and 6 were narrower than those in controls. Human results were consistent with those of porcine specimens.

CONCLUSION

The mechanism of liver atrophy after PTPE has two histological phases: Hepatocellular atrophy is likely caused by autophagy in the first 2 wk and apoptosis thereafter.

Keywords: Liver atrophy; Portal vein embolization; Autophagy; Apoptosis; Zonation; Lobule

Core tip: Liver atrophy after percutaneous transhepatic portal embolization (PTPE) in time-independent human studies is associated with hepatocyte shrinkage and apoptosis. In this preliminary study, we performed pathological examinations of liver specimens from five pigs that had undergone PTPE in a time-dependent model of liver atrophy. Two distinct phases of liver atrophy were identified: A hepatocellular atrophic phase, which may relate to autophagy, and an apoptotic phase. Despite liver atrophy appearing to be mostly resolved 2 wk after embolization, the period after PTPE could beneficially be extended to 4 wk to ensure contralateral hypertrophy and to allow the completion of liver atrophy.