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Predictors of liver cirrhosis and hepatocellular carcinoma among perioperative survivors of the Fontan operation
  1. Ryo Inuzuka1,
  2. Masaki Nii2,
  3. Kei Inai3,
  4. Eriko Shimada3,
  5. Tokuko Shinohara3,
  6. Tomomi Kogiso4,
  7. Hiroshi Ono5,
  8. Shin-ichi Otsuki6,
  9. Yoshihiko Kurita6,
  10. Atsuhito Takeda7,
  11. Keiichi Hirono8,
  12. Kota Takei9,
  13. Satoshi Yasukohchi9,
  14. Tadahiro Yoshikawa10,
  15. Yoshiyuki Furutani3,
  16. Tomohiro Shinozaki11,
  17. Yutaka Matsuyama12,
  18. Hideaki Senzaki13,
  19. Katsutoshi Tokushige4,
  20. Toshio Nakanishi3,14
  1. 1Department of Pediatrics, University of Tokyo, Tokyo, Japan
  2. 2Pediatric Cardiology, Shizuoka Children’s Hospital, Shizuoka, Japan
  3. 3Pediatric Cardiology and Adult Congenital Cardiology, Tokyo Women's Medical University, Tokyo, Japan
  4. 4Department of Medicine, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
  5. 5Department of Cardiology, National Center for Child Health and Development, Tokyo, Japan
  6. 6Department of Pediatrics, Okayama University, Okayama, Japan
  7. 7Department of Pediatrics, Hokkaido University, Sapporo, Japan
  8. 8Department of Pediatrics, University of Toyama, Toyama, Japan
  9. 9Pediatric Cardiology, Nagano Children's Hospital, Nagano, Japan
  10. 10Pediatric Cardiology, Sakakibara Heart Institute, Fuchu, Japan
  11. 11Department of Information and Computer Technology, Faculty of Engineering, Tokyo University, Tokyo, Japan
  12. 12Department of Biostatistics, School of Public Health, University of Tokyo, Tokyo, Japan
  13. 13Comprehensive Support Center for Children's Happy Life and Future, Nihon Institute of Medical Science University, Moroyama-cho, Iruma-gun, Saitama, Japan
  14. 14Sakakibara Heart Institute Clinic, Shinjuku-ku, Japan
  1. Correspondence to Dr Toshio Nakanishi, Pediatric Cardiology, Tokyo Women's Medical University, Shinjuku-ku 162-8666, Japan; pnakanis{at}


Objective Fontan-associated liver disease (FALD) is widely recognised as a common complication in patients long after the Fontan operation. However, data on the predictors of FALD that can guide its screening and management are lacking. The present study aimed to identify the predictors of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in post-Fontan patients.

Methods This was a multi-institutional retrospective cohort study. Clinical data of all perioperative survivors of Fontan operation before 2011 who underwent postoperative catheterisation were collected through a retrospective chart review.

Results A total of 1117 patients (538 women, 48.2%) underwent their first Fontan operation at a median age of 3.4 years. Postoperative cardiac catheterisation was conducted at a median of 1.0 year. During a median follow-up period of 10.3 years, 67 patients (6.0%) died; 181 (16.2%) were diagnosed with liver fibrosis, 67 (6.0%) with LC, 54 (4.8%) with focal nodular hyperplasia and 7 (0.6%) with HCC. On multivariable analysis, high central venous pressure (CVP) (HR, 1.28 (95% CI 1.01 to 1.63) per 3 mm Hg; p=0.042) and severe atrioventricular valve regurgitation (HR, 6.02 (95% CI 1.53 to 23.77); p=0.010) at the postoperative catheterisation were identified as independent predictors of LC/HCC.

Conclusions Patients with high CVP and/or severe atrioventricular valve regurgitation approximately 1 year after the Fontan operation are at increased risk of developing advanced liver disease in the long term. Whether therapeutic interventions to reduce CVP and atrioventricular valve regurgitation decrease the incidence of advanced liver disease requires further elucidation.

  • outcome assessment, health care
  • heart defects, congenital
  • fontan procedure
  • risk factors
  • cardiac catheterization

Data availability statement

Data are available upon reasonable request.

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  • RI and MN contributed equally.

  • Correction notice This article has been corrected since it was first published to amend a typographical error in affiliation 13.

  • Contributors RI, MN and TN participated in study concept and design. KI, ES, TShinoh, HO, SO, YK, AT, KH, KTa, SY, TY, TK, KTo, YF and TN were involved in data collection and participated in the data analysis. RI, TShinoz and YM performed the data analysis and statistical analysis. HS contributed to data interpretation and critical revision of the manuscript. RI and MN drafted the manuscript. TN is the corresponding author. All authors read and approved the final manuscript. TN is responsible for the overall content of the study as guarantor.

  • Funding This study was conducted as a programme of the Japan Agency for Medical Research and Development. This research was supported by AMED (grant number: JP16ek0109146) and the MHLW Health and Labour Sciences Research Grants for Research on Intractable Diseases Program (grant number: JPMH15FC122).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.