Liver Transplantation and Hepatobiliary Surgery Interplay of Technical and Theoretical Aspects - 2020 PDF

Updates in Surgery
Umberto Cillo
Luciano De Carlis Editors
Liver Transplantation
and Hepatobiliary
Surgery
Interplay of Technical
and Theoretical Aspects
Updates in Surgery
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More information about this series at http://www.springer.com/series/8147

Umberto Cillo • Luciano De Carlis
Editors
Liver Transplantation and

Hepatobiliary Surgery
Interplay of Technical and Theoretical
Aspects
Foreword by Paolo De Paolis

Editors
Umberto Cillo Luciano De Carlis
Department of Surgery, Oncology Department of General Surgery
and Gastroenterology and Transplantation
University of Padua Niguarda Hospital
Hepatobiliary Surgery and School of Medicine and Surgery
Liver Transplant Unit University of Milano-Bicocca
Padua University Hospital Milan
Padua Italy
Italy
The publication and the distribution of this volume have been supported by the Italian
Society of Surgery
ISSN 2280-9848 ISSN 2281-0854 (electronic)

Updates in Surgery
ISBN 978-3-030-19761-2 ISBN 978-3-030-19762-9 (eBook)
https://doi.org/10.1007/978-3-030-19762-9
© Springer Nature Switzerland AG 2020

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Foreword
It’s really a pleasure for me to introduce this important work by Umberto Cillo,
Luciano De Carlis, and coworkers, focusing on the interplay of technical and theo-
retical aspects of liver transplantation and hepatobiliary surgery.
Umberto and Luciano, leaders of the Italian surgical school and community,
engaged distinguished experts in the field; the significant experience and scientific
excellence of the contributors have produced a high-quality monograph.
This volume highlights all the important aspects of liver transplantation and hep-
atobiliary surgery, providing updates on hot topics in this area and regarding new
techniques, not only related to surgery but also to liver and graft preservation from
ischemic injury, and parenchymal regeneration. Many chapters describe the split
liver technique, in its various forms, but always highlighting the deep interplay
between transplant surgery and hepatobiliary surgery.
Particular attention is paid to young surgeons trained in a setting of liver and split
liver transplantation; they’ll certainly acquire relevant expertise to proceed in their
learning path toward more complex liver resection procedures.
The high scientific level and the updating of the techniques make this volume
valuable for the experienced surgeon and helpful for the less experienced surgeon,
in order to understand the evolution of surgery in this field.
On behalf of the Italian Society of Surgery, I’d like to thank all the eminent
authors who collaborated in producing this useful monograph.
Turin, Italy
Paolo De Paolis
September 2019 President
Italian Society of Surgery
v
Preface
The pages of this book are dedicated to all those young surgeons or experienced
specialists who believe that surgery is a complex patchwork of different mental
engrams originating from our multiform previous experiences, from our wide mul-
tidisciplinary knowledge, from the small details “captured” in the observations of
others, from the psychologic attitude to approach difficulties, attitude that we derive
from our personal character, strength, background, and history.
The Niguarda Hepatobiliary and Transplant Unit and the Padua Hepatobiliary
and Liver Transplant Center have developed from a similar surgical matrix and his-
tory. In Padua a great tradition of general surgery descending from Ceccarelli and
Cevese prompted Davide D’Amico to decide to embark on the liver transplantation
enterprise. Belli in Milan put his extraordinary general surgery knowledge in the
hands of young surgeons who, after attending the Galmarini and Fassati liver trans-
plant experience, built the current Niguarda program.
Vittorio Staudacher represented a relevant liaison between our two realities.
After graduating at the University of Padua in 1938, he developed there his first
studies on lung and liver transplantation before following Guido Oselladore to
Milan in 1950. He has been recently acknowledged in the American Journal of
Transplantation (2012) as the first surgeon to report on an experimental orthotopic
liver transplant in Western history in 1952.
In both our experiences at Niguarda and in Padua, transplant techniques remained
deeply anchored to the concepts of general surgery, fully contaminated by the pro-
cedures of vascular and oncologic surgery, of massive organ debulking and abdomi-
nal reconstructive surgery typical of the 1970s and 1980s. In those years,
hepatobiliary resective surgery, starting from few embryonic procedures, became
increasingly practiced in our settings. Our frequent travels abroad (in the pre video-
exchange era) allowed us to be deeply contaminated by the refined French, Japanese,
and Korean liver transection techniques, which were (already at that time) totally
devoted to the concepts of strict anatomical research of surgical planes and to the
biodynamic study of the hepatic parenchyma in normal and diseased conditions.
The Niguarda and Padua Centers were among the very first to be involved in the
extraordinary experience represented by the Italian split liver program in the context
of the North Italy Transplant program (NITp), where ourselves and all our young
surgeons had the extraordinary chance to be exposed to a complex resective surgery
in the absence of preoperative anatomical planning.
vii
viii Preface
Both centers were also the first in Italy to perform living donor-related liver
transplantations, in a pediatric case in Padua in 1996 and in an adult case at Niguarda
immediately after.
The advent of minimally invasive surgery from the 1990s onward was again
among the areas of interest our two centers embraced early on, first in general sur-
gery operations and then in the more complex videolaparoscopic and robotic liver
resections. As a result, since the early 2000s surgical activities both in Niguarda and
in Padua have been widely “blended,” including liver transplant as well as high
volumes of open and minimally invasive hepatobiliary intervention mostly, but not
exclusively, oriented to the oncologic area.
All these polyhedral surgical experiences have been crucial in developing an
extremely flexible technical attitude enabling us to proceed in transplantation and
hepatobiliary surgery with a myriad of overlapping concepts and practices.
The extensive overlap between these two (only initially distant) surgical worlds
is the topic of the following pages.
Close to 70 years after the first described hepatic lobectomy by Lortat-Jacob in
1952, the continuous and rapid evolution of the surgical technique has improved the
hemostatic control of the resected liver surface, and innovative methods of parenchy-
mal dissection have allowed an enormous expansion of the number of indications and
candidates. In the beginning, liver resection and liver transplantation were performed
by different surgical teams with poor interplay with each other. However, the evolution
of both liver resection and transplantation toward a more complex operation called for
increasingly intense interaction between these surgical techniques. Therefore, split
liver and living donor liver transplantation became popular in the transplant commu-
nity that utilized the Couinaud segmental anatomy in a very sophisticated way. Portal
and arterial resection and reconstruction became indispensable techniques to treat
Klatskin tumor infiltrating the hepatic hilum. Ex-situ techniques for resection of tumor
at the suprahepatic confluence with or without venous reconstruction and total vascular
exclusion of the liver with the use of a venovenous bypass arose from the experimental
area before transferring to clinical practice. The development of minimally invasive
liver surgery changed the treatment options for HCC patients on a waiting list for liver
transplantation, allowing for a lower degree of decompensation in cirrhotic patients
after surgery and extending the surgical indications.
The aim of this book, under the auspices of the Italian Society of Surgery, is to
offer a complete survey of the interplay between liver transplantation and hepatobi-
liary surgery through the contribution of many Italian and international experts.
This work also owes a tribute to all the pioneers and masters of hepatobiliary and liver
transplantation surgery with particular reference to Henri Bismuth, Rudolf Pichlmayr,
Roy Calne Koichi Tanaka, and, above all, Thomas Earl Starzl. They launched a clear
message by indicating pathophysiology, deep anatomic awareness, and interdisciplinary
cross-fertilization as crucial and indispensable tools for any sophisticated technical skill.
We aim to proceed along their path well aware that, day after day, this field of
surgery astonishes our eyes, challenges our minds, and gratifies our hearts.
Padua, Italy Umberto Cillo

Milan, Italy Luciano De Carlis
September 2019
Contents
1 Cross Training and Didactic Interplay in Liver

Transplantation and Hepatobiliary Surgery �� 1
Quirino Lai and Massimo Rossi
2 Preoperative Assessment of Comorbidities in Liver
Transplantation and Hepatobiliary Surgery �� 9
Duilio Pagano and Salvatore Gruttadauria
3 Liver Resection and Total Vascular Exclusion�� 21
Andrea Lauterio, Riccardo De Carlis, Stefano Di Sandro,
and Luciano De Carlis
4 Cooling Techniques and Ex Situ Liver Surgery�� 29
Umberto Cillo and Enrico Gringeri
5 Machine Perfusion in Liver Transplantation�� 41
Riccardo De Carlis, Vincenzo Buscemi, Andrea Lauterio,
Stefano Di Sandro, and Luciano De Carlis
6 Liver Vascular Reconstructions�� 53
Umberto Cillo and Alessandra Bertacco
7 Biliary Reconstruction Techniques: From Biliary Tumors to
Transplantation�� 61
Leonardo Centonze, Stefano Di Sandro, Iacopo Mangoni,
8 The Interplay Between Living Donor Liver
Transplantation and Liver Surgery�� 75
9 Pediatric Living Donor Liver Transplantation �� 85
Roberta Angelico, Chiara Grimaldi, Maria Cristina Saffioti,
Alessandro Coppola, and Marco Spada
10 Left Split Liver �� 97
Umberto Cillo and Riccardo Boetto
ix
x Contents
11 Extended Right Split Liver Graft �� 107

Giuliano Bottino and Enzo Andorno
12 Full-Left Full-Right Split Liver Transplantation�� 115
Stefania Camagni and Michele Colledan
13 Small-for-Size Syndrome�� 123
Umberto Cillo and Francesco Enrico D’Amico
14 Regeneration Techniques: TSH and ALPPS �� 139
Matteo Serenari and Elio Jovine
15 Combined Cardiothoracic and Abdominal Approach�� 145
Fabio Ferla, Vincenzo Buscemi, Riccardo De Carlis, and Luciano
De Carlis
16 Portal Vein Thrombosis in Liver Transplantation and
in Non-transplant Treatment�� 157
Umberto Cillo and Domenico Bassi
17 APOLT and RAPID Techniques �� 167
Umberto Cillo
18 Robotic Surgery in Liver Transplantation and Resection�� 175
Fabrizio Di Benedetto, Giuseppe Tarantino, Gian Piero Guerrini,
Roberto Ballarin, and Paolo Magistri
19 Other “Bridge” Therapies for Liver Transplantation:
RFA, TACE, and TARE �� 183
Giuseppe Maria Ettorre and Andrea Laurenzi
20 Interplay Between General Surgery and Liver
Transplantation�� 193
Alfonso W. Avolio, Marco M. Pascale, and Salvatore Agnes
21 Liver Transplantation as a Challenge for the Anesthesiologist:
Preoperative Cardiac Assessment to Orient the
Perioperative Period�� 203
Andrea De Gasperi, Gianni Biancofiore, Ernestina Mazza,
and Pietro Molinari
22 Liver Resection and Transplantation for Metastases from
Gastroenteropancreatic Neuroendocrine Tumors�� 221
Michele Droz dit Busset, Matteo Virdis, Christian Cotsoglou,
Jorgelina Coppa, Roberta Rossi, and Vincenzo Mazzaferro
Contributors
Salvatore Agnes Catholic University of the Sacred Heart, Rome, Italy

Division of General Surgery and Liver Transplantation, Department of Surgical
Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Enzo Andorno Hepatobiliary Pancreatic Surgery and Transplantation Unit,
Policlinico San Martino Hospital, Genoa, Italy
Roberta Angelico Division of Abdominal Transplantation and Hepatobilio
pancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
Alfonso W. Avolio Catholic University of the Sacred Heart, Rome, Italy
Division of General Surgery and Liver Transplantation, Department of Surgical
Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Roberto Ballarin Hepato-Pancreato-Biliary Surgery and Liver Transplantation
Unit, Policlinico University Hospital of Modena, University of Modena and Reggio
Emilia, Modena, Italy
Domenico Bassi Department of Surgery, Oncology and Gastroenterology,
University of Padua, Padua, Italy
Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua,
Italy
Alessandra Bertacco Department of Surgery, Oncology and Gastroenterology,
Italy
Gianni Biancofiore Unit of Anesthesia and Critical Care for General, Vascular and
Transplantation Surgery, Pisa University Hospital, Pisa, Italy
Riccardo Boetto Hepatobiliary Surgery and Liver Transplant Unit, Padua
University Hospital, Padua, Italy
Giuliano Bottino Hepatobiliary Pancreatic Surgery and Transplantation Unit,
Policlinico San Martino Hospital, Genoa, Italy
Vincenzo Buscemi Department of General Surgery and Transplantation, Niguarda
Hospital, Milan, Italy
xi
xii Contributors
Stefania Camagni Department of Organ Failure and Transplantation, ASST Papa

Giovanni XXIII, Bergamo, Italy
Leonardo Centonze Department of General Surgery and Transplantation,
Niguarda Hospital, Milan, Italy
Umberto Cillo Department of Surgery, Oncology and Gastroenterology, University
of Padua, Padua, Italy
Italy
Michele Colledan Department of Organ Failure and Transplantation, ASST Papa
Giovanni XXIII, Bergamo, Italy
Jorgelina Coppa Hepatopancreatobiliary Surgery, Gastroenterology, and Liver
Transplantation, Istituto Nazionale dei Tumori, Milan, Italy
Alessandro Coppola Division of Abdominal Transplantation and
Hepatobiliopancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome,
Italy
Christian Cotsoglou Hepatopancreatobiliary Surgery, Gastroenterology, and
Liver Transplantation, Istituto Nazionale dei Tumori, Milan, Italy
Francesco Enrico D’Amico Department of Surgery, Oncology and
Gastroenterology, University of Padua, Padua, Italy
Italy
Luciano De Carlis Department of General Surgery and Transplantation, Niguarda
School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
Riccardo De Carlis Department of General Surgery and Transplantation, Niguarda
Department of Surgical Sciences, University of Pavia, Pavia, Italy
Andrea De Gasperi Division of Anesthesia and Intensive Care 2, Niguarda
Fabrizio Di Benedetto Hepato-Pancreato-Biliary Surgery and Liver
Transplantation Unit, Policlinico University Hospital of Modena, University of
Modena and Reggio Emilia, Modena, Italy
Stefano Di Sandro Department of General Surgery and Transplantation, Niguarda
Michele Droz dit Busset Hepatopancreatobiliary Surgery, Gastroenterology, and
Giuseppe Maria Ettorre Transplantation Department, S. Camillo-Forlanini
Hospital, Rome, Italy
National Institute of Infectious Disease L. Spallanzani, Rome, Italy
Contributors xiii
Fabio Ferla Department of General Surgery and Transplantation, Niguarda

Chiara Grimaldi Division of Abdominal Transplantation and Hepatobiliopancreatic
Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
Enrico Gringeri Department of Surgery, Oncology and Gastroenterology,
Italy
Salvatore Gruttadauria Department for the Treatment and Study of Abdominal
Diseases and Abdominal Transplantation, ISMETT - Istituto Mediterraneo per i
Trapianti e Terapie ad Alta Specializzazione IRCCS / UPMC Italy, Palermo, Italy
Department of Surgery, University of Catania, Catania, Italy
Gian Piero Guerrini Hepato-Pancreato-Biliary Surgery and Liver Transplantation
Elio Jovine Department of General Surgery, Maggiore Hospital, AUSL Bologna,
Bologna, Italy
Quirino Lai Liver Transplantation and Hepatobiliary Surgery Unit, Department of
General Surgery and Surgical Specialties, Umberto I University Hospital, Sapienza
University of Rome, Rome, Italy
Andrea Laurenzi Transplantation Department, S. Camillo-Forlanini Hospital,
Rome, Italy
Andrea Lauterio Department of General Surgery and Transplantation, Niguarda
Paolo Magistri Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit,
Policlinico University Hospital of Modena, University of Modena and Reggio
Iacopo Mangoni Department of General Surgery and Transplantation, Niguarda
Ernestina Mazza Division of Anesthesia and Intensive Care 2, Niguarda Hospital,

Milan, Italy
Vincenzo Mazzaferro Hepatopancreatobiliary Surgery, Gastroenterology, and
University of Milan, Milan, Italy
Pietro Molinari Division of Anesthesia and Intensive Care 2, Niguarda Hospital,
Milan, Italy
Duilio Pagano Department for the Treatment and Study of Abdominal Diseases
and Abdominal Transplantation, ISMETT - Istituto Mediterraneo per i Trapianti e
Terapie ad Alta Specializzazione IRCCS / UPMC Italy, Palermo, Italy
xiv Contributors
Marco M. Pascale Fondazione Policlinico Universitario A. Gemelli IRCCS,

Rome, Italy
Massimo Rossi Liver Transplantation and Hepatobiliary Surgery Unit, Department
of General Surgery and Surgical Specialties, Umberto I University Hospital,
Sapienza University of Rome, Rome, Italy
Roberta Rossi Hepatopancreatobiliary Surgery, Gastroenterology, and Liver
Maria Cristina Saffioti Division of Abdominal Transplantation and
Hepatobiliopancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome,
Italy
Matteo Serenari Department of Surgical and Medical Sciences, University of
Bologna, Sant’Orsola-Malpighi Hospital, Bologna, Italy
Marco Spada Division of Abdominal Transplantation and Hepatobiliopancreatic
Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
Giuseppe Tarantino Hepato-Pancreato-Biliary Surgery and Liver Transplantation
Matteo Virdis Hepatopancreatobiliary Surgery, Gastroenterology, and Liver
Cross Training and Didactic Interplay
in Liver Transplantation 1
and Hepatobiliary Surgery
Quirino Lai and Massimo Rossi
1.1 Introduction
We need a system, and we shall surely have it, which will produce not only surgeons, but
surgeons of the highest type, men who will stimulate the first youths of our country to study
surgery and to devote their energies and their lives to raising the standard of surgical sci-
ence—William Stewart Halsted (1904)
William Halsted’s paradigm for surgical residency training is recognized as the

most appropriate educational system to become a competent general surgeon. The
length of training largely varies from a minimum of 4 years in countries such as West
Africa and Brazil to 5 years in Italy, and at least 8 years in the UK and Hong Kong [1].
Hepatopancreatobiliary (HPB) and liver transplantation (LT) surgery are the cor-
nerstones of general surgery training, because of their high prevalence and com-
plexity. However, the recent evolution observed in these fields has transformed
modern HPB surgery into a technically complex and technology-dependent proce-
dure. Moreover, a rising number of HPB cases can be routinely performed using
minimally invasive surgery (MIS), which has forced to move a number of cases out
of residents’ hands, placing them in the domain of specialist fellows or staff sur-
geons. This is particularly true in consideration of the increasing number of “disap-
pearing” HPB procedures, such as open cholecystectomy, and explains why the new
generations of resident graduates are concerned about their being unprepared for
independence. Unfortunately, such a condition gives rise to a perverse mechanism
in which many highly specialized surgeons finish their training and find a position
either going back to general surgery or moving on to other specialization branches.
Q. Lai (*) · M. Rossi

Liver Transplantation and Hepatobiliary Surgery Unit, Department of General Surgery
and Surgical Specialties, Umberto I University Hospital, Sapienza University of Rome,
Rome, Italy
e-mail: lai.quirino@libero.it; massimo.rossi@uniroma1.it
© Springer Nature Switzerland AG 2020 1

U. Cillo, L. De Carlis (eds.), Liver Transplantation and Hepatobiliary Surgery,
Updates in Surgery, https://doi.org/10.1007/978-3-030-19762-9_1
2 Q. Lai and M. Rossi
The present chapter reports on the importance and criticisms of cross training
HPB/LT surgery, with special reference to the possible implementation of the mod-
els used worldwide. It will discuss detailed aspects concerning residency and fel-
lowship in HPB and LT centers, as well as the special role of organ procurement as
a unique opportunity to teach specific open surgical skills. Further topics include the
growing role of MIS with the conflicting need to perform difficult procedures while
allowing young surgeons to acquire technical skills, and, lastly, the peculiar role of
women in a male-dominated branch of surgery.
1.2 Surgical Training in Hepatopancreatobiliary Surgery
A survey published in 2014 showed that HPB surgery presents many training routes
and practice patterns in the United States. The investigated surgeons were residents/
fellows in surgical oncology units in 28% of cases, followed by LT (24.8%), HPB
(24.2%), HPB/Complex gastrointestinal (16%) and HPB/MIS (4%) [2].
These data are confirmed by another study from the US, in which the general
surgical residency programs presenting higher rates of HPB procedures typically
have dedicated LT or HPB units [3].
Therefore, this condition should represent a shortcoming for residents trained in
hospitals without LT or HPB surgeons, limiting the possibility of performing HPB
surgery in their future practice, especially if located in remote areas. Starting from
the assumption that it is essential that a general surgeon practicing in a remote area
should be capable of performing HPB surgery, since there may not be an HPB sur-
geon in the region, a question arises on the adequacy of the residency lengths needed
to acquire the necessary technical skills for performing HPB surgery.
A recent study from the US investigated the number of complex HPB (i.e., pan-
createctomies, major hepatectomies) performed by general surgery end-of-term
residents during a 16-year-long period. In general, although the numbers increased
over the years, the reported numbers were low, typically less than five per end-of-
term resident [4]. Another study confirmed this result, showing that residents
approaching an HPB fellowship felt poorly comfortable in performing advanced
HPB or laparoscopy, citing a combination of inadequate case volume and lack of
autonomy during residency as the main reasons. In many cases, extra-rotations in
transplant, vascular surgery or MIS were believed to be most helpful in preparing
general surgery residents for HPB fellowships [5].
The difficulties of the residents starting an HPB fellowship were also confirmed by
the HPB program directors. According to the results of a survey from the US, only 50%
of program directors felt residents were competent [6]. The best way to solve the lim-
ited opportunities a resident has for acquiring enough competence in HPB surgery is
planning a fellowship trainee period after the residency. A study investigating the num-
ber of HPB cases performed during a 2-year-long fellowship in the US reported a
median number of 26 biliary cases, 19 major liver cases (hemi-livers), 28 other liver
cases, 40 pancreaticoduodenectomies, 18 distal pancreatectomies, and 9 other pancreas
cases. The programs providing LT experience offered 10 cases for each fellow [7].
1 Cross Training and Didactic Interplay in Liver Transplantation and Hepatobiliary… 3
However, some doubts have arisen about the possibility that an HPB fellowship
incorporated into an established surgical residency program might diminish the sur-
gical residents’ exposure to complex HPB procedures. As a consequence, only
high-volume centers should incorporate an HPB fellowship program into clinical
training programs without detracting from the residents’ HPB experience [8].
However, although a fellowship program allows young surgeons to perform high-
complexity procedures in high-volume centers, prolonging their training period by
at least 2 years, also the HPB surgery fellowship training has some limitations. A
large survey reported MILS and ultrasound as the most commonly identified areas
of training deficiencies [9].
1.3 Surgical Training in Liver Transplantation
The same problems observed for HPB training exist in transplant programs. The
main limitation is represented by the idea that complex LT procedures performed by
a resident/fellow can cause higher and unacceptable complication rates.
A study from Germany investigated 155 consecutive LT, correlating the results
with the degree of surgical experience of a surgeon operating for the first time. No
significant differences were reported among the cases transplanted by an experi-
enced surgeon versus a fellow in terms of complication rate, overall patient survival,
blood loss, intraoperative transfusion requirements and operating time [10]. The
so-called “July effect”, namely the increased number of complications in US aca-
demic institutions following the influx of new resident physicians, has been also
investigated in LT centers. Of a total of 108,666 LT, those performed in the month
of April showed significantly improved outcomes while in the month of December
significantly decreased outcomes were observed. Therefore, no correlation with the
arrival of new trainees was observed in the setting of LT [11].
Another problem in the LT setting is the progressive drop in the number of sur-
geons sufficiently motivated to sacrifice long years of their lives in the LT training
process. This is due to the fact that LT surgical training often ends in non-competitive
salaries and dead-end academic careers. As an example, US transplant surgeons
reported working approximately 70 h per week, with a median of 195 operative
cases per year [12]. This huge activity, entirely done in public healthcare hospitals
and often performed afterhours, does not represent a great attraction for young sur-
geons. This is particularly true at a time when an overall reduction of surgeons’
work hours is typically observed. A study from Germany observed that a long-term
commitment of surgeons to transplantation is rare. The median time passed in LT
was typically short (median = 3.5 years). Surgeons completing their training
remained in the field for 7 years. The individual total caseloads of transplant sur-
geons were relatively low [13].
Unfortunately, half a century after its introduction by Prof. Starzl, LT has become a
“routine” surgery for many, thereby losing “attractivity” and “prestige” within the med-
ical community. A survey realized by the European Society of Organ Transplantation
(ESOT) in relation to burnout and career planning of transplant surgeons reported the
following as the main reasons for abandoning a LT career: better appeal of other surgi-
cal specialties within (65%) or outside the hospital (35%), personal or familial reasons
(52%), financial reasons (21%), lack of career planning (21%), and too demanding job
(6%). When asked how to make transplant surgery more attractive as a profession, the
respondents answered: financial upgrading (100%), career planning (64%), widening
of surgical spectrum leading to a better mental rest (56%), improving administrative
help (54%), introducing flexible working time (36%), reduced workload (33%),
adapted duty Scheme (33%), and finally team building (24%) [14].
1.4 he Peculiar Importance of the Organ Procurement

T
Procedure in General Surgeons’ Training
The growing impact of MIS is progressively limiting the evolution of surgical resi-
dent experience regarding open surgical procedures. MIS has replaced many open
procedures as the current standard of care. As MIS progresses, the access of surgical
residents to open techniques is becoming significantly limited by the lack of expo-
sure to common open operations.
In the near future, new surgeons, well-versed in MIS, may suffer from inexperi-
ence with the basic principles of open surgery. As an example, a study reporting the
number of surgical procedures performed by the residents in a US center during the
period 2000–2009 confirmed a marked increase in the number of laparoscopic pro-
cedures performed and a concomitant decrease of open and trauma surgery [15].
A possible solution for the lack of open surgical experience can be enhancing
residents’ participation in organ procurement. An anonymous national survey was
performed in the US with the intention of evaluating the organ-procurement experi-
ences and attitudes of general surgical residents. Interestingly, over 85% of the resi-
dents agree that organ procurement is a good educational and operative experience,
with 73% of them believing that it will benefit their future surgical career. About
68% of the residents agree that organ procurement provides better knowledge of
anatomy and exposures [16].
Organ procurement allows trainee surgeons to perform several maneuvers and
open procedures linked not only to general surgery but also to vascular surgery,
urology, and trauma [17–19]. As an example, a significant improvement in the oper-
ative exposure and control of great vessels of the abdomen and chest was reported
in senior residents after their rotation in a Transplant Center [17]. Another study
from Canada investigated the utility of performing organ procurement by urology
residents, allowing them to obtain some expertise in open nephrectomy [18].
Organ procurement offers an almost unique lesson in overall thoraco-abdominal
anatomy and operative technique, providing the opportunity for a fundamental
understanding of complex vascular, hepatopancreatobiliary, renal, and thoracic
structures in a semi-elective scenario. All of these conditions give the trainees a
tremendous advantage before trying to achieve control over a massively bleeding
patient, thus representing a great advantage in trauma surgery as well [19]. As a

consequence, working in a Transplant Center should be mandatory in the profes-
sional education of residents and fellows, which means that every residency pro-
gram and several fellowships should incorporate a rotation in a Transplant Unit.
1.5 Minimally Invasive Liver Surgery and Training
After the First International Consensus Conference on Laparoscopic Liver Surgery

in Louisville in 2008, the number of laparoscopic liver resections performed world-
wide has exponentially increased, including not only minor resections but also
major resections, robotic hepatectomies, and living donor hepatectomies. The grow-
ing impact of MIS, mainly in liver surgery, has been obviously connected with
important implications concerning the trainee period. The Second International
Consensus of Morioka 2015 investigated this aspect very well and made the follow-
ing statement: “Major laparoscopic liver surgery requires a high level of technical
skill and has a steep learning curve. How skills should be acquired by trainees and
surgeons already in practice should be the subject of an urgent focused effort by the
leaders in this field. The future of laparoscopic liver surgery is dependent on this
issue. (STRONG recommendation)” [20].
This problem is clearly elucidated in an International survey in which the per-
ceived adequacy of HPB/MIS training was investigated among 250 surgeons.
Almost surprisingly, 50% and 80% of non-HPB surgeons do not consider them-
selves adequately trained to perform a laparoscopic common bile duct exploration
and a laparoscopic staging of upper gastrointestinal malignancy, respectively [21].
The high complexity of laparoscopic liver surgery requires longer learning
curves, and a higher rate of capacities and surgical skills. As a consequence, specific
training models and teaching courses have been implemented worldwide. As an
example, a simulated-bleeding continuously perfused training model has been cre-
ated with the intention of obtaining a suture training model for laparoscopic liver
resection [22]. Another example is represented by the use of a dedicated cadaver
laparoscopic training facility, where individuals can be safely trained and also certi-
fied within this growing technique [23].
The need to start with laparoscopic training from the beginning of a surgeon’s
career is another important aspect. A study investigating if a single-incision laparo-
scopic cholecystectomy could be efficaciously and safely incorporated into resident
education reported excellent results. All the single-incision laparoscopic cholecystec-
tomy conversions to standard laparoscopic cholecystectomy were reported at the
beginning of the learning curve, with a progressive decline in the operative times [24].
Lastly, internationally recognized courses and web databases of laparoscopic
interventions represent a further tool to be used in the learning process. The
advanced IRCAD/EITS courses organized in Strasbourg, France, and the “online
university” WebSurg (available at: https://www.websurg.com) represent the two
most famous examples.
1.6 Women in Hepatopancreatobiliary

and Transplant Surgery
Particular consideration should be given to the training of women in surgery. An

increasing portion of students entering the medical profession are women. Before
1970, women represented 6% or less of the medical student population. In drastic con-
trast, nearly half of first-time applicants to medical schools in 2011 were women [25].
However, residents in general surgery continues to experience attrition, mainly if
they are women. A survey from the US showed an incredibly high percentage of
residents (58.0%) seriously considering the idea of leaving training. The most fre-
quent reasons for this were sleep deprivation (50.0%), an undesirable future life-
style (47.0%), and excessive work hours (41.4%). After correcting for several
confounders, only women were significantly associated with serious thoughts of
leaving residency, with a 20% increased risk of leaving the residency training [26].
One of the main reasons for withdrawing from residency is pregnancy. A
Canadian survey investigated residents and program directors’ attitudes toward
pregnancy during residency. The lack of adequate policies for maternity/parenting,
major obstacles to breast-feeding, and the increased workload for fellow resident
colleagues were reported [27]. Interestingly enough, men and women have a com-
pletely different perception of the effects of marriage and childbirth during surgery
residency. A prospective, longitudinal study of general surgery residents performed
in the US during the period 2008–2010 reported that women at the end of residency
were less likely to be married (47.3 vs. 67.6%) or have children (18.0% vs. 45.8%)
(p < 0.001). Married women became worried about performing in the presence of
senior residents (p = 0.005), while married men were more likely to be happy at
work (p = 0.005). Women having a child during the residency were more likely to
feel overwhelmed (p = 0.008) and worried about financial security (p = 0.03).
Conversely, men who had a child were more likely to feel supported by faculty
(p = 0.004) [28].
All of these aspects have important repercussions also in terms of academic
career. A survey performed among senior surgical residents and early-career surgi-
cal faculty members reported that women perceived active discrimination in the
form of being treated differently and experiencing negative comments about their
sex. Sex-based attitudes inhibited the career aspirations of female surgeons [29]. A
recent study from Germany specifically investigated women’s academic career in
the setting of liver transplantation. Female surgeons in German liver transplant cen-
ters are eager to assume leadership positions and do not wish to follow traditional
role models. Interestingly, after finishing training, most female surgeons plan to
continue working at a university hospital. About 80% of the respondents intend to
continue working full time and wish to combine career and family [30].
All of these results should confirm that women are willing to fill leadership posi-
tions and that individual and institutional changes are needed to promote an equal
advancement of men and women in surgery.
1.7 Conclusions
HPB/LT training is the cornerstone of the education of general surgeons, especially

if they are willing to spend their career in rural areas far from HPB centers. Often, the
residency period is not enough to acquire specific abilities in the setting of HPB sur-
gery or transplantation. Fellowship training represents a further way to prolong the
learning course in these highly specialized fields. Only high-volume centers should
start offering fellowship programs so as not to penalize residents with regard to the
number of procedures to perform. A nationally recognized inter-hospital network
should be set up with the purpose of improving the expertise of HPB/LT surgeons.
Organ procurement represents one of the last opportunities for a resident to per-
form open procedures. Organ retrieval is also one of the best ways of acquiring
technical skills and anatomy mastery. Transplant Units should be considered an
indispensable part of the residency rotation.
Liver laparoscopic surgery is a difficult procedure to learn and consequently
requires a long-range training. Often, the learning curve exceeds the fellowship
period. Implementation of specific national and international courses is required.
Women in HPB/LT surgery still suffer from a male-dominated field. Women are
still more prone to residency withdrawal and poor academic careers. However, the
growing number of female surgeons and implementation of rules regulating some
specific situations (i.e., pregnancy) should ensure a more equal treatment for men
and women.
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Preoperative Assessment
of Comorbidities in Liver 2
Transplantation and Hepatobiliary
Surgery
Duilio Pagano and Salvatore Gruttadauria
2.1 Introduction
Preoperative assessment of comorbidities has received increasing attention in order

to expand the pool of patients that could safely undergo liver transplantation (LT)
and/or hepatobiliary surgical procedures with a radical intent [1, 2].
Understanding the principles of an appropriate operative risk assessment and
careful postoperative management is critical in ensuring high quality outcomes in
surgical patients with complex problems [3]. On the other hand, in these delicate
fields of surgery no standard preoperative assessment can fit all patients with end-
stage liver disease (ESLD) and/or hepatobiliary surgical cases because metrics of
chronic hepatic disease can influence the estimated probability of morbidity [4].
Because each patient must be narrowly assessed for risks, each test and surgical deci-
sion process must be weighed for benefits, outcomes, and health-related costs [5].
It is particularly important to develop universal models of risk prediction of post-
operative complications, increasingly advanced surgical techniques, and effective
preventive measures for the codification of those risk factors that predict the lack of
functional recovery with prolonged hospital stay and postoperative disability. At
present, though much clinical research on clinical assessments of recurrence-free
and/or overall survival in the setting of LT and hepatobiliary surgery has been
D. Pagano
Department for the Treatment and Study of Abdominal Diseases and Abdominal
Transplantation, ISMETT - Istituto Mediterraneo per i Trapianti e Terapie ad Alta
Specializzazione IRCCS / UPMC Italy, Palermo, Italy
e-mail: dpagano@ismett.edu
S. Gruttadauria (*)
Department for the Treatment and Study of Abdominal Diseases and Abdominal
Transplantation, ISMETT - Istituto Mediterraneo per i Trapianti e Terapie ad Alta
Specializzazione IRCCS/UPMC Italy, Palermo, Italy
Department of Surgery, University of Catania, Catania, Italy
e-mail: sgruttadauria@ismett.edu
10 D. Pagano and S. Gruttadauria
published, innovative clinical research lines on national and risk-adjusted models

are mandatory for exploring the preoperative estimation of the risk of morbidities
after surgery in complex surgical patients [6].
2.2 aseline Clinical Evaluation and Multidisciplinary

B
Approaches
The interplay of surgical technical skill and the expertise of multiple health care special-
ists is crucial in managing complex patients with cancer or severe ESLD who, depend-
ing on the type of the disease and risk factors (e.g., age and comorbidities) can be
managed with different therapeutic modalities, such as palliative oncologic care (e.g.,
chemotherapy), minimally invasive or open surgery, thermal ablation, liver transplanta-
tion, or those who can be monitored with active surveillance and watchful waiting [7].
The preoperative baseline clinical assessment of the surgical patient includes, pri-
marily, a thorough review of the medical history and a physical examination (H&P).
When results are considered relevant for determining the primary diagnosis, a specific
evaluation should be made of the comorbidity severities that might influence the sur-
gical risk and/or require further intervention and optimization. This evaluation func-
tions to obtain diagnostic and prognostic information additional to the clinical history,
with the aim of providing information that can confirm or question the expected diag-
nostic-therapeutic procedure (clinical management). Identifying non-manifest condi-
tions that may require treatment before surgery or change the choice of surgical or
anesthetic technique has shown to be able to reduce the damage or increase the benefit
by modifying, if necessary, the clinical pathway [8]. The evaluation of the patient who
is a candidate for extremely delicate surgical treatments such as liver resection with
radical oncologic intent and/or liver transplantation must quantify the functional and
general health reserve status. These also depend on aspects other than morphological
and functional hepatological ones, such as the social life of the individual, the cogni-
tive state, the environment in which the patient lives and moves, economic conditions,
affective conditions, and interpersonal relationships [9, 10].
Multidisciplinary management in liver surgery and transplantation allows an
appropriate approach to patients affected by hepatic tumor and/or ESLD during all
phases of the preoperative evaluation, improving outcomes with a targeted rehabili-
tative and supportive therapeutic strategy [11, 12].
It is relevant to note that the tests carried out during the preoperative evaluation
of these patients are expensive, demanding, and frequently require multi-professional
involvement. This explains why they can potentially increase the risk of morbidities
or cause additional delays due to subjective interpretations of results, especially
when considering tests that carry a significant rate of false positives [13].
Usually, the services that provide preadmission status are located in the hospital
where the surgery will take place, and procedures and local policy will apply in rela-
tion to the indications formulated in line with those of the National Institute for Health
and Care Excellence (NICE), based on the patient’s experience. Considering that in
the National Health Service (NHS) an increasing number of patients have undergone
elective general surgery in this decade (10.6 million in 2012–2013 compared to 6.61
million in 2002–2003), it is intuitive that eliminating even a small percentage of
unnecessary tests translates into an impact on a great number of patients [14, 15].
2 Preoperative Assessment of Comorbidities in Liver Transplantation… 11
2.3 Risk Stratification Tools
It is known that preoperative investigations are designed to provide diagnostic and

prognostic information additional to the patient’s medical history in assessing elec-
tion for surgery. The objective of these investigations, then, is the identification of
undiagnosed diseases that allow clinicians to operate in the best conditions and with
the most appropriate techniques, trending toward zero risk for the patient. A multi-
disciplinary approach for the stratification of surgical risk of patients with surgical
hepatobiliary disease is commonly incorporated in all medical institutions in order
to estimate the risk of morbidity and mortality, identify patients who require further
preoperative evaluation, and guide discussions regarding informed consent [16].
The collaboration of surgeons, hepatologists, pathologists, radiologists, psycholo-
gists, and other ancillary staff (e.g., family doctor, physical and respiratory thera-
pists, palliative care professional, support therapist, other allied health care
professionals), if well-organized and structured, allows the patient to be the center of
the clinical care pathway. In this setting, it may also be necessary to improve com-
munication between primary and secondary care centers to ensure that all relevant
test results are shared with the preoperative assessment facility [17]. Commonly, the
American Society of Anesthesiologists’ physical status classification (ASA-PS)
(Table 2.1) is a useful tool for assessing the patient’s fitness for general surgery [18].
Table 2.1 The American Society of Anesthesiologists physical status (ASA PS) classification
system
ASA PS
classification Definition Examples
ASA 1 A normal healthy person Fit, non-obese (BMI <30), non-smoking patient with
good exercise tolerance
ASA 2 A patient with a mild Patient with no functional limitations and a well-
systemic disease controlled disease (e.g., treated hypertension, obesity with
BMI <35, frequent social drinker or is a cigarette smoker)
ASA 3 A patient with a severe Patient with some functional limitation as a result of
systemic disease that is disease (e.g., poorly treated hypertension or diabetes,
not life-threatening morbid obesity, chronic renal failure, a bronchospastic
disease with intermittent exacerbation, stable angina,
implanted pacemaker)
ASA 4 A patient with a severe Patient with functional limitation from severe, life-
systemic disease that is a threatening disease (e.g., unstable angina, poorly
constant threat to life controlled chronic obstructive pulmonary disease,
symptomatic congestive heart failure, recent (<3 months)
myocardial infarction or stroke
ASA 5 A moribund patient who Ruptured abdominal aortic aneurysm, massive trauma,
is not expected to survive extensive intracranial hemorrhage with mass effect, etc.
beyond the next 24 h
without surgery
ASA 6 A declared brain-dead
patient whose organs are
being removed for donor
purposes
The addition of “E” to the ASA PS (e.g., ASA 2E) denotes an emergency surgical procedure. The
ASA defines an emergency as existing “when the delay in treatment of the patient would lead to a
significant increase in the threat to life or body part”. BMI body mass index
The clinical value, however, of the findings made in apparently healthy individuals is
uncertain. In this regard, there is recorded evidence that, on the one hand, indicates
that clinicians do not change the management of their patients even in the face of
pathological results and, on the other, there are negative effects for the patient in the
event of false positive results. Thus, evaluation of the underlying comorbidities and
the clinical decision-making process have to be managed with an evidence-based
approach for complex and different types of surgery-eligible patients with hepatobi-
liary disease, such as newly diagnosed patients with oncologic disease, patients at
high risk for tumor progression, or patients with complex management issues [19].
2.4 Morphologic and Functional Diagnostic Tools
Despite best-practice guidelines for these complex cases, planning for and perform-
ing elective surgery in patients with surgical hepatobiliary disease with or without
ESLD affected with severe comorbidities is most effective when a skilled anesthe-
siology specialist and experienced hepatobiliary surgeons are involved. Detailed
and attentive preoperative planning is crucial for the success of elective surgery.
This includes physical assessment, laboratory testing, genetic examinations, design-
ing plans for hemostasis and pain management, and imaging [20–22].
Radiological evaluation is a crucial element in surgical decision-making, and the
integration of radiology into the medical, social, and the political fabric of a com-
munity hospital is the thrust of the Imaging 3.0 cultural transformation, supported
by the American College of Radiology (ACR) [23]. On the other hand, this multipa-
rametric evaluation of organ function requires a specific and increasingly frequent
involvement of a surgical team and health care professionals for patients with hepa-
tobiliary surgical disease with complex comorbidities. For example, the increas-
ingly common clinical uses of computed tomography (CT) to classify patients of
both genders as sarcopenic/cachectic, or not, have several limitations in a range of
anatomical sites. For predicting treatment response in terms of prognostic value and
stratification of differential responders, the routine use of intervallic modifications
in nutritional status during preoperative assessment needs to be matched with the
following parameters: fat mass, fat-free mass, body water composition by CT scan,
tricep skinfold thickness, grip and hand strength by dynamometer, 6-min walking
distance, and quality of life by validated questionnaires [24]. In the hepatobiliary
oncologic surgery setting, the methods for the measurement of the minimal future
remnant liver volume (FRLV) range from two-dimensional (2D) volume through
CT, to perioperative three-dimensional (3D) modeling to be adapted in patients with
end-stage liver disease [25].
Computational software allows for the definition, either manual or automatic, of
the parenchymal anatomy of the liver on all the individual iconographic sections of
the CT scan or magnetic resonance imaging (MRI), allowing an extremely detailed
calculation of hepatic volume [26]. Despite the fact that the hepatic parenchyma can
regenerate in the FRLV, if it is less than 20% of the preoperative liver volume imme-
diately after resection, the healthy liver’s activity might not meet physiologic needs
and detoxification requirements. It could lead to post-hepatectomy liver failure, and

in patients with ESLD disease this percentage limit needs to be higher [27, 28]. The
need to evaluate liver function in detail has led to the development of innovative
methods, such as the combination of the fibrosis index based on the four factors and
future liver remnant volume ratios as a predictor of post-hepatectomy outcomes
[29]. Hepatic MRI with gadolinium-based compound (ethoxybenzyl diethylenetri-
amine penta-acetic acid with gadolinium, Gd-EOB-DTPA) can provide information
about the enhancement of the function of the individual segments and sectors [30].
Liver parenchyma scintigraphy with galactosylated human serum albumin (GSA)
and labeled with technetium-99 (99mTc), and hepatobiliary scintigraphy with labeled
mebrofenin with 99mTc with single-photon emission CT (SPECT) offer a metabolic
analysis to quantify the degree of functional reserve in relation to the uptake level of
the radiocompound [31].
2.5 Surgical Decision-Making
Hepatobiliary surgery and LT has achieved important technical breakthroughs, but

there is still a lack of clinical policy and/or evidenced-based guidelines concerning
the preoperative assessment of high-risk patients, and only a limited number of
studies in the literature have addressed this issue [32]. In the meantime, a planned
preoperative assessment could aid in not delaying surgery for a progressive disease
such as ESLD associated with hepatocellular carcinoma in patients who are opera-
ble at the time they are diagnosed, and who might become inoperable if surgery is
not performed promptly [33]. New guidelines and evidence-based protocols can
help face surgical dogma regarding the preoperative assessment of patients with
complex comorbidities, streamlining the perioperative management of patients and
improving outcomes in the following specific clinical scenario.
2.5.1 The Elderly
Thanks to the global improvement of care and living conditions, the world popula-
tion is increasingly aging [34]. The elderly patient who is a candidate for hepatobili-
ary surgery requires a comprehensive preoperative assessment that takes into
account certain specific aspects and related ages, which are not normally evaluated
in the adult patient. In addition to the anamnesis (associated diseases, basic thera-
pies, anesthesiologic anamnesis) and objective examination, it is necessary to inves-
tigate the effects of the aging processes (functional reserves) and functional status.
The functional status is evaluated through a set of parameters, widely used in geri-
atrics, which constitute the multi-parametric evaluation [33].
Currently, some elderly patients who do not have disability or comorbidity can
undergo radical standard treatment without changes in therapeutic protocols (“fit”
patients), while “fragile” patients with different comorbidities, and/or disability
and/or a geriatric syndrome are candidates for palliative treatments, with the aim of
improving quality of life. There are, then, elderly people who do not fall into the
first two categories, and are patients (vulnerable or unfit) who can tolerate only
some individualized or palliative treatments in order to both improve survival and
quality of life [11].
For these elderly patients the situation is more complicated since, despite having
a good general state before treatment, their physiological reserves can be quite
reduced, with a very precarious homeostatic equilibrium that can expose them to
risks of very rapid worsening during oncological treatments. In particular, there are
already the means to address some critical questions related to the elderly patient:
what is the patient’s life expectancy and risk of postoperative morbidities based on
patient basic conditions?
However, the tools used to answer these questions must be continually renewed
with new information on aging, also taking into account the social and demographic
changes taking place [35].
To date, there are no simple screening systems that allow physicians responsible
for treatment to identify these patients with increased postoperative risk. Identifying
patients at risk is in fact the first step in the process through which it is possible to
prevent postoperative complications such as delirium, cardiovascular events, and
loss of overall functionality with consequent loss of autonomy. Some systems have
proven to be promising in this regard, such as the Comprehensive Geriatric
Assessment (CGA), based not only on the molecular profile of the disease but also
on perceived experience and psychophysical conditions [36]. The results provided
by the use of this tool have also enabled the identification of macro-taxonomic cat-
egories within which to include the single elderly patient who approaches for the
first time any therapeutic, diagnostic or rehabilitative pathway. This revolutionary
subdivision allows the identification of particular profiles, each of which is charac-
terized by different rehabilitation potentials, life expectancy, and stress tolerance
characteristics, which help to better direct the individual patient towards appropriate
social and health intervention plans [37].
2.5.2 Chronic Degenerative Disease
Identification of risk factors in patients undergoing LT and hepatobiliary surgery is

critical and can be assessed in the patient’s H&P. The risk factors include the follow-
ing clinical conditions: congestive heart failure (CHF), cardiomyopathy, ischemic
and/or valvular heart disease, arrhythmias, diabetes mellitus or renal insufficiency,
pulmonary vascular disease and/or chronic obstructive pulmonary disease, as well as
poor functional status. Supplemental preoperative assessments and/or optimization
are usually necessary in these at-risk patients. The Revised Cardiac Risk Index
(RCRI) [38] and the American College of Surgeons NSQIP Risk Calculator have
been proposed for estimating the perioperative cardiac event risk after non-cardiac
surgery. The RCRI incorporates high-risk surgical procedures, history of CHF and/or
ischemic heart disease and/or cerebrovascular disease, preoperative dosage of serum
creatinine (>2 mg/dL), and preoperative insulin-based therapy.
The NSQIP risk calculator is a valid tool for calculating not only the risk of car-
diac complications, but also of postoperative infection risk, such as surgical site
infections and/or pneumonia, readmission and/or reoperation, venous thromboem-
bolism, and death [17]. Patients with active cardiac symptoms (e.g., heart failure or
unstable angina) have a particularly high perioperative risk. Patients with unstable
angina have a risk of approximately 28% for perioperative myocardial infarction.
The degree of exercise tolerance is a very important clinical test for patients with
stable angina: patients with active cardiac symptoms, therefore, require an accurate
assessment prior to surgery [39]. Specific heart conditions, such as unstable angina,
could constitute a main indication for coronary revascularization, and if these patho-
logic cases cannot be corrected before LT or hepatobiliary surgery it might be nec-
essary to perform pulmonary artery catheterization for preoperative and/or
intraoperative monitoring.
Many patients with hepatobiliary cancer who require oncologic surgery may be
at increased risk because of limited pulmonary function. A pneumologic preopera-
tive assessment is mandatory for assessing the overall surgical risk and for introduc-
ing a smoking cessation program before hepatobiliary surgery and during waiting-list
time for LT [40]. Smoking cessation before surgery (even 3 weeks before) can
reduce the incidence of pneumologic morbidities after oncologic surgery. An appro-
priate estimate of the pulmonary pathophysiology of these patients is central for the
surgeon in order to place proper indications for lung resection [41].
2.5.3 Nutritional Status
Pathological changes in nutritional status increase the risk of surgical morbidities in

adult patients. The nutritional status can be examined preoperatively with H&P and
laboratory tests. A malnutrition status can be determined when H&P reveals a weight
loss of more than 10% of body weight in 6 months, or 5% in 1 month, indicative
findings on physical examination (e.g., muscular atrophy, or typical nutritional defi-
ciencies), low albumin levels in the serum. Serum albumin assay is an inexpensive
malnutrition indicator; it must be measured preoperatively in patients who may be
undernourished. Values <2.8 g/dL predict an increase in morbidity and mortality
[42]. Since the half-life of serum albumin is 14–18 days, levels cannot reflect acute
malnutrition. If more acute malnutrition is suspected, a protein with a shorter half-
life can be measured: for example, transferrin (half-life, 7 days) or transthyretin
(half-life, 3–5 days). Generally, therapeutic nutritional support can improve out-
comes in patients with severe malnutrition, and sometimes, LT and/or hepatobiliary
surgery can be postponed for several weeks [43]. On the other hand, a body mass
index (BMI) greater than 40 kg/m2 can augment the risk of perioperative morbidity
(e.g., arterial hypertension, pulmonary hypertension, left ventricular hypertrophy,
heart failure, and coronary artery disease) and mortality [44]. Obesity is an indepen-
dent risk factor for deep vein thrombosis and pulmonary embolism; preparatory pro-
phylaxis for venous thromboembolism is indicated in most obese patients. Obesity
also increases the risk of postoperative wound complications (e.g., dehiscence,
surgical site infection). The significant long-term weight control resulting from sur-
gical therapy has been recently advocated in the LT setting because it is associated
with improvement and, often, resolution of comorbidities, including diabetes, hyper-
tension, hyperlipidemia, and pulmonary insufficiency [45]. In this setting, the most
recent joint guidelines of the American Association of Clinical Endocrinologists,
The Obesity Society, and the American Society of Bariatric Surgeons have confirmed
the previously proposed BMI cut-offs, and better identified which comorbidities can
be considered to lower the BMI cut-off for surgery selection from 40 kg/m2 to 35 kg/
m2. These comorbidities include ischemic heart disease, type 2 diabetes, obstructive
sleep apnea syndrome, obesity/hypoventilation syndrome, non-alcoholic liver dis-
ease and steatohepatitis, hypertension, dyslipidemia, gastroesophageal reflux dis-
ease, asthma, venous stasis, severe urinary incontinence, disabling arthropathy, or a
serious impoverishment of quality of life linked to obesity. These same guidelines
reaffirmed the current absence of sufficient data to recommend the use of bariatric
surgery in patients with a BMI below 35 kg/m2 [46].
2.6 Referral Center
The increasing impact that LT and surgical procedures combined with systemic
therapy has in the natural history of hepatobiliary oncological pathologies, both
primary and metastatic, even in the context of chronic degenerative diseases with
compromised organ function, has led to a progressive increase of 3% per year in
Italian patients who survive a cancer diagnosis [47].
With the availability of increasingly active and expensive hepatobiliary surgical
therapies [48], it is clear that a straightforward focus on tertiary referral centers is
appropriate for targeting investments in order to grant access for all the population
to quality and curative surgery therapies [49]. The introduction of new imaging
techniques and biochemical tests for the preoperative multidisciplinary evaluation
of the functional reserve and of body homeostasis will help to allow referral centers
to obtain a further reduction of the already low incidence of perioperative complica-
tions after hepatobiliary surgical treatment of cancer patients and LT for ESLD.
Today, precise diagnostic-therapeutic pathways for patients with ESLD are wide-
spread, but an improved capacity of both preoperative multidisciplinary evaluation
and optimization management before hepatobiliary surgery and LT is needed in
order to achieve better outcomes [50], to expand the pool of patients, and to over-
come the thresholds [51]. As part of our ongoing program, we performed 1221 LTs
from July 1999 to October 2018. Of these, 906 (74.2%) were performed using a
whole graft, and 315 (25.8%) using a partial liver graft. In 133 (10.9%) cases, the
procedure was living-related LT, and 169 (17%) it was split LT (Fig. 2.1). In the same
period of time, we performed 1102 liver resections (LRs) at our institute (Fig. 2.2).
102
87
81 88
75 79 77
76
68 69 66
61 62 63 62 67
60 57 60
48 53 54 55 55
49 51 51 51 50
39 40
38
25 32
24
24 26 24
22 20
13 19 19
13 17 14
9 12 12
9 9 9 10
3
7 6 4 7 5 68 5 6 46
2 4 2 2 33 3
00 00 00 0 0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Living donor LT Split graft Whole graft Total
Fig. 2.1 Annual number of liver transplants (LTs) at ISMETT by graft type, between July 1999
and October 2018
107
Open LR MI–LR
96
91
77 77
74
68 70
64
60 51 58 81
59
53 53
46 45 53 52
41 40 40 44 49
64
55
55 55 27 43
53
44 45
41 40 38 40 38
27 24 24 25 26
21
3
10 9 10
3 2 4 5 2
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Fig. 2.2 Annual number of liver resections at ISMETT between July 1999 and December 2018.
The clustered stacked column chart displays for each year the total amount of liver resections and
the number of liver resections with open surgery (OPEN-LR) and with minimally invasive
approach (MI-LR)
Of these 217 cases (19.7%) were performed with a minimally invasive approach.
There has been an incremental surgical activity in this setting over the years, and in
the year 2018 we performed 107 liver resections crossing the threshold of 100 proce-
dures per year required to be classified as a high-volume Italian referral center [49].
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Liver Resection and Total
Vascular Exclusion 3
3.1 Introduction and Historical Background
More than 50 years ago, Heaney et al. first described the technique of total vascular
exclusion (TVE), both from laboratory experiences and clinical reports [1].
However, initial reports in the mid-to-late 1980s showed less encouraging mortality
rates than other techniques [2, 3]. Indeed, Bismuth et al. and Huguet et al. demon-
strated that TVE could be performed with acceptable results in terms of mortality
and morbidity [4–6].
Simultaneously, the number of liver transplantations (LT) increased dramatically
over time, which also contributed to surgeon expertise and knowledge of liver resec-
tions (LR).
The extensive dissection to mobilize the liver adopted for TVE is in fact the tech-
nique used in performing recipient hepatectomy during LT. A better understanding of
the concepts related to LT, such as ischemia-reperfusion injury and the subsequent
Electronic supplementary material The online version of this chapter (https://doi.org/10.1007/

978-3-030-19762-9_3) contains supplementary material, which is available to authorized users.
A. Lauterio (*) · S. Di Sandro
Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy
e-mail: andrea.lauterio@ospedaleniguarda.it; stefano.disandro@ospedaleniguarda.it
R. De Carlis
e-mail: riccardo.decarlis@ospedaleniguarda.it
L. De Carlis
e-mail: luciano.decarlis@ospedaleniguarda.it

22 A. Lauterio et al.
risk of liver failure, has led to combined TVE and hypothermic perfusion (HP) of the
future remnant liver, and the benefits of this combination have been reported [7].
Prolonged TVE inevitably results in renal injury, splanchnic congestion subse-
quent to portal clamping, and systemic hemodynamic changes related to the right
heart preload. This may be avoided by the systematic use of the venovenous (VV)
bypass, which has a beneficial role on kidney protection, splanchnic congestion, and
hemodynamics, as seen in LT [8].
Recently, association of a temporary portocaval shunt (PCS) has made LR with
TVE possible, thereby avoiding the disadvantages of an extracorporeal VV bypass.
The last few years have seen an increasing number of complex LR using standard
TVE and in situ hypothermic liver perfusion as a result of increasing experience
with the surgical technique, and a better understanding of preoperative predictors of
patient morbidity and mortality [7, 9].
3.2 Fundamental Surgical Considerations
Classic TVE including portal triad clamping and clamping of the infra- and suprahe-
patic inferior vena cava (IVC) has been fully described by others [4, 6, 10, 11]. We
will briefly summarize some technical fundamentals of this complex surgical proce-
dure. Complete and extensive mobilization of the liver is mandatory for safe TVE,
and in order to evaluate the resectability of the mass, especially in the case of tumors
involving the vena cava and/or the suprahepatic veins confluent to the vena cava. The
vena cava is dissected and encircled with an umbilical tape above and below the liver
by dividing the falciform ligament and taking down the left and right triangular liga-
ments to fully expose the bare area. The right adrenal vein should be divided to avoid
any risk of tearing during vena cava mobilization or during clamping.
The extension of hilar dissection with clear identification of the resection plane
should be performed before clamping since this reduces total ischemic time.
A test clamp is usually performed by occluding the suprahepatic vena cava and the
hepatic hilum for a few minutes, administering fluid to patients whose mean arterial
pressure decreases, repeating the test clamp until they remain hemodynamically stable.
After clamping, the liver parenchyma is transected with the technique of choice.
After LR is completed, the suprahepatic and infrahepatic clamps are released first,
and any major bleeding controlled before unclamping the portal vein (PV) and the
hepatic artery.
To avoid the well-known hemodynamic consequences of total IVC clamping, a
VV bypass may be systematically installed, possibly using the percutaneous tech-
nique to establish venous cannulation [7].
3.2.1 Reperfusion
Especially for the benefit of hepatobiliary surgeons not yet confident with LT, the
following is a summary of certain fundamental liver reperfusion steps after TVE.
3 Liver Resection and Total Vascular Exclusion 23
As in the case of LT, after ensuring that the anesthesia is prepared for release of the
vascular clamps, the suprahepatic clamp(s) is(are) first released, followed by the
infrahepatic clamp. Then the PV clamp is gently released as dictated by the
patient’s hemodynamics. In our opinion, the unclamping sequence plays an impor-
tant perioperative role in terms of hemodynamic variations. Unclamping the vena
cava before restoring the inflow optimizes venous return (from the lower extremi-
ties) and cardiac load before reperfusing the liver, counteracting the effects of the
blood from the ischemic liver.
3.3 Surgical Procedures
Different surgical refinements have been described since 1974 when Fortner et al.
reported the first series of LR with TVE combined with in situ HP of the liver [12].
The schematization of the different surgical techniques is reported in Fig. 3.1.
3.3.1 Total Vascular Exclusion Preserving Caval Flow
Although hemodynamic tolerance to TVE can be achieved in most cases, some

patients with borderline cardiac function do not tolerate TVE because of persistent
hypotension despite adequate intraoperative management. This situation may
require the use of extracorporeal VV bypass, or may even make LR not feasible.
Another hepatic vascular exclusion method associating portal triad clamping with
TVE TVE preserving TVE with in situ

caval flow hypothermic perfusion
TVE preserving caval Ante situm liver

flow and portocaval resection
shunt
Fig. 3.1 Schematic representation of the different techniques used to perform total vascular
exclusion. TVE total vascular exclusion
clamping of the major hepatic veins and preserving the caval flow was reported by
Elias et al. in 1995 [13], with or without the association of HP.
In 1999, Cherqui et al., reported the technique and results of their method of
vascular clamping during LR that allows both inflow and outflow occlusion while
preserving caval flow [14]. Again, this technique represents the application in LR of
observations made in LT with preservation of the caval flow using the “piggy-back”
procedure.
In the authors’ experience, vascular inflow is occluded by portal triad clamping
while outflow is occluded by clamping the major hepatic veins, including any major
right inferior hepatic vein, if present, and on the basis of the LR planned.
3.3.2 T
otal Vascular Exclusion with In Situ
Hypothermic Perfusion
In 2005, Azoulay et al. analyzed the benefit of resection under in situ hypothermic
perfusion of the liver over standard TVE [7]. In the authors’ experience, a VV
bypass was systematically installed. After a TVE and VV bypass, the PV was can-
nulated above the portal clamp, and a University of Wisconsin solution at 4 °C
administered for in situ HP of the liver. Both the volume and type of solution may
vary according to center preference. A cavotomy is usually performed above the
IVC clamp to drain the perfusate. Perfusion of the liver with cold solution, com-
bined with packing of the remnant liver with crushed ice has been demonstrated to
decrease liver temperature to a range of 13–21 °C. When the LR and vascular recon-
structions were completed, the liver was flushed with room-temperature serum
albumin (500 mL) via the catheter placed in the PV, after which, circulation was
restored as for the standard TVE.
3.3.3 T
otal Vascular Exclusion Preserving Caval Flow
and Portocaval Shunt
Further surgical refinements, such as the combination of preserved caval flow and
temporary PCS, are valuable techniques allowing resecting of tumors involving the
hepatocaval confluence while preventing hemodynamic and renal consequences
due to caval clamping and splanchnic congestion caused by PV clamping, and
avoiding the inconvenience of the VV bypass [9, 15].
Complete liver mobilization is accomplished as for standard TVE, with the pres-
ervation of the caval flow. Whatever the type of LR planned, the PV is dissected, and
the proximal stump of one of the portal branches (depending on the LR) is divided
to a sufficient length to enable end-to-side anastomosis to the infrahepatic IVC. A
side-to-side PCS may be performed between the main PV should the PV branches
prove to be too short. All the other hilar structures (the main bile duct, the common
hepatic and the other PV branch above the PCS) are properly clamped, including the
hepatic veins remaining with the remnant liver. A catheter into the remaining PV
branch above the clamp is used for the HP as already described. A venotomy is usu-
ally performed just below the clamp placed on the remaining hepatic vein(s) to drain
the perfusate. After completion of the LR, the liver is usually flushed with room-
temperature serum albumin (500 mL), the portal catheter removed, the vein inci-
sions (remaining PV branch and hepatic vein) sutured, and the PCS divided and
closed by suturing or stapling.
Very recently, the Reims team has proposed performing a latero-lateral PCS
using a prosthetic (Dacron) graft instead of the direct anastomoses between the
portal vein and the vena cava in the classic fashion, as already described by others
[9]. In the authors’ opinion, this anastomosis seems easier and feasible regardless of
the length of the proximal stump of the PV, affording complete mobility of the liver
during parenchymal transection. In addition, the authors proposed discharging the
cold perfusate through an opening of one of the proximal stumps of the resected
hepatic vein. This maneuver is aimed at preventing possible complications due to
future stenosis caused by suture of the remnant hepatic vein.
3.3.4 Ante Situm Liver Resection
Despite the term “ante situm”, this type of LR has not yet gained firm consensus.
A complex procedure, this type of LR is characterized by two fundamental opera-
tive steps: the ventral rotation and retraction of the whole liver to the ante situm
position, achieved by dividing the suprahepatic IVC; and preservation of the por-
tal pedicle. The principles of the ante situm procedure were first introduced by
Hannoun et al. in 1991 while the “ante situm resection technique” was reported by
Pichlmayr et al. in 1995 [16]. No more than sixty cases have been reported in the
literature [17].
Leaving aside certain technical variations and refinements that have been
described, the ante situm procedure can be summarized as follows. The liver is
completely mobilized as described for other TVE procedures, and the IVC com-
pletely dissected from the diaphragmatic hiatus to the level of the right renal vein.
An extracorporeal VV bypass is established similar to those reported and used in
LT, the PV is transected, and the portal inflow is included in the extracorporeal cir-
cuit. A cannula is inserted into the distal side of the transected PV for HP of the liver
during vascular exclusion. After clamping the infrahepatic IVC, hepatic artery and
bile duct, and once extracorporeal circulation is established, another clamp is placed
on the suprahepatic IVC, creating a TVE of the liver. We take particular care to dis-
sect the suprahepatic IVC from the surrounding diaphragm in order to ensure an
adequate portion of vena cava for later suturing of any kind of graft or complex
reconstruction of the hepatic vein confluence.
After portal HP, the suprahepatic IVC is transected below the clamp, and the
liver retracted and anteriorly rotated to the ante situm position. This position pro-
vides an excellent view of the confluence of the IVC and hepatic veins as well as the
inside wall of the vena cava from the back of the liver. Parenchymal transection can
be performed in different ways and will depend on surgeon preference.
Different kinds of graft can be used to replace the IVC in order to reconstruct
hepatic venous outflow. These include expanded polytetrafluoroethylene (ePTFE)
prostheses, knitted Dacron prostheses, bovine pericardium conduits, and cryopre-
served veins.
In our opinion, the notable advantage of the ante situm operation over the ex situ
LR is that it provides excellent exposure of the confluences of the hepatic veins
without artery or bile duct sectioning, thereby avoiding the risk of complications
related to hepatic artery reconstruction but also the potential risk of bacterial con-
tamination of the prosthetic graft caused by biliary reconstruction.
Recently, de Santibañes et al., reported a novel technique to avoid the shortcom-
ings of extracorporeal VV bypass, combining IVC replacement and PCS during an
ante situm LR [18]. The authors propose a side-to-side shunt between the PV and
the infrahepatic IVC using bank-preserved vein graft during a transitory TVE by
cross-clamping and sectioning the supra- and infrahepatic IVC before IVC replace-
ment using a PTFE prosthesis. They also indicate that during the time spent recon-
structing caval venous continuity with a prosthesis, splanchnic vascular flow was
diverted to the distal IVC below the vascular clamp through the venous graft
PCS. Following LR (including the retrohepatic IVC and the hepatic vein conflu-
ence), with the liver in an ante situm position and perfused with the hypothermic
preservation solution, reconstruction of the hepatocaval confluence was completed,
the portal cannula removed, and the PCS divided using stapler.
While we believe this uncommon procedure will be feasible and justified for
carefully selected patients, it should be stressed that given its complexity, ante situm
LR should be the exclusive province of teams of surgeons and anesthesiologists
familiar with LR and LT operating in a large-volume center.
3.4 Authors’ Comments
TVE is a further example of how LT and LR have benefited from each other’s expe-
rience. As more surgeons gained experience with LT, they became more confident
and comfortable, applying TVE during LR. Again, the attitude toward TVE varies
among centers: surgeons who perform hepatobiliary surgery and transplantation are
more likely to use this technique. The literature on this uncommon setting of hepa-
tobiliary surgery is scarce and includes only a limited number of cases performed,
with major focus on the technical aspects. Only one published experience highlights
patient morbidity and long-term results along with the surgical refinements [9].
It should be stressed that one of the most important aspects of these complex
operations is having a good anesthesia team. All our complex LR with vascular
exclusion have been performed with anesthesiologists with considerable experi-
ence of patients undergoing LT. In our institution we usually perform LT without
VV bypass, and our anesthesia team is getting much better at refining the intraop-
erative management of those patients who undergo clamping of both the suprahe-
patic and portal veins, confident in their ability to maintain hemodynamic stability
in that setting.
TVE during LR has attracted wide attention since its first description over 30 years
ago. Irrespective of the diagnosis, careful patient selection is crucial to ensure the
benefits outweigh the risks. However, despite advances in patient selection and surgi-
cal refinements, it remains a technically demanding surgical procedure. We believe
every general surgeon should know how to perform vascular exclusion, especially if
he/she is involved with trauma surgery or liver resection where the procedure is really
useful to repair hepatic veins. In agreement with other authors, we believe that patient
selection, experience with LT, and experienced intraoperative monitoring play a cru-
cial role in this complex procedure where the goal is to avoid unnecessary surgery.
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2. Foster JH, Berman MM. Solid liver tumors. Major Probl Clin Surg. 1977;22:1–342.
3. Huguet C, Nordlinger B, Galopin JJ, et al. Normothermic hepatic vascular exclusion for exten-
sive hepatectomy. Surg Gynecol Obstet. 1978;147:689–93.
4. Bismuth H, Castaing D, Garden OJ. Major hepatic resection under total vascular exclusion.
Ann Surg. 1989;210:13–9.
5. Huguet C, Vacher B, Delva E, et al. Hepatectomy for tumor under vascular exclusion.
Development of the ideas in the last decade. Apropos of experience with 41 cases. Chirurgie.
1983;109:146–51. [Article in French]
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extensive liver resection. Am J Surg. 1992;163:602–5.
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standard total vascular exclusion for complex liver resection. Ann Surg. 2005;241:277–85.
8. Shaw BW, Martin DJ, Marquez JM, et al. Venous bypass in clinical liver transplantation. Ann
Surg. 1984;200:524–34.
9. Azoulay D, Lim C, Salloum C, et al. Complex liver resection using standard total vascu-
lar exclusion, venovenous bypass, and in situ hypothermic portal perfusion. Ann Surg.
2015;262:93–104.
10. Emond JC, Kelley SD, Heffron TG, et al. Surgical and anesthetic management of patients under-
going major hepatectomy using total vascular exclusion. Liver Transpl Surg. 1996;2:91–8.
11. Habib N, Zografos G, Dalla Serra G, et al. Liver resection with total vascular exclusion for
malignant tumours. Br J Surg. 1994;81:1181–4.
12. Fortner JG, Shiu MH, Kinne DW, et al. Major hepatic resection using vascular isolation and
hypothermic perfusion. Ann Surg. 1974;180:644–52.
13. Elias D, Lasser P, Debaene B, et al. Intermittent vascular exclusion of the liver (without vena
cava clamping) during major hepatectomy. Br J Surg. 1995;82:1535–9.
14. Cherqui D, Malassagne B, Colau PI, et al. Hepatic vascular exclusion with preservation of the
caval flow for liver resections. Ann Surg. 1999;230:24–30.
15. Sommacale D, Rhaiem R, Piardi T, et al. Liver resection using total vascular exclusion of the
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shunt: a new technique for central tumors. Hepatobiliary Surg Nutr. 2017;6:207–9.
16. Pichlmayr R, Weimann A, Oldhafer KJ, et al. Role of liver transplantation in the treatment of
unresectable liver cancer. World J Surg. 1995;19:807–13.
17. Yamamoto Y. Ante-situm hepatic resection for tumors involving the confluence of hepatic
veins and IVC. J Hepatobiliary Pancreat Sci. 2013;20:313–23.
18. de Santibañes E, Cristiano A, de Santibañes M, et al. Ante-situm resection: a novel approach
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2015;17:94–6.
Cooling Techniques and Ex Situ
Liver Surgery 4
Umberto Cillo and Enrico Gringeri
4.1 Cooling Techniques
Hypothermic preservation is a strategy to reduce ischemia-reperfusion injury in both

liver transplantation and liver resection procedures. Despite numerous improvements
in the last few decades, hypothermic perfusion still remains the main method for liver
preservation. The liver is flushed and cooled with preservation solution, then stored
in ice. Hypothermia (4 °C) has been successfully used in the liver transplantation
setting since the early 1960s to prolong the viability of harvested liver grafts [1].
Hypothermia of the graft is obtained using two methods: hypothermic perfusion and
topical cooling. Hypothermic perfusion is achieved through abdominal aorta cannu-
lation or through portal vein cannulation. Topical cooling can be obtained by putting
ice on the liver surface and then storing the graft in an ice-bag. This specific process
of preservation—static cold storage (SCS)—is able to reduce cellular metabolism by
10- to 12-fold and to slow down energy demand. Despite the minimization of metab-
olism, a consistent anaerobic activity remains during hypothermic preservation. This
condition leads to adenine nucleotide pool depletion [2], lactate acidosis [3], increase
of chelatable iron [4], intracellular calcium accumulation [5], and sinusoidal endo-
thelial damage [6]. The depletion of energy stores, during the anoxia phase, creates
the generation of reactive oxygen species [7] leading to severe ischemia/reperfusion
injury of the graft when the oxygenated blood inflow is restored [8]. Two distinct
phases could be distinguished after reperfusion: an early phase (during the first 2 h)

U. Cillo (*) · E. Gringeri
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy
e-mail: cillo@unipd.it; enrico.gringeri@unipd.it

30 U. Cillo and E. Gringeri
and a late phase (from 6 to 48 h after reperfusion). During the first 2 h (early phase)
the activation of immune cells and oxidative stress occurs. At the beginning, Kupffer
cells are activated and ROS generation starts. This initial process causes moderate
hepatocellular oxidative damage. Subsequently the release of several proinflamma-
tory chemokines and cytokines—e.g., tumor necrosis factor (TNF-α) and interleukin
(IL-12 and IL-1β)—will promote and amplify the later secondary inflammatory
phase [9, 10]. The late phase (6–48 h after reperfusion) is characterized by the neu-
trophils releasing proteases (involved by the chemokines released in the early stage)
and other cytotoxic enzymes (e.g., collagenase, elastase, cathepsin G, and heparan-
ase) that act within cellular membranes and on matrix components, thereby promot-
ing cellular degradation [11].
The application of cooling techniques and the interest in the study of the patho-
physiology of liver ischemia/reperfusion injury has been translated from the trans-
plant setting to the liver surgery.
In the liver transplantation scenario, the cooling technique still represents the
main procedure for liver preservation. After harvesting, the liver graft is maintained
in a bag surrounded by ice in order to obtain a temperature of 4 °C until transplanta-
tion. This kind of preservation is named static cold storage preservation. However,
static cold storage preservation is not able to protect some types of damaged grafts
and particularly those obtained from donors after cardiac death. The lack of perfu-
sion during static cold storage preservation and subsequent reperfusion leads to fatal
morphological changes of endothelial cells by activation of Kupffer cells, apoptosis
and leukocyte adherence. These processes lead to an alteration of microcirculation.
On the other hand, the ATP depletion during static cold storage preservation leads
to a biliary epithelium alteration with damage to cholangiocytes. This type of injury
is the main cause of biliary stricture after liver transplantation, in particular when
liver grafts obtained from donors after cardiac death are used.
In the last decade, some machine perfusion preservation systems have been
developed with growing interest. Machine perfusion preservation is an engineered
dynamic continuous liver perfusion system that is able to mimic the physiologic
conditions able to remove toxic agents generated during ischemic phase. Regarding
the temperature settings, several types of preservation system have been developed.
The dynamic preservation of the graft is feasible in conditions of:
• hypothermia hypothermic (4 °C) machine perfusion (HMP)
• subnormothermia subnormothermic (20–30 °C) machine perfusion (SNMP)
• normothermia normothermic (37 °C) machine perfusion (NMP).
Several clinical and preclinical papers report the pros and cons of each preserva-
tion temperature setting.
4.2 Total Vascular Exclusion and Ex Situ Liver Surgery
Hepatic resection represents the gold standard treatment for primary [12] and meta-
static liver tumors [13]. New oncological and biological protocols have improved
overall survival and hepatic resectability defining new surgical criteria. Particularly,
4 Cooling Techniques and Ex Situ Liver Surgery 31
personalized medicine and precision medicine have redefined surgical indication

and therapeutic strategies [14]. The improved efficacy of oncological protocols
pushed the surgeon to think differently. The recent concept of surgical resectability
moved from the old paradigm “what can be resected?” to the new paradigm “what
has to remain?” in which patient survival and the radicality of liver resection (R0)
are the primary end-points. Extreme hepatic resections are accepted respecting the
same considerations: hepatic vascular inflow and outflow have to be preserved and
vena cava and hepatic veins reconstruction are allowed; biliary drainage has to be
guaranteed; future remnant liver (FRL) has to be adequate; R0 resection is the goal.
4.2.1 Total Vascular Exclusion
With these concepts in mind some technical knowledge can be translated from the
transplant setting to the not-transplant one. Hypothermic liver perfusion is routinely
used in high-volume centers by surgical teams with liver transplant expertise. In the
presence of a liver cancer with critical location close to hepatocaval confluence, liver
resection can be safely performed under total vascular exclusion (TVE) and con-
comitant hypothermic parenchymal perfusion. The first case was described by
Huguet et al. in 1976 [15]. Bismuth et al. published the first large series of liver resec-
tion under TVE in 1989 [16]. They reported 51 cases of TVE. One death 45 days
after surgery for multiorgan failure and sepsis was described, with a morbidity rate
of 14%. The mean duration of vascular exclusion was 46.5 ± 5.0 min (range,
20–70 min). When TVE exceeds 60 min hypothermic perfusion probably has to be
associated. Azoulay and Bismuth compared TVE <60 min with TVE ≥60 min and
hypothermic perfusion [17]. They concluded that, compared with standard TVE of
any duration, hypothermic perfusion of the liver is associated with a better tolerance
to ischemia. In addition, compared with TVE ≥60 min, hypothermic perfusion is
associated with better postoperative liver and renal functions and a lower morbidity,
suggesting the use of hypothermic perfusion when TVE exceeds 60 min.
Much more has to be understood about the pathophysiology of hypothermic per-
fusion. Even though the perfusate is at 4 °C, in the best possible conditions, intrapa-
renchymal temperatures usually do not go below 12–14 °C. Furthermore,
intraparenchymal temperatures during perfusion may hugely vary according to
peripheral perfusion conditions, amount of perfusate, duration of perfusion, loss of
perfusate from the transection surface, and environmental temperatures. Such a
variability may have different degrees of relevance on the overall effects of ischemia-
reperfusion injury. With a number of parallelisms with the liver transplant setting,
the presence of underlying parenchymal morbidities such as steatosis, fibrosis,
severe degrees of inflammation may impact the overall results of the hypothermic
process.
For these reasons we adopted a machine perfusion system during TVE to warrant
more stable and enduring ischemic temperatures more homogeneously perfusing
the whole liver parenchyma during the entire transection time. This experience
(Video 4.1), as far as we are concerned, is the first in humans ever.
4.2.2 Ex Situ Surgery
When the tumor grows close to the hepatocaval confluence involving all the three
hepatic veins or infiltrates the vena cava and a complex vascular reconstruction may
be too difficult to be radically excised by means of a TVE, an ex situ liver resection
may be needed.
Ex situ liver resection was first described by Pichlmayr in the early 1980s but
was progressively abandoned due to his high morbidity and mortality rate [18]. This
complex kind of surgery requires surgical expertise in liver transplantation for the
use of measures originally developed for transplantation, such as hypothermic liver
perfusion, venovenous bypass, complex vascular reconstructions. Ex situ liver sur-
gery includes ex situ in vivo (or ante situm) liver surgery and ex situ ex vivo liver
surgery (or liver autotransplantation) (Fig. 4.1).
In ex situ in vivo liver resection (ante situm) the vena cava is transected 1 cm
above the confluence of the hepatic veins and the liver can be rotated anteriorly in
order to expose its posterior face. The hepatic hilum is not interrupted.
On the contrary, in the ex situ ex vivo liver resection (autotransplantation) the
vena cava, portal vein and hepatic artery are totally sectioned. The liver undergoes
a bench procedure in order to better control the liver partition, to improve the capa-
bility to detect and preserve small glissonian and/or hepatic pedicles and to perform
complex vascular reconstructions. The bench surgery can be performed while a
machine perfusion liver preservation is applied (Figs. 4.2, 4.3, and 4.4).
Ex situ liver resection is indicated for primary and metastatic liver cancer (hepa-
tocarcinoma, cholangiocarcinoma, colorectal liver metastases) considered unresect-
able with conventional surgery [19].
Clearly, the ex situ surgery represents an extreme therapeutic approach to be
dedicated only to carefully selected complex cases.
Our first experience in this field was carried out on large animals. We created a
porcine model of autotransplant using subnormothermic machine perfusion for
organ preservation during the bench surgery [20]. This allowed us to study and
understand the various problems with the aim to translate the surgical model to the
clinical setting (Fig. 4.5).
The ex situ surgery of unresectable liver tumors has been developed to overcome
some fundamental limitations of liver resection and liver transplantation. As already
mentioned, conventional liver resection, in fact, is not indicated in the treatment of
hepatic neoplasms with critical locations, in particular when they arise close to the
outflow of the hepatic veins into the inferior vena cava. In the literature there are no
unanimous criteria to define an unresectable tumor with the exception of those cases
in which there is a simultaneous involvement of all the hepatic veins. Liver transplan-
tation, however, is only suitable for a small group of cancer patients: the problem of
post-transplant immunosuppression and the consequent potential for higher inci-
dence of recurrent disease significantly limit the use of liver transplant for the major-
ity of tumors. Ex situ surgery allows the surgeon to access tough-to-reach areas
allowing operating in a bloodless field for long periods. In this way it is possible to
perform accurate parenchymal resection but also complex vascular reconstruction.
Fig. 4.1 Different liver a

resection strategies with
vascular control: total 1
vascular exclusion and ex
situ liver resection. (a)
Total vascular exclusion:
the vena cava, portal vein 2
and hepatic artery are
clamped; in situ 3
hypothermic perfusion. (b)
Ex situ in vivo or ante
situm: the vena cava is
transectioned 1 cm above
the confluence of the
hepatic veins; the liver can
be anteriorly rotated. (c)
Ex situ ex vivo or b
autotransplantation: the
vena cava, portal vein and 1
hepatic artery are totally
sectioned; the liver is
subjected to a bench
procedure. 1, portal vein 2
line perfusion; 2, portal
line of venovenous bypass:
3, hepatic artery 3
A number of clinical series have been reported so far. One of the biggest is from
the University of Hannover [21]. It includes 47 patients, 24 of whom underwent ex
situ ex vivo liver resections and the remaining 23 ante situm liver resections. All
patients had liver tumors located in critical positions. Most of them were suffering
from metastatic colorectal carcinoma. Analyzing the “ex vivo” group of patients,
Fig. 4.2 Bench surgery during hypothermic machine perfusion preservation (scheme)
Fig. 4.3 Bench surgery

during hypothermic
machine perfusion
preservation (U. Cillo’s
experience)
Fig. 4.4 Bench surgery

during hypothermic
machine perfusion
preservation (U. Cillo’s
experience)
Fig. 4.5 Porcine model of ex situ ex vivo liver surgery
the authors observed a high incidence of liver failure after surgery (6 out of 24). Five
patients underwent liver transplantation as a salvage procedure. If we consider all
the series, liver transplantation was done in seven patients for liver failure or inabil-
ity to complete the bench resection but only two survived more than 6 months after
the transplant. The current regulation for organ allocation would not permit liver
transplantation in such cases in many countries. In general, only seven patients sur-
vived more than 18 months but in the subgroup of patients treated for colorectal
metastasis, the median survival reached 21 months. The patients with Klastkin’s
tumor had instead the worst prognosis probably due to the extension of disease to
the hilum structures along with a major cholestatic disease that reduces ischemic
tolerance.
The Paul Brousse group (Paris) presented its series of four patients undergoing
ante situm liver resection [22–24]. No perioperative mortality was described.
Belghiti et al. [25] published in 1991 their series of three patients undergoing
liver resection with ante situm liver resection. Two patients, who were operated on
without using a femoro-porto-jugular bypass, had hemodynamic decompensations
during reperfusion of the liver and one patient died.
Mehrabi et al. (Heidelberg) published in 2011, their series of seven patients
undergoing ante situm liver resection [26]. They reported a 10-month survival of
100%. Complete oncological radicality was achieved in five patients, in one case the
margins were not evaluable, and one patient received a R1 resection. The authors
suggest that ante situm surgery can be applicable in clinical practice with a low risk
of perioperative mortality compared with ex vivo surgery, which is associated with
high risk of liver failure.
The University of Florida group (Gainesville) presented their own experience on
ex situ liver surgery [27–29]. They operated on five patients: four patients received
ex situ ex vivo liver surgery and one received an ante situm liver resection. They
describe one death: one patient who underwent ex situ ex vivo liver resection died
4 months after surgery due to sepsis for bowel perforation.
Malde et al. published in 2011 their series of patients who received inferior vena
cava resection with hepatectomy [30]. Six patients underwent an ex situ ex vivo
liver resection and patients an ante situm liver resection. They reported one periop-
erative death due to respiratory failure after ex situ ex vivo liver surgery.
Our experience, the first in Italy, started in 2011 and includes now 15 cases of
various underlying oncologic etiologies. The details about the long-term results and
patient characteristics are under submission for publication in these weeks.
In the literature, 89 cases of ex situ liver surgery are reported: 44 ex vivo ex situ
and 45 ante situm.
Only two intraoperative deaths are described: one for massive retroperitoneal
bleeding in a patient with renal cell carcinoma with liver metastases who underwent
an ante situm liver resection [31] and the other for hemodynamic failure at reperfu-
sion during ante situm surgery [25]. Globally seven patients died in the first months
after surgery, the majority due to respiratory distress.
When the tumor invades the vena cava, vascular replacement is needed and
associated with the ex situ liver resection (Figs. 4.6 and 4.7). Recently Tomimaru
et al. reviewed the literature about vena cava replacement during ex situ liver resec-
tion [32]. They selected in their analysis 13 papers with vena cava replacement
including 111 patients. For the caval patch, an artificial vascular graft, an expanded
polytetrafluoroethylene (ePTFE) graft (Gore-Tex; WL Gore & Associates Inc.,
Flagstaff, AZ, USA), or bovine or horse pericardium were used. The ePTFE graft
was used in most cases as the artificial vascular graft for the circumferential
replacement of IVC, and the Dacron graft (Hemashield; Meadox Medicals Inc.,
Oakland, NJ, USA) was used in limited cases. Operative mortality was found in
nine cases (8.1%) out of 111 cases reported in the studies, and a thrombus in the
Fig. 4.6 Hepatocaval
confluence reconstruction
(U. Cillo’s experience)
Fig. 4.7 Vena cava replacement (U. Cillo’s experience)
vascular graft was observed in two cases. In more than half of the previous studies,
antithrombotic therapy was given after the reconstruction, but no clear criteria for
giving antithrombotic therapy were commented upon in any study. The review
failed to record the prosthesis infection that represents another crucial point in the
use of artificial vascular grafts.
In conclusion, ex situ liver resection is a challenging type of surgery feasible
only in a superselected category of patients. It could require caval replacement and
complex vascular reconstructions. The mortality and morbidity rates are higher than
in conventional surgery (close to 30% as reported by Pichlmayr) [18]. Some surgi-
cal procedures are transferred from the transplant setting making this surgery fea-
sible only by experienced surgeons in high-volume centers.
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Machine Perfusion in Liver
Transplantation 5
Riccardo De Carlis, Vincenzo Buscemi, Andrea Lauterio,
Stefano Di Sandro, and Luciano De Carlis
5.1 Introduction
There are two strategies to protect the liver graft from ischemic injury in the inter-
val between procurement and implantation: static cold storage (SCS) and machine
perfusion (MP). In SCS, the graft is immersed in the preservation solution and
maintained on ice. In ex situ MP, the preservation solution is actively circulated
through the graft. In situ MP refers to graft perfusion within the donor before
organ procurement, such as the normothermic regional perfusion (NRP), during
which the donor’s circulation is maintained by an extracorporeal pump and
regionalized to the abdomen by occluding the descending aorta [1]. Herein, we
will focus on ex situ MP in liver transplantation practice and its potential applica-
tions in liver resection surgery.
R. De Carlis (*)
V. Buscemi · A. Lauterio · S. Di Sandro
e-mail: vincenzo.buscemi@ospedaleniguarda.it; andrea.lauterio@ospedaleniguarda.it;
stefano.disandro@ospedaleniguarda.it
L. De Carlis

42 R. De Carlis et al.
5.2 History
Machine perfusion (MP) of the liver was first introduced by Brettschneider and
Starzl in the late 1960s [2]. In the Brettschneider machine, the liver was maintained
in a refrigerated hyperbaric chamber and perfused with fresh homologous blood
through the hepatic artery and portal vein [3]. However, this device was cumber-
some and heavy to transport, and its use was soon abandoned for SCS, which
became the standard for liver preservation after the introduction of the University of
Wisconsin (UW) preservation solution [4].
5.3 Indications
In recent years, there has been a resurgence of interest in MP for the care of grafts
with extended criteria. Extended criteria include grafts with a high amount of mac-
rosteatosis (>30% or >40%), prolonged cold ischemia (>12 h), a very high donor
age (>80 years), or additional warm ischemia as in the case of donation after circu-
latory death (DCD) [5, 6]. These grafts are more vulnerable to cold ischemia and
therefore need optimization before implantation, especially when transplanted into
high-risk recipients—retransplantation, high MELD (model for end-stage liver dis-
ease) score. MP offers three main advantages over SCS: a high-quality and pro-
longed preservation, the ability to optimize graft function (reconditioning), and the
possibility of testing the graft’s viability prior to implantation [7].
5.4 Timing and Temperature
There are different types of MP, which differ according to timing and temperature.
SCS and MP are not mutually exclusive and can be used in combination. If used for
the entire preservation time, MP requires a transportable device or a donor local to
the transplant center. In this modality, a short period of SCS is still required in the
last phase of organ procurement, throughout back-table preparation, and during
implantation to avoid warm ischemia when anastomoses are performed. Therefore,
MP is most frequently used in the recipient hospital after the organ is maintained in
SCS during initial transportation (Fig. 5.1). Three temperature ranges have been
reported for MP in animal and clinical studies [7]:
• 0–12 °C for hypothermic MP (HMP)

• 13–34 °C (usually 20–22 °C) for subnormothermic MP (SNMP)
• 35–38 °C for normothermic MP (NMP).
The main differences between SCS and MP at different temperatures are sum-
marized in Table 5.1.
5 Machine Perfusion in Liver Transplantation 43
Procurement Transport Implantation
In situ MP
SCS
SCS MP
MP
MP SCS
Fig. 5.1 Timing of machine perfusion (MP). In situ MP refers to graft perfusion within the donor
before organ procurement. Ex situ MP is most frequently used in the recipient hospital after the
organ is maintained in static cold storage (SCS) during initial transportation. If used for the entire
preservation time, MP requires a transportable device or a donor local to the transplant center. MP
before SCS has also been reported
Table 5.1 Characteristics of different preservation methods

Characteristic SCS HMP SNMP NMP
Temperature 4 °C 0–12 °C 20–22 °C 35–38 °C
Vessel No Single/dual Dual Dual
cannulation
Perfusate Perfusion Perfusion Perfusion solution/oxygen Oxygen carrier
solution solution carrier
Oxygen No No/(yes for Yes Yes
HOPE)
Metabolism Low Low Decreased Yes
Energy recovery No No/(yes for Yes Yes
HOPE)
Bile production No No Decreased Yes
Viability testing No No (ongoing Yes Yes
research)
Reperfusion Yes Low Decreased Yes
injury
HMP hypothermic machine perfusion, HOPE hypothermic oxygenated perfusion, NMP normo-
thermic machine perfusion, SCS static cold storage, SNMP subnormothermic machine perfusion
5.5 Hypothermic Machine Perfusion
After Brettschneider’s early attempts, there were no clinical applications of HMP

until Guarrera et al. showed in 2010 that HMP of standard livers was associated
with lesser ischemic injury than SCS [8]. Subsequently, Dutkowski et al. explored
the possibility of delivering oxygen during HMP at a higher pressure than atmo-
spheric oxygen partial pressure (PO2), an approach called hypothermic oxygenated
perfusion (HOPE). They first used this approach in human livers from DCD [9]. An
example of an HMP circuit is shown in (Fig. 5.2).
5.5.1 Physiological Mechanisms
The rate of most enzymatic reactions decreases with decreasing temperature,

according to the van’t Hoff equation [10]. Under hypothermic conditions, metabo-
lism is reduced but not entirely halted, leading to the depletion of energy stores and
accumulation of metabolites. The continuous flow of preservation solution through
the graft, which permits sinusoidal cleaning and repair of the glycocalyx, makes
HMP more advantageous than SCS [11, 12]. Additional advantages are linked to
HOPE. Delivery of gaseous oxygen directly through the hepatic veins before reper-
fusion (oxygen persufflation) has been reported to improve early aerobic metabo-
lism and primary graft function after liver transplantation [13, 14]. Several studies
have demonstrated that only 1–2 h of HOPE promote adenine triphosphate (ATP)
resynthesis and, notably improves mitochondrial activity by promoting forward
instead of reverse electron flow, as observed in animals during hibernation or winter
rest. Consequently, reperfusion of ischemic livers that have undergone HOPE sig-
nificantly reduces the release of reactive oxygen species and inflammatory media-
tors, thereby reducing reperfusion injury (Fig. 5.3) [6, 11, 12].
Fig. 5.2 Example of a

hypothermic machine
perfusion circuit. The
perfusion solution is
pumped through the
hepatic artery and portal
vein (dual perfusion), then
drains passively into a
reservoir over which the
liver is suspended. In
single portal perfusion,
only the portal vein is
cannulated. Cannulation is
always performed far away
from the anastomotic sites
Electron leakage
Kupffer cell ROS

e– O2 e–
DAMPS I II III IV
Endothelial cell
Reduces ROS
release
Stellate cell
ROS Sinusoidal cleaning
glycocalyx repair HOPE
Allow ATP
resynthesis
Mitochondrion
hepatocyte
Fig. 5.3 Mechanisms of hypothermic oxygenated perfusion (HOPE). HOPE promotes adenine
triphosphate resynthesis and reduces the release of reactive oxygen species (ROS) and damage-
associated molecular pattern signaling (DAMPS) proteins, which activate Kupffer cells after reper-
fusion. Sinusoidal cleaning and glycocalyx repair do not depend on oxygenation
5.5.2 Hypothermic Oxygenated Perfusion in Clinical Practice
According to the HOPE protocol, liver grafts are perfused through the portal vein
with cooled (10 °C) and oxygenated (40–60 kPa) UW gluconate solution, with a
perfusion pressure of no more than 3 mmHg to limit shear stress. Schlegel et al.
demonstrated that HOPE spreads to the entire biliary tree, exclusively via the portal
vein, within the first 5 min of perfusion, which eliminates the need for arterial perfu-
sion [15]. Perfusion is maintained for 1–2 h until the recipient hepatectomy is com-
pleted [9]. This approach has been reported to reduce preservation injury and
ischemic cholangiopathy, thus prolonging graft survival in DCD livers [16]. Our
group first reported the sequential use of NRP and HOPE in human DCD livers to
overcome the legal no-touch period of 20 min for death declaration in Italy [17].
The resulting protocol has proven effective in salvaging DCD livers that would
otherwise be discarded because of their prolonged warm ischemia [18, 19].
5.5.3 Limitations and Future Perspectives
Although successful liver transplantation has been reported even after 72 h of HMP
[3, 20], it remains unclear how long a liver graft can be safely maintained with this
method. Indeed, a time-dependent increase in vascular resistance has been observed
when HMP extends beyond 18 h, which has been attributed to prolonged shear
stress on the sinusoids [11, 21]. However, we have recently demonstrated that a
limited period of HOPE after SCS can be used when necessary, to safely prolong the
total cold ischemia time for up to 20 h [22].
The main limitation of HMP is the current shortage of methods to assess graft
function during perfusion. As a result, liver selection during HMP is difficult to
perform in clinical practice. Indeed, no active bile production can be observed dur-
ing hypothermia [6]. Although vascular resistance is currently used as a marker of
graft function for kidneys, this parameter is insensitive for the liver [23]. Only one
recent study suggested a potential role of arterial resistance in liver evaluation [24].
We await the results of various ongoing studies to clarify whether analysis of per-
fusate during HMP will permit reliable graft selection.
5.6 Normothermic Machine Perfusion
The rationale for NMP is to reproduce physiologic circulation outside the body
using warm oxygenated blood or a surrogate solution. This would promote ATP
resynthesis and enable the transplant surgeon to make an assessment of liver func-
tion prior to transplantation, with appropriate predictive tools [25]. At least three
commercial devices have been used in clinical trials to date. All function on similar
principles but differ in terms of portability, degree of automation, substrate type and
delivery, pressure, and flow targets. NMP devices use a normothermic suspension of
red blood cells in a colloid to perfuse the liver in a fully cannulated system or an
open system. The perfusate is pumped out of the inferior vena cava using a centrifu-
gal pump or allowed to drain passively, and then heated and oxygenated. This is
followed by diversion of the perfusion either to the hepatic artery via a high-pressure,
low-flow system or to the portal vein via a high-flow, low-pressure system.
Continuous blood gas analysis enables monitoring and control of PO2 and PCO2
levels, which facilitates the maintenance of acid-base homeostasis. Continuous
infusions ensure sufficient vasodilation, protection against coagulation, and provi-
sion of an environment that enables near-physiologic, metabolic, and synthetic liver
function [26].
5.6.1 A
dvantages of Normothermic Machine Perfusion
and Clinical Practice
NMP may help overcome complications, such as primary graft non-function or

early graft dysfunction, by allowing liver function assessment prior to implantation.
The benefits of NMP have been tested in several studies, which suggest that the
viability of donor organs can be predicted by a combination of synthetic, hemody-
namic, and metabolic parameters during the perfusion phase. This provides a func-
tional assessment of the donor liver that is not possible with SCS or HMP [27].
These parameters include bile production, stability of hepatic artery and portal vein
blood flow and/or pressure, and lactate and transaminase levels. Mergental et al.
suggested criteria that included perfusate lactate <2.5 mmol/L, bile production
within 2 h of initiating NMP, pH>7.3, hepatic artery flow >150 mL/min, portal vein
flow >500 mL/min, and homogenous graft perfusion with soft parenchymal consis-
tency achieved within 3 h of initiating NMP [28].
Friend et al. were the first to describe NMP and its benefits by measuring alanine
aminotransferase levels and Factor V production during perfusion [29]. The first
human NMP trial in 2013 confirmed the safety of this technology. In 20 patients
transplanted with livers after NMP, graft survival and patient survival were both at
100% at 6 months [30]. A similarly structured trial in Canada reported one graft loss
over 10 cases because of technical failure and noted a prolonged hospital stay for
patients that underwent this procedure [31].
A recent randomized clinical trial of 220 liver transplantations reported that
NMP was associated with a 50% lower level of graft injury than conventional
SCS, as measured by hepatocellular enzyme release; this occurred despite a
54% longer mean preservation time. Early allograft dysfunction was 72% lower
in the NMP group than in the SCS group, and post-reperfusion syndrome was
more common with SCS. Interestingly, the number of discarded organs was over
50% lesser in the NMP group than the SCS group, which resulted in 20% more
transplanted livers. A 20% increase in the number of transplantable donor livers
would hugely impact the mortality or dropout rates of patients on transplanta-
tion waiting lists around the world. However, this trial failed to demonstrate a
significant difference in bile duct complications, graft survival, or overall sur-
vival with NMP compared with SCS [32]. As summarized in Table 5.2, similar
beneficial results of NMP have been reported in few other clinical trials pub-
lished to date [30, 31, 33].
5.6.2 Limitations and Remaining Questions
NMP technology does not eliminate reperfusion injury, but rather brings the process
ex situ. Few studies have compared NMP with HMP with respect to reperfusion
injury. In a study of rodent DCD livers, Schlegel et al. demonstrated that NMP
reduced ischemic injury compared with SCS but was not as effective as HOPE in
decreasing hepatocyte injury and inflammation because the full cascade of reperfu-
sion injury was initiated with NMP [34].
In theory, NMP could indefinitely prolong total preservation time. In a study
conducted by Ravikumar et al., one liver was perfused for 18.5 h before successful
transplantation [30]. Similarly, Bral et al. reported maintaining a DCD liver with
NMP for 22.5 h before successful transplantation [31].
Nevertheless, NMP requires high expertise for correct use and strict surveillance
throughout the entire perfusion period. Unrecognized vascular occlusion or system
failure during NMP could produce irreversible graft damage because of warm isch-
emia, whereas HMP does not face such challenges. Bral et al. reported one case of
discarded liver after NMP caused by an unrecognized twist in the donor portal vein,
which was hidden above the tissues of the hilar plate [31]. Watson et al. described
48
Table 5.2 Outcomes following NMP or SCS in clinical trials

Discard 30-Day 6-Month 6-Month biliary
Authors NMP:SCS TIT Peak AST EAD rate PNF mortality GS complications 1-Year OS
Ravikumar et al. [30] 20:40 nsd NMP nsd na nsd nsd nsd nsd nsd
Bral et al. [31] 10:30 NMP nsd nsd na nsd nsd nsd nsd nsd
Nasralla et al. [32] 137:133 NMP NMP NMP NPM nsd nsd nsd nsd nsd
AST aspartate aminotransferase, EAD early graft dysfunction, GS graft survival, na not available, NMP normothermic machine perfusion, nsd not significantly
different, OS overall survival, PNF primary non-function, SCS static cold storage, TIT total ischemic time
R. De Carlis et al.
two types of technical problems during NMP: occlusion of the biliary catheter, which
prevented the assessment of bile production (but without long-term biliary sequelae),
and occlusion of the hepatic vein catheter shortly after initiating perfusion [35].
Current widespread use of NMP for liver transplantation is limited by high cost
and shortage of clinical trial evidence. Further research is necessary to evaluate the
full potential of NMP and its advantages.
5.7 Subnormothermic Machine Perfusion
SNMP combines the benefits of lower metabolic demands at a subphysiological

temperature with the benefits of maintaining sufficient metabolism for viability test-
ing and improved graft function [36, 37]. Therefore, it can serve an intermediate
role between HMP and NMP. Gradual rewarming during SNMP possibly reduces
reperfusion injury by employing stepwise normalization of temperature and meta-
bolic demands [38, 39]. Recently, Tolboom et al. reported that oxygen carriers were
unnecessary with SNMP preservation for 5 h [40]. Berendsen et al. also demon-
strated successful preservation of rat DCD livers using temperature-uncontrolled
SNMP without oxygen carriers for 3 h, and subsequent transplantation, with good
survival outcomes [36].
Data from animal experiments and human discarded livers [41] using SNMP
appear promising for introducing this technology into clinical practice. Future stud-
ies should assess the potential advantages of SNMP over the gold standard SCS, and
over HMP and NMP.
5.8 I nterplay Between Machine Perfusion

and Hepatobiliary Surgery
5.8.1 Liver Splitting During Machine Perfusion
Split-liver transplantation involves the division of one liver graft into two hemi-
grafts. It is used to overcome the shortage of donor organs, especially pediatric
donors. There are two main techniques of liver partition: the ex situ method and the
in situ method. The in situ technique involves parenchymal transection in the donor
prior to aortic cross-clamping. It reduces cold ischemia time and simplifies the iden-
tification of biliary and vascular structures, but requires a longer operative time [42].
Conversely, the ex situ technique has been associated with a higher incidence of
postoperative hemorrhage [43].
The use of MP in liver splitting has the potential to combine the advantages of
both liver partition techniques. Throughout splitting, the cut surface can be inspected
and vessels ligated to ensure hemostasis. NMP permits continuous viability assess-
ment. This may contribute to recipient selection, aid with informed decision-making,
and facilitate the logistics of transplanting two grafts by preventing a long cold isch-
emia time. Barney et al. described a case of ex situ liver splitting using NMP in a liver
that was unsuitable for transplantation [44]. A similar case was described by
Brockmann et al. using a discarded DCD liver, which emphasized that splitting can
be performed in the context of a fully anticoagulated perfusion system without loss
of perfusion, thereby minimizing ischemic injury [26].
5.8.2 Machine Perfusion in Liver Resections
A large liver tumor, with or without vascular infiltration, is a challenge even for an
expert liver surgeon. The need for extended liver resection and vascular reconstruc-
tion often requires prolonged vascular clamping and multiple blood transfusions
because of major blood loss. Intermittent hilar clamping or total vascular exclusion
(TVE) are frequently used by most liver surgeons, but are generally limited to short
periods to avoid ischemic liver injury [45–47].
When longer durations are required, other techniques, such as in situ hypother-
mic perfusion, venovenous bypass, portacaval temporary shunt, or an ex situ tech-
nique, are required to reduce the risk of postoperative liver failure [48–50]. The ex
situ technique allows vascular reconstruction or complex hepatectomies to be per-
formed at a comfortable bench table for a prolonged time, which limits bleeding and
the need for transfusions. However, it requires vascular anastomosis for liver auto-
transplantation, which increases morbidity and mortality [50–52].
For prolonged and complex ex situ resection and vascular reconstruction,
Gringeri et al. have proposed using MP, which could prevent cold ischemic injury
and may be suitable in livers with chronic disease [53]. Currently, MP use during
complex hepatectomies is limited by costs, a prolonged anhepatic phase, and
restricted liver mobilization during perfusion. Further studies are necessary to eval-
uate the advantages of using MP in ex situ liver resections.
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Liver Vascular Reconstructions
6
Umberto Cillo and Alessandra Bertacco
6.1 Introduction
Liver resection, with R0 margins, is associated with improved survival over non-
operative treatments for both primary and secondary liver malignancies.
In the past, liver tumors with vascular involvement were considered unresectable
and with a poor outcome. These patients were directed to alternative non-curative
therapies. In recent years, there has been an evolution in surgical attitude and many
centers perform vascular resections and reconstructions in order to achieve R0
resection with a potential for an improved oncological outcome and a consequent
survival benefit. Experience in the liver transplant field, improvements in surgical
techniques (i.e., ex vivo resection, in situ cold perfusion), the use of microvascular
surgeries, careful preoperative assessment and intraoperative anesthesiological sup-
port are the main features representing the backbone of this new tendency. Evolution
in the management of liver malignancies has led to extend long-term survival in part
by means of an increased rate of resectability with curative intent. If portal vein
resection (PVR) is currently routinely performed, experiences with the hepatic
artery, hepatic veins and inferior vena cava (IVC) are increasing; at the same time
the mortality and morbidity related to this complex surgery are decreasing in high-
volume centers. The lack of alternative therapies and the poor outcome of non-
operative management seem to justify this aggressive approach.
In the particular setting of perihilar cholangiocarcinoma (pCCA), the “no touch”
technique was introduced in 1999 by Neuhaus et al. [1]. They observed an improved
middle-long-term postoperative survival when an extended hepatic resection was
combined with an en bloc resection of the portal confluence, carefully avoiding any
U. Cillo (*) · A. Bertacco

e-mail: cillo@unipd.it; bertaccoale@gmail.com

54 U. Cillo and A. Bertacco
dissection close to the tumor. The rationale for such an en bloc resection is to avoid
the risk of cancer cells dissemination during portal vein dissection in the hilar region.
In 2012 the same group [2] confirmed the oncological superiority of the “no touch”
resection compared to classic major hepatectomy for hilar cholangiocarcinoma
(5-year survival, 58% vs. 29%, p = 0.021). Since then, this technique has represented
one the core concepts in hepatobiliary cancer surgery.
6.2 Inferior Vena Cava and Hepatic Veins
Major vascular involvement is one of the most common reasons for unresectability.
Tumor location in tight adhesion to the IVC may represent a tough challenge; nev-
ertheless, skills acquired in the liver transplant field and in living donor liver trans-
plantation (LDLT) have played a relevant role in no longer considering it a
prohibitive region to approach. Resection of the vena cava is now diffusely accepted
for all hepatic tumors, including human hepatocellular carcinoma, cholangiocarci-
noma, and colorectal liver metastases; it has become reasonably safe, but it is still
limited and with heterogenous applications among different centers. Over the last 2
decades, advances in surgical techniques, perioperative care and interdisciplinary
teamwork have represented a paradigm shift for patients undergoing complex liver
reconstruction after vascular resections. Liver resection extended to the IVC is man-
datory to achieve R0 resection when major vascular invasion is detected pre- or
intraoperatively. In the case of involvement of the hepatic veins (HVs) a combined
liver-HVs resection is required not only to obtain a clear margin but also to avoid
major hepatectomies in cases of insufficient/borderline future remnant livers. A
“parenchymal-sparing” approach with HVs reconstruction can be an alternative to
major hepatectomies especially in patients that have received intensive chemother-
apy before surgery.
An Italian group has recently produced the results of a vascular detachment
series. In the case of liver metastases from colorectal cancer the long-term results
were similar to those achieved with R0 resection. A further approach allows the
sacrifice of one major invaded HV after confirming the presence of venous collater-
als draining into the contralateral HVs.
We believe that when approaching a tumor with potential vascular involvement
the team has to guarantee the ability to manage the case by both detachment or vas-
cular reconstruction with or without total vascular exclusion (TVE) with the same
degree of confidence.
Surgical procedure has to be carefully planned; grafts of adequate diameter and
length need to be available and advanced techniques—such as TVE, venovenous
bypass (VVB), ante situm resection—need to be in the armamentarium of the team
facing hepatic vascular invading tumors.
TVE consists of clamping the portal triad and IVC above and below the liver and
results in various degrees of ischemic damage that could be attenuated by using in
situ hypothermic portal perfusion under a VVB [3] or a venovenous extracorporeal
membrane oxygenation (VV-ECMO) [4]. VVB is used in the case of hemodynamic
6 Liver Vascular Reconstructions 55
intolerance to caval clamping but concomitant liver and IVC resection is reported to
be safe also without using VVB [5].
Worldwide experiences with IVC or HVs reconstructions have reported periop-
erative mortality rates ranging from 0% to 16.7%; the most common causes of death
were sepsis, multiorgan failure, small-for-size syndrome, and bleeding. Overall
morbidity ranged from 16.7% to 50% while overall 5-year survival was around 40%
[6]. However, reports are mainly from single-center experiences and include only
limited data with variable tumor histopathology types and length of follow-up.
The type of resection and repair are based on tumor location and IVC involve-
ment. When involvement is minimal, the IVC can be reconstructed by primary
suture or with a patch graft (49.2% of cases); when the defect is larger a patch graft
or a complete IVC replacement is necessary (50.8%) [6]. Li et al. [7] proposed that
if IVC involvement is less than 30% of the IVC circumference and 2 cm of the
length, the defect can be sutured transversely after removing the invaded IVC wall.
If IVC involvement is 30% to 50% of IVC circumference and longer than 2 cm, an
autologous vein such as great saphenous vein patches or expanded polytetrafluoro-
ethylene (ePTFE; Gore-Tex, Flagstaff, AZ, USA) patches have to be used for IVC
repair or replacement. According to Azoulay et al. [8], if less than 50% of the cir-
cumference of the IVC wall is involved, a transverse suture is recommended to
prevent stenosis; if 50% or more of IVC is resected, a 20-mm diameter PTFE graft
should be used [7, 8]. In the case of involvement of the HVs, the remaining stump
of hepatic vein after the resection has to be reimplanted directly into the vena cava,
or with an interposed reinforced ePTFE graft or a venous graft. Reconstruction is
necessary to preserve outflow and to avoid liver congestion. Clearly, the use of a
conduit to reach the vena cava has potential for postoperative complication, namely
kinking, thrombosis and in turn outflow obstruction. Therefore, an accurate design
and realization of the implant has to be undertaken. Long-term transplant and par-
ticularly LDLT experience is of great help. For the patch different materials reported
in the literature are nowadays available:
• Artificial/synthetic vascular graft (Dacron, ring-reinforced PTFE) (Fig. 6.1).

Dacron was the option of choice in the past, but it was associated with high
thrombosis and stenosis rate. PTFE graft is an inert and biocompatible material:
it is widely used [8] but requires concomitant anticoagulant therapy over a long
period. Bleeding requiring reoperation was reported in 4.7% of cases [8]. For
these reasons and for the concretely increased possibility of serious postopera-
tive infections some authors [9, 10] prefer the use of autologous grafts.
• Biological grafts (bovine-horse pericardium) or cold-storage cadaveric venous
grafts (Fig. 6.2). Probably among the most effective and easy to use, these types
of grafts are available only at transplant centers (cold-storage cadaveric venous
grafts). Furthermore, some regulatory issues have been raised related to the qual-
ity of storage and donor data traceability. Since cadaveric venous grafts have
been diffusely used in Italy, a national effort has to be undertaken to provide
regulation patterns and promote sharing among transplant and non-transplant
high-specialty hepatobiliary centers.
Fig. 6.1 Female, 62 years with colorectal liver metastases; previous extended right hepatectomy.
Computed tomography scan: 30 mm lesion with left hepatic vein infiltration (left). Segment 2
hepatic resection and left hepatic vein reconstruction with Gore-Tex patch (right)
Fig. 6.2 Female, 65 years with colorectal liver metastases. Magnetic resonance imaging: 25 mm
lesion of segment 7 with right hepatic vein involvement (left). Hepatic resection and right hepatic
vein reconstruction with cadaveric graft (right)
• Autologous grafts. Autologous vein grafts are widely used but have some limita-
tions. External iliac vein grafts are most suitable for reconstructing the major HV
because of its length and caliber; however, grafting the external iliac vein requires
an extensive surgical dissection and causes edema of the extremities on the ipsi-
lateral side. Left renal vein grafts are easy to use and of adequate caliber but are
often limited in length. Saphenous vein grafts are usually about 3 cm in length
and 8 Fr in caliber, which may be sufficient for interposing one of the major HVs
in the absence of alternatives; however, it is a preferred option for segmental HV
interposition. Grafting the great saphenous vein reaching up to 12 cm in length
may take 20 to 30 min. Other experiences reported the use of the umbilical vein,
portal vein and ovarian vein. The use of autologous grafts is associated with
longer surgical times and the need for a second incision.
• Cryopreserved homologous grafts. Yamamoto et al. (2017) [11] reported the
largest experience in HVs reconstruction using cryopreserved grafts, reporting
no difference in patency compared to autologous grafts. Cost, need to elec-
tively program the interventions and the fact that many biobanks do not accept
the return of unused grafts fully charging for costs are among some of the limi-
tations reported.
• Parietal peritoneum can be used for patches [12] or tubularized [13] for cava
replacement; preliminary series suggest this option in cases of infected surgical
sites, complex abdominal trauma or malignancies requiring the resection of
involved adjacent digestive structures. Our group routinely use parietal perito-
neum for the reconstruction of portal defects when needed in major hepatecto-
mies associated with PVR.
Standard perioperative anticoagulant therapy is necessary, but standardized pro-

tocols are absent.
6.3 Portal Vein
Until the late 1990s portal vein thrombosis was considered a contraindication to
resection for pCCA. Klempnauer et al. [14] described for the first time a combined
extended right hepatectomy and PVR. This concept was then adapted by Neuhaus
et al. [1] who in 1999 introduced the “no touch technique” reporting a benefit in
survival for hilar cancer after PVR. Since then many studies have confirmed the
increased curative effect of PVR, which has nowadays become diffusely practiced
and strongly recommended for biliary hilar tumors. Unfortunately, despite the
improvements in preoperative imaging and staging, often the involvement of the
portal vein is discovered intraoperatively. Mortality rates reported in the literature
for PVR ranged from 0% to 5% while complications ranged from 43% to 100%
[15]. Three-year survival after PVR and reconstruction for pCCA is reported
between 19% and 58%. The adoption of aggressive surgical techniques (major
resection, vascular reconstruction) demonstrated an increased 2-year survival from
33% (1993–1998) to 60% (1998–2003) [16].
In the particular subset of patients with hepatocellular carcinoma, neoplastic por-
tal thrombosis is considered a formal contraindication to liver resection. According
to recent EASL guidelines a certain degree of stage migration is allowed based on
the very low adherence of clinicians to previous guidelines. In the context of a mul-
tidisciplinary decision-making setting, a major resection associated with PVR may
be a therapeutic option.
PVR and reconstruction can be performed either before or after the liver paren-
chymal transection. Anastomosis follows the classic roles of liver transplantation
and can be completed by means of a primary end-to-end suture or with a graft inter-
position. A wide liver transplant experience may be of relevant help in reducing the
postoperative complications and prevalence of portal thrombosis.
6.4 Hepatic Artery
Hepatic artery resection (HAR) may be necessary to achieve R0 especially for hilar
malignancies: the involvement of hilar structures may require concomitant multi-
vascular resections (PVR, HAR) and reconstructions. Currently, while PVR is more
diffusely applied, HAR adoption remains controversial.
Recent series report the use of different arterial reconstruction techniques to
obtain negative margins. Before the seminal paper of Nagino et al. in 2010 [17],
previous reported experiences of arterial resection/reconstruction for biliary cancer
were numerically scarce (<10 cases) and discouraging [18] due to poor outcomes
both in terms of morbidity (78%) and mortality (33%) with a 2-year reported sur-
vival rate of 0%.
Nagino et al. [17] described retrospectively the largest (n = 50) series of hepatec-
tomies for advanced hilar cancer with simultaneous PVR and HAR. The results of
the study were somehow favorable: mortality 2%, morbidity 54% and survival rate
of 30% at 5 years. Since then arterial involvement is no longer considered an abso-
lute contraindication for surgery when performed by an experienced surgeon in a
high-volume center: it remains technically difficult and complications can be lethal.
Recently Matsuyama et al. [19] reported their experience of HAR with/without
PVR in 44 cases of pCCA: morbidity was 81.8% and 90-day mortality 9% with a
5-year survival of 22%. Deaths were related to liver failure due to vascular throm-
bosis. Noji et al. [20] reported 28 HAR for pCCA; morbidity was 57.1% and in-
hospital mortality 3.6%. Alternative options were also described when arterial
resection was necessary: Peng et al. [21] reported a series of 26 left hepatectomies
combined with HAR but without reconstruction: two patients developed liver
abscess, and three developed liver failure. Noji et al. [22] reported their experience
with arterioportal shunting (APS): their high frequency of liver abscess formation
suggests that APS has to be considered a sort of salvage procedure in those cases
where artery cannot be by any means microscopically reconstructed. Sugiura et al.
[23] reported a new approach (12 cases) for Bismuth I/II pCCA with insufficient left
liver reserve consisting of left hepatectomy with HAR and reconstruction: no HAR-
related complications were reported.
Hepatic artery reconstruction can be performed in different ways:
(a) end-to-end anastomosis

(b) a graft interposition as the greater saphenous vein or the radial artery
(c) anastomosis to the right gastric artery or to the left hepatic artery coming from
the left gastric artery or the gastroduodenal artery
(d) end-to-side anastomosis of the common hepatic artery and portal vein (APS).
Complete mobilization of the artery is necessary to prevent tension on the anas-

tomosis, and care must be taken in manipulation and clamping of these small arter-
ies since intimal tears can occur. Transplant skill in preparing vascular stumps,
designing and realizing a correct tension-free arterial anastomosis is close to being
mandatory to warrant a sufficient degree of success. Some pure hepatobiliary
centers may obviate that by involving a cardiovascular or plastic surgeon but with a
clear lack of decisional freedom and autonomy.
This raises the issue whether in the presence of a suspected vascular involvement
the patient should be immediately directed to a high-volume vascular reconstruction
center.
References
1. Neuhaus P, Jonas S, Bechstein WO, et al. Extended resections for hilar cholangiocarcinoma.
Ann Surg. 1999;230:808–18. discussion 819
2. Neuhaus P, Thelen A, Jonas S, et al. Oncological superiority of hilar en bloc resection for the
treatment of hilar cholangiocarcinoma. Ann Surg Oncol. 2012;19:1602–8.
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exclusion, venovenous bypass, and in situ hypothermic portal perfusion: an audit of 77 con-
secutive cases. Ann Surg. 2015;262:93–104.
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carcinoma: hepatic vein reconstruction with in-situ hypothermic perfusion and extracorporeal
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5. Stattner S, Yip V, Jones RP, et al. Liver resection with concomitant inferior vena cava resection:
experiences without veno-venous bypass. Surg Today. 2014;44:1063–71.
6. Papamichail M, Marmagkiolis K, Pizanias M, et al. Safety and efficacy of inferior
vena cava reconstruction during hepatic resection. Scand J Surg. 2018; https://doi.
org/10.1177/1457496918798213. [Epub ahead of print]
7. Li W, Han J, Wu ZP, et al. Surgical management of liver diseases invading the hepatocaval con-
fluence based on IH classification: the surgical guideline in our center. World J Gastroenterol.
2017;23:3702–12.
8. Azoulay D, Pascal G, Salloum C, et al. Vascular reconstruction combined with liver resection
for malignant tumours. Br J Surg. 2013;100:1764–75.
9. Ko S, Kirihataya Y, Matsusaka M, et al. Parenchyma-sparing hepatectomy with vascular
reconstruction techniques for resection of colorectal liver metastases with major vascular inva-
sion. Ann Surg Oncol. 2016;23(Suppl 4):501–7.
10. Saiura A, Yamamoto J, Sakamoto Y, et al. Safety and efficacy of hepatic vein reconstruction for
colorectal liver metastases. Am J Surg. 2011;202:449–54.
11. Yamamoto M, Akamatsu N, Aoki T, et al. Safety and efficacy of cryopreserved homologous
veins for venous reconstruction in pancreatoduodenectomy. Surgery. 2017;161:385–93.
12. Dokmak S, Aussilhou B, Sauvanet A, et al. Parietal peritoneum as an autologous substitute for
venous reconstruction in hepatopancreatobiliary surgery. Ann Surg. 2015;262:366–71.
13. Coubeau L, Rico Juri JM, Ciccarelli O, et al. The use of autologous peritoneum for complete
caval replacement following resection of major intra-abdominal malignancies. World J Surg.
2017;41:1005–11.
14. Klempnauer J, Ridder GJ, Werner M, et al. What constitutes long-term survival after surgery
for hilar cholangiocarcinoma? Cancer. 1997;79:26–34.
15. Mekeel KL, Hemming AW. Evolving role of vascular resection and reconstruction in hepatic
surgery for malignancy. Hepat Oncol. 2014;1:53–65.
16. Dinant S, Gerhards MF, Rauws EA, et al. Improved outcome of resection of hilar cholangio-
carcinoma (Klatskin tumor). Ann Surg Oncol. 2006;13:872–80.
17. Nagino M, Nimura Y, Nishio H, et al. Hepatectomy with simultaneous resection of the portal
vein and hepatic artery for advanced perihilar cholangiocarcinoma: an audit of 50 consecutive
cases. Ann Surg. 2010;252:115–23.
18. Miyazaki M, Kato A, Ito H, et al. Combined vascular resection in operative resection for hilar
cholangiocarcinoma: does it work or not? Surgery. 2007;141:581–8.
19. Matsuyama R, Mori R, Ota Y, et al. Significance of vascular resection and reconstruction in
surgery for hilar cholangiocarcinoma: with special reference to hepatic arterial resection and
reconstruction. Ann Surg Oncol. 2016;23(Suppl 4):475–84.
20. Noji T, Tsuchikawa T, Okamura K, et al. Concomitant hepatic artery resection for advanced
perihilar cholangiocarcinoma: a case-control study with propensity score matching. J
Hepatobiliary Pancreat Sci. 2016;23:442–8.
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2015;19:675–81.
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Surg. 2019;43:894–901.
Biliary Reconstruction Techniques:
From Biliary Tumors to Transplantation 7
Leonardo Centonze, Stefano Di Sandro, Iacopo Mangoni,
7.1 Introduction
Restoration of bilioenteric continuity after bile duct resection for hepatopancreato-

biliary (HPB) tumors or during liver transplantation plays a central role in HPB and
transplant surgery.
The earliest reports of biliary reconstructions are dated back between the end of
the nineteenth and the beginning of the twentieth century: in 1909, Dahl described
the technique of Roux-en-Y hepaticojejunostomy, which still represents the gold
standard for biliary-reconstruction following bile duct resection.
Concerning liver transplantation, restoration of the graft’s biliary drainage repre-
sented the Achilles heel of the whole transplant operation for many years, leading to
many casualties at the beginning of transplant history: several techniques were
advocated in early transplantation reports, involving the gallbladder, the duodenum,
and the common bile duct. Many of these techniques were gradually abandoned,
and eventually the duct-to-duct anastomosis (DDA, or choledochocholedochos-
tomy) and hepaticojejunostomy (HJ) became standard techniques for biliary recon-
struction after liver transplantation.

L. Centonze (*) · S. Di Sandro · I. Mangoni
e-mail: centonze.leonardo@gmail.com; stefano.disandro@ospedaleniguarda.it;
iacopo.mangoni@ospedaleniguarda.it
L. De Carlis

62 L. Centonze et al.
Nowadays the basic principles and technical aspects of biliary anastomosis are
well-established and widely accepted by HPB and transplant surgeons. The next sec-
tion briefly recalls the historical milestones of biliary reconstruction techniques.
7.2 istorical Milestones of Biliary

H
Reconstruction Techniques
The earliest reports of biliary reconstructions date back between the end of the nine-
teenth and the beginning of the twentieth century: at that time, these operations were
generally performed for calculous disease or more rarely for HPB neoplasms, but the
difficult pursuit of the best approach to biliary reconstruction eventually led to the
development of the basic anastomotic techniques that were subsequently adopted in
oncological HPB surgery and liver transplantation.
The first anastomosis between the biliary tree and the alimentary tract was per-
formed in 1880 by Alexander von Winiwarter, in Liège, when he attempted to perform
a two-step cholecystocolostomy in order to relieve a common bile duct obstruction:
the postoperative course was difficult, as it ended in the formation of a chronic biliary
and enteral fistula that took six reinterventions to heal. These poor results dissuaded
other surgeons from attempting other derivative interventions until 1887, when the
first palliative cholecystojejunostomies for pancreatic cancer were successfully per-
formed by Otto Kappeler in Switzerland and by Nestor Dmitrievic Monastyrski in
Russia. By that time, utilization of the common bile duct for bilioenteric anastomosis
had only been advocated by Langenbuch in 1884, who suggested that choledochot-
omy could be performed to remove common bile duct stones and that choledochoen-
terostomy could be fashioned on ectatic common bile ducts.
It was in 1891 that the German surgeon Oskar Sprengel described the first success-
ful anastomosis (a side-to-side choledochoduodenostomy) between the common bile
duct and the duodenum in the setting of common bile duct lithiasis. Finally, in 1909,
the Swedish surgeon Robert Dahl described the utilization of a Roux jejunal limb to
perform a HJ, which still represents the gold standard for biliary reconstruction fol-
lowing bile duct resection [1].
These biliary reconstruction techniques allowed HPB surgeons to deal with
benign and malignant diseases of the extrahepatic biliary tree, and to perform bili-
ary reconstruction following pancreatoduodenectomy for pancreatic and periampul-
lary diseases.
The development of resective surgery for hilar cholangiocarcinoma, which
started to spread in the second half of the twentieth century, challenged HPB sur-
geons with the problem of performing biliary reconstructions utilizing the intrahe-
patic ducts: the first hepatic resection with en-bloc bile duct resection and
cholangiojejunal anastomosis was described in 1965 by Julian K. Quattelbaum [2].
Meanwhile, Thomas E. Starzl was giving birth to the field of human liver trans-
plantation with his first attempts at the University of Colorado, in 1963 [3].
Biliary reconstruction during liver transplantation has represented a main chal-
lenge since the beginning of transplant history, when biliary complications proved
to be one of the most frequent causes of early post-transplant casualties.
7 Biliary Reconstruction Techniques: From Biliary Tumors to Transplantation 63
In 1974, 11 years after the first attempt at liver transplantation, Starzl et al.
reported five different techniques (choledochocholedochostomy with or without a
T-tube, cholecystoduodenostomy, choledochoduodenostomy, Roux-en-Y cholecys-
tojejunostomy) in his series of 82 patients, all of them with a different risk of fistula,
obstruction or ascending cholangitis [4].
In the same years, in Europe, Sir Calne was dealing with the same problems and
exploring other techniques for biliary reconstruction, such as the use of the gallblad-
der as a pedicle graft between the donor’s and recipient’s bile duct [5], with variable
success rates.
Because of the frequent obstruction of the cystic duct with subsequent jaundice
and the risk of duodenal fistula in the case of a re-do of the anastomosis, the use of
biliary reconstructions involving the gallbladder and the duodenum was gradually
abandoned [6], and technical refinements coupled to better immunosuppressive regi-
mens led to acceptable surgical outcomes following duct-to-duct reconstruction.
Nowadays, DDA (or choledochocholedocostomy) and HJ are the most widely
used techniques for biliary reconstruction in liver transplantation.
After a review of biliary anatomy, the next sections will focus on biliary recon-
struction techniques in oncological HPB surgery and liver transplantation.
7.3 Biliary Anatomy
We will briefly review the anatomy of the intrahepatic and extrahepatic biliary sys-
tem, without focusing on a description of all the anatomical variants.
7.3.1 Anatomy of the Intrahepatic Bile Ducts
The right and left livers are drained by the right and the left hepatic ducts, whereas the
caudate lobe is drained by several ducts that join both the right and left hepatic ducts.
The left hepatic duct drains the three segments—2, 3, and 4—that constitute the
left liver.
The duct that drains segment 3 is located slightly behind the left horn of the
umbilical recess. It is joined by the tributary from segment 4b to form the left duct,
which is similarly joined by the duct of segment 2 and the duct of segment 4a, where
the left branch of the portal vein turns forward and caudally. The left hepatic duct
traverses beneath the left liver at the base of segment 4, just above and behind the
left branch of the portal vein; it crosses the anterior edge of that vein and joins the
right hepatic duct to constitute the hepatic ductal confluence; in its transverse por-
tion, it receives a few small branches from segment 4.
The right hepatic duct drains segments 5, 6, 7, and 8 and arises from the junction
of two main sectional duct tributaries: the posterior (or lateral) duct and the anterior
(or medial) duct. The right posterior sectional duct has an almost horizontal course
and is formed by the confluence of the ducts of segments 6 and 7. The duct then runs
to join the right anterior sectional duct, as it descends in a vertical manner. The right
anterior sectional duct is formed by the confluence of the ducts draining segments
5 and 8. Its main trunk is located to the left of the right anterior sectional branch of
the portal vein, which pursues an ascending course. The junction of these two main
right biliary channels usually occurs above the right branch of the portal vein. The
right hepatic duct is short and joins the left hepatic duct to constitute the confluence
lying in front of the right portal vein and forming the common hepatic duct.
The caudate lobe is divided into right and left portions and a caudate process and
has a separate biliary drainage. In 44% of individuals, three separate ducts drain
these three parts of the lobe, whereas in another 26%, a common duct lies between
the right portion of the caudate lobe proper and the caudate process and an indepen-
dent duct that drains the left part of the caudate lobe. The site of drainage of these
ducts varies. In 78% of cases, drainage of the caudate lobe is into the right and left
hepatic ducts, but in 15%, drainage is by the left hepatic ductal system only. In about
7%, the drainage is into the right hepatic system.
7.3.2 Anatomy of the Extrahepatic Bile Ducts
The extrahepatic bile ducts are represented by the extrahepatic segments of the right
and left hepatic ducts, joining to form the biliary confluence and the common bile
duct draining to the duodenum.
The confluence of the right and left hepatic ducts occurs at the right of the hilar
fissure of the liver, anterior to the portal venous bifurcation and overlying the origin
of the right branch of the portal vein. The extrahepatic segment of the right duct is
short, but the left duct has a much longer extrahepatic course. The biliary confluence
is separated from the posterior aspect of segment 4b of the liver by the hilar plate,
which is the fusion of connective tissue enclosing the biliary and vascular elements
with the Glisson capsule.
Because of the absence of any major vascular interposition, it is possible to open
the connective tissue constituting the hilar plate at the inferior border of segment 4
and, by elevating it, to display the biliary confluence and left hepatic duct.
The main bile duct is about 6 mm in diameter and is divided into two portions:
the upper portion is called the common hepatic duct and is situated above the cystic
duct, which joins it to form the lower portion, the common bile duct. The common
duct courses downward anterior to the portal vein, in the free edge of the lesser
omentum; it is closely applied to the hepatic artery, which runs upward on its left,
giving rise to the right branch of the hepatic artery, which crosses the main bile duct
usually posteriorly, although in about 20% of cases, it crosses anteriorly.
The gallbladder is a reservoir located on the undersurface of the right lobe of the
liver, within the cystic fossa; it is separated from the hepatic parenchyma by the cystic
plate, which is composed of connective tissue that extends to the left as the hilar plate.
The cystic duct arises from the neck or infundibulum of the gallbladder and extends to
join the common hepatic duct. Its lumen usually measures approximately 1 to 3 mm,
and its length varies, depending on the type of union with the common hepatic duct.
The arterial vascularization of the common bile duct basically consists of two main
arteries running at the right and left border of the bile duct, the “3 o’clock” and
“9 o’clock” arteries, which variably arise from the retroportal, retroduodenal or gastro-
duodenal arteries and communicate with the right or less often with the left hepatic artery.
The gallbladder arterial supply is granted by the cystic artery, which usually arises
from the right branch of the hepatic artery and is identified in the Calot triangle,
whose right border is constituted by the common hepatic duct, while its upper border
is represented by the right lobe and its lower border by the cystic duct [7].
7.4 iliary Reconstruction Techniques in Oncological

B
HPB Surgery
The indications for performing a bilioenteric anastomosis in oncological HPB sur-

gery are represented by all those tumors whose treatment involves resection of the
common bile duct, such as pancreatic neoplasms, ampullary and duodenal tumors
as well as biliary tract cancers.
The surgical procedures that entail bile duct resection (and biliary reconstruc-
tion) are basically pancreaticoduodenectomy and hepatic resection, coupled to bile
duct resection. In these settings, the main anastomotic technique is represented by
HJ involving the common bile duct or cholangiojejunostomy (CJ), in the case of
bile duct resection extending to the biliary confluence. These two techniques are
described below.
7.4.1 Hepaticojejunostomy in Oncological HPB Surgery
HJ is indicated in cases of resection of the common bile duct below the biliary con-
fluence, typically during resections performed for primary bile duct malignancies or
gallbladder cancer or during pancreatoduodenectomy performed for pancreatic neo-
plasms, distal bile duct cancer, ampullary and duodenal cancer.
The first step of this procedure involves the creation of a Roux-en-Y jejunal limb.
First, the jejunum is divided approximately 30 cm distal to the ligament of Treitz
with a stapler in order to construct a 40 cm defunctionalized Roux-en-Y jejunal
limb; the distal end of the stapled Roux-en-Y is oversewn with a running polyglac-
tin-910 (Vicryl) 3/0 suture and a double layer end-to-side jejunojejunostomy is per-
formed at the other end of the jejunal limb. The anastomotic limb is then brought up
in a retrocolic/anteduodenal fashion through an orifice made in the bottom of the
mesocolon taking care to ensure a tension-free jejunal limb with sufficient length.
Subsequently, the anastomotic orifice on the antimesenteric side of the jejunal limb
is created; this should be slightly smaller than the width of the bile duct, as it usually
tends to enlarge during anastomosis creation.
There are basically two techniques for creating the HJ: interrupted and continu-
ous suture technique. The advantage of the interrupted suture technique is the uni-
versal use even for small bile ducts, despite increased costs and operating time. On
the other hand, the continuous technique might offer better sealing of the anastomo-
sis in the case of larger bile ducts, despite supporters of the interrupted technique
claiming that the continuous suture might lead to a higher rate of anastomotic stric-
tures in the long term [8].
Concerning the use of transanastomotic stents, these may help prevent early
anastomotic occlusion by mucosal edema or prevent technical error such as catch-
ing of the posterior wall during placement of the anterior row of sutures [9].
We usually perform a running 5/0 or 6/0 polyglycolide-trimethylene carbonate
(Maxon) end-to-side HJ: the anastomosis starts at the 3 o’clock side of the biliary
duct, where the two ends of the suture are passed inside-out on the biliary and intes-
tinal orifices and tied outside the anastomosis; the posterior wall of the anastomosis
is then sewn using one end of the abovementioned suture, taking a proper amount of
small bowel seromuscular layer but avoiding the mucosa in order to ensure a proper
mucosa-to-mucosa alignment; another separate stitch is applied at the 9 o’clock side
of the anastomosis and tied outside the anastomosis, and one of its two ends is knot-
ted with the corresponding posterior wall suture; finally, the remaining ends of the
3 and 9 o’clock sutures are used to sew the anterior wall of the anastomosis and
knotted together at 12 o’clock (Fig. 7.1).
The analysis of our personal experience with HJ following pancreatoduodenec-
tomy revealed a 2% rate of biliary leaks (unpublished data), which is consistent with
other published series [10].
7.4.2 I ntrahepatic Cholangiojejunostomy

in Oncological HPB Surgery
Resective surgery of hilar cholangiocarcinoma poses the challenge of performing

bilioenteric anastomoses utilizing the intrahepatic bile ducts.
Compared with HJ, biliary reconstructions proximal to the hepatic hilum—
namely, intrahepatic CJ—are technically demanding, as the bile ducts are small and
fragile, and multiple anastomoses are often necessary. The main challenge in CJ is
represented by multiple duct orifices: a useful trick to solve this problem is to per-
form a ductoplasty in order to create a single biliary orifice to be anastomosed [11].
In order to avoid tension and narrowing of the duct lumen, the ductoplasty must be
performed by vertically dividing the adjacent walls of the single ducts, and suturing
the newly created septum vertically, thus creating a large opening [12] (Fig. 7.2).
Another possible reconstruction technique for plural neighboring ducts implies
utilizing the Glissonian sheath (including plural orifices) as a single duct by regard-
ing the septa as a thick wall of the duct.
When more than one duct orifice appears separately and too distant from one
another for a ductoplasty, plural orifices in the jejunum should be created according
to the distance between the ducts. During the reconstruction of multiple individual
anastomoses, the posterior walls of every single anastomosis should be performed
first, followed by the anterior rows, because attempts to complete one anastomosis
and then another may be difficult or sometimes impossible [13].
These techniques have proven to be safe and effective, with a reported biliary
complication rate varying from 1% to 22% [11].
7 Biliary Reconstruction Techniques: From Biliary Tumors to Transplantation
Fig. 7.1 Hepaticojejunostomy performed during a total pancreatectomy for intraductal papillary mucinous neoplasm; in this case we proceed with the place-
ment of a silicon internal tutor
67
Fig. 7.2 Cholangiojejunostomy performed during a right hepatectomy with bile duct resection for
a Bismuth 3a hilar cholangiocarcinoma; in this case the left hepatic duct and the duct draining seg-
ment 4b were joined together through a ductoplasty (see text), and an intraoperative percutaneous
transhepatic biliary drain was positioned
7.5 iliary Reconstruction Techniques in Liver

B
Transplantation
As mentioned, DDA and HJ are the most widely used techniques for biliary recon-
struction in liver transplantation. DDA represents the preferred anastomotic tech-
nique in all fields of liver transplantation, including living donor liver transplantation
(LDLT), while the use of HJ is limited to cases of important size disparity between
donor and recipient bile duct, diseased recipient duct (as in primary sclerosing chol-
angitis), re-transplantation or previous biliary surgery.
A description of DDA is provided below, whereas special considerations con-
cerning reconstruction techniques in LDLT are presented in Sect. 7.5.3.
7.5.1 Duct-to-Duct Anastomosis in Liver Transplantation
DDA represents the standard anastomotic technique in liver transplantation.

Compared to HJ, DDA needs a shorter operation time, causes fewer septic
complications, leaves patients with better physiologic enteric function, and allows
easier endoscopic access to the biliary tract in the event of a future need. The basic
principles for a correct DDA technique are an adequate arterial supply of the donor
and recipient ducts, and appropriate length of the stumps in order to obtain a tension-
free anastomosis.
As mentioned, the arterial vascularization of the common bile duct basically con-
sists of two main arteries running at the right and left border of the bile duct, the “3
o’clock” and “9 o’clock” arteries, which variably arise from the retroportal, retro-
duodenal or gastroduodenal arteries and communicate with the right or, less often,
with the left hepatic artery [14]. In order to provide an optimal arterial supply of the
biliary stumps, the recipient and graft bile ducts must be manipulated as little as pos-
sible, preserving sufficient periductal tissue to avoid vascular injuries; the presence
of active bleeding at the biliary ends represents an indirect sign of proper vasculariza-
tion [15], and should be controlled with separate stitches rather than cautery.
When performing a DDA, surgeons should pay attention to the length of the
recipient and graft biliary stumps to avoid kinking or tension of the anastomosis,
which may predispose to stenosis or leak, respectively.
DDA may be performed in an end-to-end or end-to-side fashion, as well as with
running versus interrupted suture. Differences in the diameter of the graft and recip-
ient bile ducts may be adjusted with a side-cut at 6 and 12 o’clock. A randomized
trial comparing end-to-end versus end-to-side reconstruction showed no significant
differences between the two techniques [16], and similarly no differences between
running versus interrupted suture technique were reported [17].
Our technique of choice is represented by a running 5/0 polyglycolide-
trimethylene carbonate (Maxon) end-to-end anastomosis with a side-cut bilioplasty
at 6 o’clock in the recipient bile duct and 12 o’clock in the graft bile duct in order to
tailor duct diameters and compensate for the tissue that is effectively lost in the
suture line and prevent a “stricturing” effect of the suture line.
The first stitch is passed in the middle of the posterior wall of the two bile ducts,
and tied outside; afterwards, each end of the suture is used to perform a running
suture towards the 9 o’clock and 3 o’clock angles of the anastomosis, and the two
sutures are grasped by a rubber-shod clamp (small rubber-tipped forceps) and gently
pulled laterally to better expose the anastomosis for anterior wall reconstruction;
suture of the anterior wall of the anastomosis starts at the middle of the anterior wall
with a U-shaped stitch that is tied outside the anastomosis; each end of this suture is
used to make two running sutures towards the 9 o’clock and 3 o’clock angles of the
anastomosis, and finally tied with the respective sutures of the posterior wall
(Fig. 7.3).
T-tube positioning still represents a debated issue, and its utilization generally
depends on the center’s preferences. On one hand, T-tube allows monitoring of
bile flow and color, offers direct access to the biliary tree allowing direct diagnos-
tic cholangiography, and may be helpful in the management of small postopera-
tive leaks [18]; on the other hand, some studies have pointed out that T-tube
utilization may increase the risk of bile leaks, cholangitis, and peritonitis after
removal [19].
70
Fig. 7.3 Duct-to-duct anastomosis performed during an orthotopic liver transplantation from a donor after cardiac death; the T-tube was inserted through a
choledochotomy on the recipient bile duct and fixed with a purse string suture after completion of the anastomosis
L. Centonze et al.
Several retrospective studies did not conclude in favor of the use of a T tube [20],
and a recent meta-analysis including six prospective randomized trials demon-
strated no benefit for T-tube utilization [21].
Niguarda’s policy towards T-tube utilization limits its application to re-
transplantation, marginal grafts from donors after cardiac death (DCD) or extracor-
poreal membrane oxygenation (ECMO), split-liver, and LDLT. Whenever needed,
the T-tube is inserted through a small choledochotomy on the recipient’s bile duct,
its upper branch passing over the anastomosis, and fixed through a purse-string
suture at its exit site. In a retrospective review of our recent experience with 816
liver transplantations performed between 2007 and 2015, we found a 9% rate of
anastomotic strictures and a 4% rate of biliary leaks after DDA (unpublished data),
which is consistent with the reports from other studies [18].
7.5.2 Hepaticojejunostomy in Liver Transplantation
HJ is usually chosen in the case of important size disparity between the donor’s and
recipient’s bile duct, diseased recipient’s duct (as in primary sclerosing cholangitis),
re-transplantation or previous biliary surgery.
The surgical technique is the same as described above for HPB.
7.5.3 A
dult Living Donor Liver Transplantation:
Special Considerations
LDLT poses a special challenge for biliary reconstruction, with a reported biliary
complication rate varying between 9% to nearly 40% in the current literature [22].
DDA and HJ are the two most common methods for bile duct reconstruction. HJ
was once the standard biliary reconstruction technique, but it has given way to DDA
because of its several advantages: in fact, DDA is faster and simpler to perform,
preserves physiologic bilioenteric continuity, eliminates intestinal manipulation and
facilitates endoscopic investigation for the management of biliary complications
[23, 24]. Despite these advantages, an association between DDA and postoperative
biliary stricture has been suggested [25], and the incidence of biliary strictures fol-
lowing duct-to-duct reconstruction is higher in recipients of liver grafts from living
donors compared with recipients of whole liver grafts [26]. These findings are at
least partially explained by the interruption of physiologic arterial supply and
venous drainage during donor hepatectomy.
Several technical tips have been described in order to provide the best outcome
after biliary reconstruction in LDLT.
The application of intraoperative cholangiography helps to precisely locate the
right hepatic duct before division, which avoids having to deal which two or three
duct openings that require more complex reconstructions [9].
Avoiding dissection of between the right hepatic artery and the right hepatic
duct preserves a better arterial supply, while the preservation of the hepatic paren-
chyma overlying the right hepatic duct protects its venous drainage [27].
As the biliary confluence lies on the left of the gallbladder fossa, it is necessary
to deviate the parenchymal transection line to the left side of the gallbladder fossa
so that the upper part of the right hepatic duct is not denuded and venous drainage
of right hepatic duct is preserved [28].
Concerning the recipient’s operation, it is of paramount importance to ensure an
optimal arterial supply of the recipient bile duct, preserving sufficient periductal
tissue to avoid vascular injuries, similarly to duct-to-duct reconstruction in whole
graft transplantation; application of a high hilar dissection technique [29] provides
a good length of the recipient common bile duct, which ensures a tension-free anas-
tomosis as well as multiple openings of second-order bile ducts, which might be
useful in the anastomosis of multiple ducts.
In our experience of 100 adult-to-adult right lobe LDLT, we had a 28% compli-
cation rate, which is consistent with the literature findings.
7.6 Conclusions
Nowadays, the techniques for biliary reconstruction are widely accepted, and there is a
deep correlation between their application in HPB surgery and liver transplantation.
The increasing volume of complex HPB procedures and the development of liver trans-
plantation during the second half of the past century triggered a continuous technical
refinement, and better understanding of intra- and extrahepatic biliary and vascular
anatomy helped to improve the outcomes of biliary reconstruction through the years.
Advances in the treatment of hilar cholangiocarcinoma as well as the develop-
ment of LDLT posed the most difficult challenge in biliary reconstruction to HPB
and transplant surgeons, and technical stratagems learned in one field were applied
to the other, leading to better outcomes. The interlink between these closely related
disciplines represents a fascinating field in the history of surgery; HPB and trans-
plant surgeons should always keep an eye beneath the “virtual” fence between them
to keep making each others’ grass greener day after day!
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The Interplay Between Living Donor
Liver Transplantation and Liver Surgery 8
8.1 Introduction and Historical Background
The story of Prometheus in Greek mythology first described the liver’s regenerative
capacity more than 2500 years ago. Although the mechanism of liver regeneration
remains incompletely understood, this complex process has played a crucial role in
the successful development of liver surgery and living donor liver transplantation
(LDLT).
A systematic approach to the segmental anatomy of the liver, first introduced by
Couinaud and subsequently by Tùng and Bismuth, led to improved outcomes and
the increased practice of liver surgery [1–3]. By the end of the 1980s, the consoli-
dated liver surgery experience of several centers for a range of pathological condi-
tions led to the development of the concept of reduced-size liver transplantation in
children [4, 5]. Left lateral resection in turn paved the way for split-liver transplan-
tation (SLT), allowing full use of the removed deceased donor liver by allocating the

A. Lauterio (*) · S. Di Sandro
e-mail: andrea.lauterio@ospedaleniguarda.it; stefano.disandro@ospedaleniguarda.it
R. De Carlis
L. De Carlis

smaller segment to a child and the larger one to an adult. The Hannover team was
the first, in 1988, to demonstrate the feasibility of this innovative surgical option [6].
Following on from this preliminary experience with reduced-size liver transplan-
tation in children and SLT, the first LDLT of segments 2, and 3 of a mother’s liver
in her 18-month old son was performed by Strong in Australia in 1989 [7]. The first
successful LDLTs in adult recipients were carried out in Japan, first transplanting
the left lobe and then the right [8, 9]. In Italy, the Padua University team was the first
to report an adult-to-child LDLT in 1997 while the first adult-to-adult LDLT was
performed in Milan by the Niguarda team in March 2001.
In recent years, LDLT outcomes have improved. Concomitantly, organ shortages
together with religious and ethical issues related to deceased organ donation con-
tinue to impact the distribution of living liver donation worldwide.
8.2 echnical Interplay Between Living Donor Liver

T
Transplantation and Liver Surgery (and Vice Versa)
8.2.1 The Role of Liver Volume
When planning and performing live donor surgery, size matching and remnant liver
volume are critical issues. Unlike patients with decompensated cirrhosis, recipients
with liver tumors and no portal hypertension require significantly less liver graft
volume than those with ascites and significant varices. The ideal volume of the
future liver remnant has been largely discussed in the literature and mathematical
formulas to calculate it have been proposed [10].
8.2.2 Small-for-Size Syndrome and Its Implications
Some of the initially poor outcomes in left lobe adult LDLT were due to underesti-
mation of the importance of size matching between donor and recipient [11]. The
condition developed by recipients of relatively small grafts—prolonged cholestasis,
liver dysfunction, intractable ascites and encephalopathy by the end of the first post-
operative week—was first described by Dahm and colleagues and became known as
the small-for-size syndrome (SFSS) [12].
Experience in LDLT recipients suffering from SFSS despite an adequate graft-to-
recipient weight ratio (GRWR) led to a better understanding of the crucial impor-
tance of graft venous inflow and outflow and the impact on functional graft size [13].
Actual graft size, remnant hepatic parenchymal cell function, together with optimal
venous drainage and portal flow are all fundamental considerations when planning
repeated resections, major liver resections, and staged hepatectomy procedures.
Posthepatectomy liver failure (PLF) has been described in liver surgery after
extended hepatic resection [14]. The pathophysiologic patterns, clinical presenta-
tion and outcomes of both SFSS and PLF are very similar and demonstrate another
link between liver surgery and LDLT. In addition, when considering liver surgery
8 The Interplay Between Living Donor Liver Transplantation and Liver Surgery 77
for hepatic malignancies, assessment of volume ratios should be correlated to the

etiology and severity of chronic liver disease.
In the live donor setting, we believe a graft weight/standard liver volume ratio of
<40% should be considered a small-for-size graft. With a few exceptions, we agree
with the literature that a GRWR of ≥0.8% should be considered the graft safety limit.
Likewise, although the recommended minimal functional liver remnant volume fol-
lowing extended liver resection is 25–30%, this becomes at least 40% in patients with
moderate to severe steatosis, fibrosis, cirrhosis or who have undergone chemotherapy
[13]. However, both these cut-offs are currently the subject of ongoing investigation.
Large patient population studies in LDLT where the GRWR was below 0.8%
showed that variously modulating portal pressure by, for example, portocaval anas-
tomosis and splenic artery ligation, prevented the appearance of the histological
characteristics of SFSS, improving overall patient and graft survival [15]. In the
authors’ opinion, the role of inflow modulation to offset the development of PLF
following major hepatic resection is as yet incompletely defined and should be sys-
tematically investigated in the future.
Given the crucial importance of size-matching between donor and recipient, the
choice of right or left lobe for LDLT and the impact on morbidity and mortality in
both donor and recipient continue to be debated [10].
8.2.3 From LDLT to ALPPS
The surgical experience gained in partial liver transplantation from both deceased
and living donors against a backdrop of two-stage hepatectomy paved the way for
the development of a new two-step surgical technique to obtain adequate parenchy-
mal hypertrophy in oncologic patients requiring major hepatectomy with limited
functional reserve. The team of the Regensburg University Hospital first reported
right portal vein ligation combined with in situ splitting to induce rapid left lateral
liver hypertrophy, followed by a second-step procedure extending right hepatic
resection in a small-for-size setting [16]. This association of liver partition and por-
tal vein ligation in staged hepatectomy was called ALPPS.
The accuracy of preoperative liver volume assessment in the living donor and its
clinical implications have been a major focus for some time since they play a crucial
role in this innovative and complex surgical procedure (Fig. 8.1). Liver volume
assessment and remnant liver-to-patient body weight ratio are also performed before
the first operation, while the new liver volume is always assessed before the second
procedure.
In terms of surgical technique, hilar structure dissection and in situ splitting of
the liver parenchyma are performed in a similar way to living donor hepatectomy.
Two-stage hepatectomy and ALPPS are complex surgical procedures that should
be considered part of the multidisciplinary process to treat liver malignancies.
Indeed, the multidisciplinary approach to liver disease is widely acknowledged in
the transplant field, especially in the case of LDLT where evaluation of both donor
and recipient is crucial.
a b
Fig. 8.1 Preoperative liver volume assessment in the living donor. (a) Computed tomography
volumetry showing the liver area: total liver volume 1770,8 cc; liver remnant volume (in pink
color) 636,5 cc (35.9%). (b) 3D image of the liver remnant volume
8.2.4 Minimally Invasive Liver Surgery: A Mutual Understanding
The advantages and technical refinements achieved in laparoscopic liver surgery

have been widely reported in recent years, and indications for the procedure have
long been the subject of consensus debates [17]. The application of the minimally
invasive approach to transplantation surgery began unexpectedly with the first lapa-
roscopic living donor nephrectomy reported by Ratner et al. at the Johns Hopkins
University Hospital more than 20 years ago. The widespread application of mini-
mally invasive procedures such as laparoscopic and robotic living donor nephrec-
tomy has led to an increasing number of living donor kidney transplantations in
recent years [18].
Pioneer reports also demonstrated the feasibility and reproducibility of laparo-
scopic left lateral liver sectionectomy (segments 2–3) followed by successfully
transplantation in pediatric recipients [19]. The undoubted potential benefits of this
minimally invasive approach in pediatric transplantation, together with a recent
multicenter study providing the first validation of the laparoscopic procedure in
pediatric LDLT have meant that left lateral sectionectomy is now considered the
new standard practice [20]. However, extending the minimally invasive approach to
major donor hepatectomy, especially for right lobe living donation remains a chal-
lenge. Nonetheless, several reports from a high-volume center with extensive expe-
rience in laparoscopic liver resection have documented the move away from the
hand-assisted to the completely laparoscopic approach, confirming the feasibility of
totally laparoscopic left and right lobe hepatectomy [21, 22]. Nonetheless, although
there are reports of minimally invasive robotic surgery being used for right lobe
donor hepatectomy, larger series are needed to thoroughly assess the true advan-
tages of this procedure in living liver donation [23].
The report of the Second International Consensus Conference on laparo-
scopic liver resections, held in Morioka, Japan, in October 2014, classifies
laparoscopic donor hepatectomy as being in a stage 2a development phase

according to the Balliol Classification of IDEAL, based on findings that laparos-
copy presents no difference compared with open surgery in highly specialized
centers but that there are still insufficient data on long-term outcomes in donors
and recipients [17].
In our opinion, minimal invasive surgery in living donor liver donation poses the
major ethical issue of reconciling the steep learning curve required of practitioners
to achieve reproducible outcomes in such complex and challenging procedures and
the profession’s mandatory commitment to donor safety.
8.3 Surgical Technique: The Niguarda Experience
8.3.1 Donor Hepatectomy (Right Lobe: Segments 5, 6, 7, and 8)
Briefly, the donor’s abdomen is opened through a Makuuchi incision, and the liga-
mentum teres and the falciform ligament divided. The left triangular ligament and
the gastrohepatic ligament are left intact so as to avoid excessive mobility of the
remaining left lobe, which could lead to torsion and outflow occlusion. A cholecys-
tectomy is performed leaving the cystic duct as long as possible if an intraoperative
cholangiogram becomes necessary.
The hilar dissection is kept as high as possible to avoid unnecessary dissection of
the hilar structures, which would lead to devascularization of the donor bile duct.
The right hepatic artery is dissected, exposed and encircled with a vessel loop, tak-
ing care to avoid the bile duct and its adventitia to the right of the common hepatic
duct as far as possible. After mobilization of the right hepatic artery, complete isola-
tion of the common trunk and the right portal vein is undertaken to obtain maximum
length and so ensure safe placement of an endovascular TA stapler or a small
Satinsky vascular clamp when the graft is removed. The right lobe of the liver is
then mobilized, its diaphragmatic attachments sectioned, and the right ligament
detached. The retrohepatic vena cava is then exposed, after which all the short
hepatic veins draining the posterior side of the right lobe are ligated and divided.
The right hepatic vein (RHV) is then encircled with a vessel loop. Any accessory
right inferior hepatic veins draining segments 6 or 7 are dissected and preserved if
greater than 5 mm in diameter.
The line of parenchymal transection is determined by first occluding both the
right hepatic artery and right portal vein with an atraumatic bulldog clamp, and
then locating the middle hepatic vein (MHV) using an intraoperative ultrasound
probe to better define the line of demarcation. Once the path of the MHV has been
marked, the line of transection is then adjusted so that it lies to right of the
MHV. As widely reported in adult LDLT studies, inclusion of the MHV with the
right lobe graft (segments 5, 6, 7, and 8) remains a surgical controversy that is the
subject of contradictory recommendations [10]. Whenever possible we preserve
the MHV in the left lobe to optimize liver function and remnant liver regeneration
in the donor.
We prefer to transect the liver parenchyma associating the Cavitron Ultrasonic

Surgical Aspirator (CUSA) and bipolar irrigated forceps. Before completion of the
parenchymal transection, the right biliary plate and the hepatic duct are cleanly
divided with a scalpel. The remaining biliary stump(s) is(are) then closed with 6/0
polydioxanone suture. Before removal of the right lobe graft, 2500–5000 U of hepa-
rin are systemically administered intravenously.
The hepatic artery is ligated with silk ties and clips. The right portal vein is
secured and divided with an endovascular TA stapler or a small Satinsky vascular
clamp, and the remaining vein stump sutured. Finally, the RHV is secured and
divided with an endovascular TA stapler, or clamped, divided, and sutured depend-
ing on the anatomy. Particular attention should be paid to minimize and prevent left
lobe torsion. In addition, before closing the abdomen, the falciform ligament should
be fixed to the abdominal wall. On the back table, the right lobe graft is flushed
(through both the hepatic artery and portal vein), with 500 mL of cold perfusion
solution while the bile duct is gently flushed with a syringe.
8.3.2 Recipient Hepatectomy and Implantation of Right Lobe
Recipient surgery is begun shortly after the start of the donor procedure. The hepa-
tectomy is performed preserving the retrohepatic vena cava. A venovenous bypass
or portocaval shunt are not routinely used.
As in the donor procedure, the hilar dissection should be as high as possible, and
both the right and left hepatic arteries and portal veins dissected close to the paren-
chyma in order to preserve an adequate length for any vascular reconstruction. Given
the importance of blood supply to the recipient’s bile duct from the right hepatic
artery, we usually avoid unnecessary dissection between the right hepatic artery and
the bile duct. Once the recipient’s liver is fully mobilized, the right hepatic vein and
the confluence of the left and middle hepatic veins are encircled with a vessel loop.
After clamping and dividing the portal vein as described above, the liver is removed,
by clamping and dividing the RHV and the confluence of the left and middle hepatic
veins with vascular staplers or clamps depending on the venous anatomy.
The graft’s RHV can be anastomosed to the recipient’s vena cava in different
ways, always remembering the importance of venous outflow, especially in the
presence of venous branches from segments 5 and 8 draining into the donor’s MHV
(Fig. 8.2). As elsewhere described, the vein anastomoses are performed with par-
ticular emphasis on shortening any redundancies between the donor and recipient
vena cava to avoid any risk of graft rotation and kinking of the venous outflow [24].
The graft right portal vein is then anastomosed end-to-end to the recipient’s portal
vein. Patch venoplasty or vein reconstruction for anomalous portal vein branching
is performed on case-by-case basis. The hepatic artery of the right lobe graft is usu-
ally anastomosed to the recipient’s common or right hepatic artery depending on the
arterial diameters. In our experience, a duct-to-duct anastomosis with interrupted
6–0 PDS sutures is the procedure of choice and is always performed with placement
of external biliary drainage.
a c
b d
Fig. 8.2 (a) Preoperative donor’s imaging showing a large venous hepatic branch (V8) originating
from segment 8 and draining into the middle hepatic vein (MHV). (b) Parenchymal transection
performed preserving any large venous branches. (c) Reconstruction of the venous branch (V8)
with a venous graft interposition. (d) Recipient’s imaging showing the patency of the reconstructed
venous branch
8.4 Italy: Recent Advances and Future Prospects
According to the Italian National Transplant Center (CNT) registry, from 2001 to
2017, a total of 367 LDLTs were performed in Italy [25]. The two leading centers at
the time—Niguarda in Milan, and ISMETT in Palermo—each carried out more than
100 living donor procedures. LDLTs accounted for less than 3% of the total liver
transplantations performed in the same period, a similar percentage to that reported
for the US and other European countries, much lower than LDLT figures reported
for Asia, where more than 300 procedures were performed a year by a single
Institution in South Korea [26].
Despite an enthusiastic beginning, recent years have seen only a few Italian cen-
ters take up LDLT, and only four centers have performed more than 20 cases.
Considering the overall Italian experience, the reported 1-year patient and graft sur-
vival rates were 79.9% and 74.5% respectively, comparing favorably with other
recently reported series [26]. Considering our experience, by the end of 2018, 1926
liver transplantations had been performed at our institution, including 101 LDLT
a Long term survival-LDLT b Long term survival-LDLT vs. all LT

100 100
80 80 77.4%
10-years
90.1% 77.4% 77.4% 77.4%
60 1-years 5-years 10-years 60 5-years
%
%
40 40
LDLT
AII LT
20 20
0 0
0 20 40 60 80 100 120 0 50 100 150 200 250 300
Months post-transplantation Months post-transplantation
Fig. 8.3 (a) Recipient long-term survival after living donor liver transplant (LDLT). (b) Recipient
long-term survival: LDLTs vs. overall all liver transplants (All LT)
(10 LDLT proctorships to other institutions worldwide). At 1, 5 and 10 years after

LDLT patient survival rates were 90.1%, 77.4%, and 77.4%, while graft survival
rates were 85.1%, 77.4%, 77.4% (Fig. 8.3a). The outcomes of our LDLT series
compare favorably with the overall liver transplantation outcomes (Fig. 8.3b).
Ethical aspects and donor safety have been the principal concerns worldwide
since the first report of a successful LDLT performed in 1989. In fact, donor mor-
bidity and mortality still limit the use of living liver donation in all countries. An
Italian multicenter survey on donor safety in LDLT reported postoperative donor
outcomes in 246 consecutive living donations performed by seven transplant cen-
ters [27]. The review showed right lobe (segments 5, 6, 7 and 8) without the middle
hepatic vein to be the segment of choice (220/246; 89%). This probably reflects the
surgical experience gained in hepatobiliary surgery as well as the favorable
GRWR. There was no donor mortality regardless of graft type but major complica-
tions (Clavien grade ≥ 3) were observed in 12.6% of cases (31/246). However,
donor outcomes in this multicenter series compare favorably with recently reported
overall outcomes.
8.5 Experts’ Comments
A complete understanding of liver anatomy and accurate liver volume assessment

are fundamental when approaching the complex LDLT surgical procedure.
Regardless of the type of liver resection performed, biliary anatomy is one of the
most demanding issues in liver surgery and LDLT.
Better understanding of the mechanisms leading to the development of small-
for-size syndrome and posthepatectomy liver failure show that liver remnant vol-
ume is not the only main variable responsible for liver dysfunction after major liver
resection or small graft LDLT. The quality of the liver remnant’s parenchyma,
venous outflow, portal blood flow, and pressure must also be taken into account
when planning small graft transplantation or embarking on complex surgical strate-
gies for malignancies.
Despite its recent progress and undoubted advantages, minimally invasive liver
surgery should only be recommended for those centers with consolidated experi-
ence in both open liver surgery and laparoscopic liver resection.
Although continued interest in left lobe procurement is important and likely to
increase in view of minimally invasive transplants, the accepted standard procedure
is a well-regimented right lobe living donation as exemplified by the large series
reported.
LDLT has attracted wide attention since the first case reported over 30 years ago.
However, despite technical refinements in both donor and recipient surgery, it
remains a technically demanding surgical procedure. The liver surgeon should be
eclectic and able to adapt the originally planned surgical strategy to contingencies
presenting on the spot. Indeed, the first successful right lobe LDLT was performed
when the surgeon, confronted with an unfeasible left lobe anatomy, changed his
approach and removed the right lobe [9].
The evolution of LDLT has been the keystone of developments in complex liver
surgery, and vice versa. These knock-on effects will continue to benefit both LDLT,
on the one hand, and complex liver surgery, on the other.
References
1. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Paris: Masson Editeur; 1957.
2. Tùng TT. Les résections majeures et mineures du foie. Paris: Masson Editeur; 1979.
3. Bismuth H, Houssin D. Reduced-sized orthotopic liver graft in hepatic transplantation in chil-
dren. Surgery. 1984;95:367–70.
4. Broelsch CE, Emond JC, Thistlethwaite JR, et al. Liver transplantation with reduced size
donor organs. Transplantation. 1988;45:519–23.
5. Broelsch CE, Emond JC, Thistlethwaite JR, et al. Liver transplantation, including the concept
of reduced size liver transplants in children. Ann Surg. 1988;208:410–20.
6. Pichlmayr R, Ringe B, Gubernatis G, et al. Transplantation of a donor liver to 2 recipients
(splitting transplantation) – a new method in the further development of segmental liver trans-
plantation. Langenbecks Arch Chir. 1988;373:127–30.
7. Strong RW, Lynch SV, Hong TH. Successful liver transplantation from a living donor to her
son. N Engl J Med. 1990;322:1505–7.
8. Hashikura Y, Makuuchi M, Kawasaki S, et al. Successful living-related partial liver transplan-
tation to an adult patient. Lancet. 1994;343:1233–4.
9. Yamaoka Y, Washida M, Honda K, et al. Liver transplantation using a right lobe graft from a
living related donor. Transplantation. 1994;57:1127–30.
10. Miller CM, Durand F, Heimbach JK, et al. The International Liver Transplant Society Guideline
on living liver donation. Transplantation. 2016;100:1238–43.
11. Sugawara Y, Makuuchi M, Takayama T, et al. Small-for-size grafts in living-related liver trans-
plantation. J Am Coll Surg. 2001;192:510–3.
12. Dahm F, Georgiev P, Clavien PA. Small-for-size syndrome after partial liver transplantation:
definition, mechanisms of disease and clinical implications. Am J Transplant. 2005;5:2605–10.
13. Ben-Haim M, Emre S, Fishbein TM, et al. Critical graft size in adult-to-adult living donor liver
transplantation: impact of the recipient’s disease. Liver Transpl. 2001;7:948–53.
14. Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grad-
ing by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149:713–24.
15. Troisi RI, Berardi G, Tomassini F, Sainz-Barriga M. Graft inflow modulation in adult-to-adult
living donor liver transplantation: a systematic review. Transplant Rev. 2017;31:127–35.
16. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in
situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right
hepatic resection in small-for-size settings. Ann Surg. 2012;255:405–14.
2015;261:619–29.
18. Ratner LE, Hiller J, Sroka M, et al. Laparoscopic live donor nephrectomy removes disincen-
tives to live donation. Transplant Proc. 1997;29:3402–3.
19. Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic left lateral sectionectomy in liv-
ing donors: safety and reproducibility of the technique in a single center. Ann Surg.
2006;244:815–20.
20. Soubrane O, de Rougemont O, Kim K-H, et al. Laparoscopic living donor left lateral sectio-
nectomy: a new standard practice for donor hepatectomy. Ann Surg. 2015;262:757–61.
21. Samstein B, Cherqui D, Rotellar F, et al. Totally laparoscopic full left hepatectomy for living
donor liver transplantation in adolescents and adults. Am J Transplant. 2013;13:2462–6.
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living donor liver transplantation: useful strategies to enhance safety. Am J Transplant.
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Transpl Int. 2012;25:e5–9.
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Pediatric Living Donor Liver
Transplantation 9
Roberta Angelico, Chiara Grimaldi, Maria Cristina Saffioti,
Alessandro Coppola, and Marco Spada
9.1 Introduction
Liver transplantation (LT) is the treatment of choice for an increasing number of liver
diseases in the pediatric population and has achieved survival rates up to 90% [1].
As pediatric cadaveric donors are limited, children candidate to LT are disadvantaged
due to the lack of size-matched donors.
In late 1980s, different surgical techniques were developed to increase the avail-
ability of partial grafts suitable for children both from deceased donor, with split-
liver transplantation (SLT), and from living donor. The first living donor liver
transplantation (LDLT) was attempted in 1987 by Raia, but the recipient did not
survive after transplantation [2]. In the same year, Strong reported the first success-
ful LDLT in Australia [3]. Later, the adult-to-child LDLT procedure was redefined
by Broelsch [4], and its introduction drastically decreased the pediatric waiting list
mortality, from approximately 25% to 10% [4, 5].
In most Asian countries, LDLT represents the principal resource for LT. In Japan,
during the last 25 years, 96% of LT candidates received a living-donor graft, and of
these 34% were pediatric recipients [6, 7]. In Western countries, the volume of
LDLT activity has been lower due to a greater availability of deceased donors and
the consequent diffusion of SLT: in 2016 within the United Network of Organ
Sharing (UNOS), 10.5% of pediatric LT candidates received a living-related graft
[8]; in Europe LDLT represented 32.9% of all pediatric LT in 2010–2013 [9].
In pediatric LDLT, the most common donor surgical procedure is left lateral
sectionectomy, which nowadays is a straightforward procedure if performed in
R. Angelico · C. Grimaldi · M. C. Saffioti · A. Coppola · M. Spada (*)

Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery,
Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
e-mail: roberta.angelico@opbg.net; chiara.grimaldi@opbg.net; mcristina.saffioti@opbg.net;
alessandro.coppola@opbg.net; marco.spada@opbg.net

86 R. Angelico et al.
specialized centers. LDLT allows optimization of the timing of transplantation as

well as planning of the best surgical strategy, resulting in maximized recipient out-
comes and low risks in well-selected donors. Thus, a thorough evaluation of the
donor and of the recipient is essential to detect potential risk factors.
9.2 Pediatric Recipients
The indications for pediatric LT are summarized in Table 9.1; biliary atresia is the
leading diagnosis, accounting for approximately 40% of pediatric LDLT [7, 9]. At
the time of transplantation, more than 55% of children are ≤2 years, about 50% of
procedures are performed in children ≤10 kg and almost 10% in recipients ≤6 kg of
body weight [6].
The early referral of children potentially candidate to LT to a pediatric transplant
center is recommended for a multidisciplinary evaluation to exclude absolute
Table 9.1 Main indications for pediatric liver transplantation

Age (years old)
Indication for liver transplantation 0–2 2–18
Cholestatic disease 76.3% 46.5%
• Biliary Atresia
• Alagille syndrome
• Familial intrahepatic cholestatic syndrome
• Primary sclerosing cholangitis
Metabolic disease 8.5% 23.4%
• Wilson’s disease
• α1 Antitrypsin deficiency
• Urea cycle defects
• Primary hyperoxaluria
• Glycogen storage diseases
• Crigler-Najjar syndrome
• Cystic fibrosis
• Hemochromatosis
• Familial hypercholesterolemia
Acute hepatic failure 8.2% 15.9%
• Neonatal hepatitis
• Drug induced (e.g., acetaminophen)
• Acute viral hepatitis
• Autoimmune hepatitis
• Other infection hepatic failure (syphilis, toxoplasmosis, bacterial)
• Idiopathic
Liver malignancies 4.2% 6.4%
• Hepatoblastoma
• Hepatocellular carcinoma
• Hemangioendothelioma
Other disease 2.8% 7.8%
• Budd Chiari syndrome
• Congenital hepatic fibrosis
Data from the European liver transplant registry
9 Pediatric Living Donor Liver Transplantation 87
contraindications and to optimize the timing of transplantation according to the

recipient’s clinical condition, body weight and immunization status [10].
9.3 Donor Evaluation and Selection
The donor evaluation consists of a multistep screening process that includes:
1. assessment of the donor’s health status to exclude contraindications to donation

such as active infections, malignancies and systemic diseases;
2. definition of the anatomy and volumetry of the liver;
3. psychological evaluation to verify that the donor makes a free and conscious
choice.
To protect the donor, in many centers the donor evaluation is independent from
that of the recipient and an independent living donor advocate is nominated as a
supportive role for his health care.
Approximately 30% of potential donors evaluated for LDLT are excluded from
donation because of medical reasons (35%) [fatty liver (50%), hypercoagulability
risk (12%), metabolic diseases (9%), HBV/HCV carrier (11%)], withdrawal of con-
sent (26%) or ABO incompatibility (14%) [11, 12]. Most centers disqualify living
donor candidates with ≥10% hepatic steatosis; the grade of steatosis can be well
evaluated by non-invasive imaging such as magnetic resonance spectroscopy–pro-
ton density fat fraction, limiting donor liver biopsy only to unclear cases [13].
9.3.1 L
iving Donor Liver Transplantation in Inheritable
Metabolic Disorders
If the recipient has an inherited metabolic disease, suitability for donation from a
parent, who may be affected by the same disease, must be determined by genetic
testing or liver biopsy to measure the activity of the target enzyme. Most cases of
inherited metabolic disorders are autosomal recessive, for which the use of geneti-
cally proven heterozygous donors showed no negative impact on either the donor or
the recipient (5- and 10-year recipient survival of 88% and 87%, respectively). With
regard to X-linked ornithine transcarbamylase deficiency, it has been reported that
symptomatic heterozygote maternal donors are at risk of the disease, presumably due
to liver mosaicism, and should not be considered potential donor candidates [10].
9.4 Preoperative Planning
The aims of the preoperative surgical planning in pediatric LDLT are:
1. to define the portion of donor liver to be retrieved for the best graft-to-recipient
dimensional matching;
2. to evaluate vascular and biliary anatomy in order to plan the optimal surgical
strategy, and possible need for reconstructions at the back table;
3. to correlate the graft’s anatomy to the recipient’s anatomy and identify additional
needs (i.e., donor grafts for portal vein or cava reconstruction);
4. to evaluate the possible laparoscopic approach in the donor’s procedure.
The ratio between graft weight and recipient weight is defined as graft-to-
recipient weight ratio (GRWR). An ideal GRWR is between 1.5 and 3 for pediat-
ric recipients; a GRWR <1 is associated with an increased risk of failure or
delayed functional recovery of the graft, a condition known as “small-for-size
syndrome”. On the other hand, when the GRWR is >4, a “large-for-size syn-
drome” may occur, characterized by the impossibility to directly close the abdom-
inal wall without compression of the vessels, causing vascular complications and
graft dysfunction [14].
The weight of an adult’s liver accounts for about 2% of body weight and the left
lateral segment (LLS) constitutes about 15–20% of the total volume of the liver. Since
over 70% of pediatric LT candidates weigh <15 kg, the majority of pediatric LDLT can
be performed with an LLS from a 60–80 kg donor. Children with body weight < 5 kg
often require a further size reduction of the LLS to avoid large-for-size syndrome,
while children with body weight > 15 kg need a larger graft such as a full left lobe.
Computed tomography angiography (angio-CT) is essential in the donor workup
as it provides important information on liver segments: segment volume; arterial
anatomy (accessory/replaced hepatic artery, vessels size, origin of branch for seg-
ment 4); portal vein (PV) and hepatic vein anatomy. The donor’s biliary anatomy is
usually evaluated by magnetic resonance cholangiopancreatography or three-
dimensional reconstruction of high-resolution CT images (Fig. 9.1).
9.5 Donor Surgery
9.5.1 Left Lateral Segment Graft
The left lateral sectionectomy (segments 2–3) for LDLT is a well-standardized pro-
cedure [15]. Whether performed by an open or laparoscopic approach, the first step
is dissection of the hepatogastric ligament. If an accessory or replaced left hepatic
artery originating from the left gastric artery is present, this needs to be preserved.
The left side of the hepatic pedicle is dissected to identify the left hepatic artery.
The artery to segment 4 is left in place if it arises from the right hepatic artery while,
if it originates from the left hepatic artery, it will be preserved or ligated based on
the length and size of the left hepatic artery retrieved for the LLS. The round liga-
ment is completely dissected and all the branches for segment 4 are divided, expos-
ing the left PV, which is dissected down to the main bifurcation. Branches to
segment 1, if present, are ligated and divided. With the sectioning of the Arantius
ligament, the left hepatic vein (LHV) can be encircled extra-parenchymally.
a b
c d
Fig. 9.1 Three-dimensional reconstruction of graft types used in pediatric living donor liver trans-
plantation. (a) Left lateral segment graft. (b) Left lobe graft. (c) Reduced left lateral segment graft.
(d) Segment 2 monosegment graft (Images by courtesy of: © 2018 MeVis Medical Solutions AG)
Alternatively, the LHV might be approached at the end of the parenchymal transec-
tion. To obtain a modified “hanging maneuver”, helpful during parenchymal tran-
section, an umbilical tape is placed between the LHV and the middle hepatic vein
(MHV) and passed over the left PV and left hepatic artery.
Dissection of the parenchyma is then performed to the right of the falciform liga-
ment, using bipolar forceps, clips, sutures and electronic dissection and sealing
devices. During this phase, to avoid bleeding it is important to be aware of the pres-
ence of umbilical fissure vein(s). According to the recipient’s need, the parenchymal
section plane can be moved further toward segment 4 to obtain additional liver
parenchyma. To preserve vascularization of the left bile duct(s), the hilar plate is not
dissected but sharply divided at the level of the Rex recessus. In selected cases,
intraoperative cholangiography helps to avoid iatrogenic biliary lesions and to cut
the left bile duct before its bifurcation into segments 2 and 3. The stump of the bile
duct of the donor’s remnant liver is closed with sutures. When the parenchymal
transection is completed, the left hepatic artery, the left PV and the LHV are sequen-
tially divided, using mechanical staplers or vascular clamp and suture closure.
After harvesting, the graft is perfused with preservation solution on the back
table; vascular reconstruction might be performed. Hemostasis and biliostasis need
to be ensured on the donor’s remnant liver. Systemic heparinization may be per-

formed in the donor before graft procurement (which is associated with higher rate
of postoperative bleeding) or on the back table; however, to date there is no consen-
sus on the use of heparinization in the donor surgery for LDLT [16].
9.5.2 Laparoscopic Left Lateral Sectionectomy
In 2006 Soubrane described the first series of full laparoscopic left lateral sectionec-
tomy for LDLT [17]. So far more than 200 laparoscopic donor left lateral sectionec-
tomies have been reported. In 2017, the Southampton consensus on laparoscopic
liver surgery [18] stated that laparoscopic donor left lateral sectionectomy is a safe
procedure in expert centers, achieving similar results to open surgery in terms of
graft and recipient outcomes, with advantages in donor blood losses, postoperative
recovery and abdominal wall complications, such as infections or hernias [19].
9.5.3 Reduced and Hyper-Reduced Left Lateral Segment Grafts
Technical variant LLS grafts are used to avoid the large-for-size syndrome, espe-
cially in neonatal LDLT. These include:
• non-anatomical reduction of an LLS, obtained by removing the lateral and/or

caudal portions of the LLS graft, taking into account the intraparenchymal distri-
bution of the branches of the left suprahepatic vein;
• anatomical reduction of an LLS, which means the use of only segment 2 or 3 [7];
in this latter case the resection is carried out according to the anatomy of the PV
branches, defined by means of Doppler ultrasound, possibly with the aid of sono-
graphic contrast agent or selective PV injection of methylene blue.
The main limitation of non-anatomical reductions is that they allow decreasing

the volume of the graft, but not its thickness. In very small recipients, in particular
those without portal hypertension and ascites, the maximum thickness of the graft
must not exceed the maximum anterior-posterior diameter of the recipient’s abdom-
inal cavity (ratio < 1). Segment 2 monosegment graft is a reduced-thickness graft
that offers a greater possibility of direct closure of the abdominal wall with a lower
risk of vascular compression [20]. Recently, the full laparoscopic procurement of
segment 2 for LDLT has been described [21].
9.5.4 Left Lobe Graft
The left lobe graft is a valid option for LDLT in medium-large pediatric recipients.
The full left lobe represents 30% to 40% of the whole liver in adults. The additional
inclusion of the caudate lobe can increase the graft weight from 2% to 10%.
In spite of regular or extended LLS, for this type of graft the MHV is retained
with the left graft [22].
Hilar dissection is started to expose the left hepatic artery and the origin of seg-
ment 4 artery; then the left PV is looped. The length of the left PV dissection
depends on whether or not the caudate lobe is included in the graft. Thus, if the
caudate lobe is to be taken with the graft, the caudate veins entering the inferior
vena cava (IVC) are carefully divided. The common trunk of the MHV/LHV is
looped, and a modified “hanging maneuver” facilitates faster parenchymal transec-
tion. The arterial and portal inflow to the left lobe can be temporary interrupted to
identify the left lobe demarcation on the surface of the liver for the transection line
(along the Cantlie line). Once the parenchymal transection is completed, the left
hepatic artery, the left PV and the common trunk of the MHV/LHV are clamped and
divided, and the graft is retrieved. The portal and hepatic stumps in the donor are
then sutured as described for left lateral sectionectomy.
Above 90 cases of laparoscopic-assisted living donor left hepatectomy have been
reported, showing that the laparoscopic procedure is associated with less pain,
improved postoperative symptoms, and faster recovery in comparison with conven-
tional open surgery, but takes longer operative times [19]. The laparoscopic approach
has been defined as technically safe and feasible in expert centers, thus larger stud-
ies are needed to further establish its reproducibility [19].
9.6 Recipient Surgery
In pediatric LDLT, hepatectomy with native IVC preservation is usually performed

[23]. During implantation of a partial graft, attention is needed in graft positioning
to ensure a good portal and arterial inflow as well as vein outflow. The proper graft
position is obtained if the graft is rotated clockwise 45° on a transverse plane and
slightly on a frontal plane.
To guarantee a good outflow, Emond described the triangulation technique to
anastomose the LHV of the graft to the recipient IVC: after the creation of a single
opening, cutting of the ostium of the hepatic veins (right hepatic vein plus MHV;
LHV can be included or sutured) and cutting the anterior face of the IVC in order to
obtain a wide reversed triangular orifice, the LHV of the graft, cut as short as pos-
sible to avoid kinking, is anastomosed to the triangular ostium by performing three
running sutures [24]. In case the native IVC has to be removed (i.e., IVC occlusion
for tumoral infiltration or Budd-Chiari Syndrome), it may be replaced by interposi-
tion of a cryopreserved vascular (aorta, cava, iliac vein) or synthetic graft [25].
An end-to-end anastomosis between the graft’s left PV and the recipient PV is
fashioned by using 6–0 or 7–0 running absorbable or non-absorbable single-fila-
ment sutures. If the native PV is of insufficient length, a vein graft (the donor ovar-
ian or inferior mesenteric vein) is interposed between the graft PV and the recipient’s
PV. If the native PV appears sclerotic or stenotic (<4 mm), a portoplasty technique
is needed: after dissection of the recipient’s PV down to the confluence of the supe-
rior mesenteric vein and splenic vein, the anterior wall of the PV is opened
longitudinally, and a vein patch is sutured to the PV with side-to-side anastomoses

to enlarge the PV diameter [26].
Hepatic artery anastomoses are usually done with surgical loupes (magnification
× 3.5–4.5) or with the microscope, in an interrupted fashion with 8–0 monofilament
sutures. Biliary reconstruction is via Roux-en-Y hepaticojejunostomy to the left bile
duct(s) with 6–0 or 7–0 polydioxanone. Doppler ultrasound is repeated intraopera-
tively and after abdominal closure to check the patency of vascular structures.
Postoperative anticoagulant therapy might be used according to the center’s proto-
col [27].
9.7 Outcomes
In the last few decades, pediatric LDLT has reached excellent outcomes, with an
overall survival rate above 90% at 5 years and 75% at 20 years [9]. When compared
to adult LDLT, the outcomes of pediatric LDLT are superior since most pediatric
indications for LT do not recur after transplantation [10]. In countries where living
donation is the primary source of donors, the success of LDLT is also related to the
early referral for transplantation, which makes it possible to optimize the timing of
LT based not only on the recipient’s clinical status but also on optimal recipient
size-matching (5-year patient survival, range of 94–100%) [7]. In other scenarios,
where both living and deceased donor grafts are used, LDLT and deceased LT
achieved similar outcomes (5-year patient survival, 83.7% after LDLT and 81%
after deceased donor LT; p = 0.062) [9], thus LDLT showed advantages associated
with shorter ischemic times and lower ischemia-reperfusion injury, while no clear
immunological benefits have been reported [1]. A recent experience reported that
the 5-year recipient survival rates are similar if the donor left lateral sectionectomy
is performed by laparoscopic or open approaches (91% vs. 87%; p = 0.28) [28].
Predictors of graft survival after LDLT include recipient age, ABO incompatibil-
ity (ABOi), donor body mass index, graft type, and center experience [6, 29]. Some
series observed that recipients with ≤10 kg of body weight have a worse survival
(83%), compared with those >10 kg (94%), with even worse survival for children
<5 kg (80%) [10, 29], whereas a recent Japanese report failed to find any differences
in small recipients (<6 kg) [6]. For recipients with GRWR >5 the use of monoseg-
mental grafts resulted in increased patient survival rates when compared to those
receiving LLS grafts (80% vs. 72%) [7]. Moreover, anatomical reduction of LLS
showed superior results compared to non-anatomical reduction of LLS (3-year
patient survival of 95% vs. 81% and graft survival of 92% vs. 72%, respectively)
[30].
Although ABOi LDLT is performed safely in infants <2 years of age (20-year
graft survival rate, 80%) due to incomplete development of the recipient’s immune
system, the long-term results of ABOi LDLT are still not satisfactory in children
≥2 years of age (20-year graft survival rate, 50%) because they are characterized by
higher rates of hepatic necrosis and late ischemic cholangiopathy [7]. New strate-
gies for preventing antibody-mediated rejection in ABOi LDLT include
rituximab-based desensitization, pre-LDLT plasma exchange, and mycophenolate

mofetil as an additional immunosuppressant to overcome the ABO-blood barrier,
but their efficiency needs to be further explored [31].
Recipient morbidity rate in pediatric LDLT is similar to other technical variant
grafts, except for whole LT (45% whole, 67% split, 66% reduced, 52% live-donor)
[32]. The most frequent technical complications are biliary complications (5–20%)
[1], hepatic artery thrombosis (5–18%) [1, 28], PV thrombosis (1–5%) [26], outflow
obstruction (1–2%) [25].
Donor mortality has been reported to be 0.1% for left lateral sectionectomy and
0.1–0.2% for left lobe hepatectomy, while the complication rate is approximately
10–20% mainly related to biliary fistulas, incisional hernias, and bleeding [17, 19].
9.8 iving Donor Liver Transplantation at the Bambino

L
Gesù Children’s Hospital
At the Bambino Gesù Children’s Hospital the pediatric transplant program was
started in 2008 and has included both living and deceased donor LT. Between
September 2008 and October 2018, 221 pediatric LT were performed including 166
(75%) deceased donor LT and 55 (25%) LDLT. The LDLT grafts were 52 (94.5%)
LLS grafts, 2 (3.6%) full left lobe grafts, 1 (1.9%) domino LDLT. Three cases of
LDLT were liver-kidney transplantation (one sequential, one combined) from the
same donor and one sequential from two different donors.
The median recipient age was 16 months (6–99) with a body weight of 8 kg
(6–22). The GRWR was 5 (2.6–11.2). The 5-year LDLT patient and graft survival
rates were 100%. The postoperative morbidity rate was 36%, including 5 (9%) cases
of vascular thrombosis and 6 (10.9%) of biliary stenosis.
The donor surgery consisted of a minimally invasive approach in 15 (27%) cases.
All donors recovered well after surgery and were discharged on postoperative day 5
(4–20) days. No donor mortality occurred, and the donor morbidity rate was 5%
(one biliary fistula and three incisional hernias).
9.9 Conclusions
In pediatric LDLT the LLS is the most common used graft with a standardized sur-
gical technique, which has achieved excellent outcomes; the left lobe graft is a valid
option to ensure adequate GRWR in medium-large children. In countries where
deceased donation is limited, LDLT is a fundamental source of organs, which has
yielded good results also in high-risk categories such as ABOi transplantation and
monosegmental grafts for very small infants. In other scenarios where substantial
deceased donor activity is present, LDLT is used together with the optimization of
split liver transplantation to eliminate mortality on the pediatric LT waiting lists and
to transplant recipients who are disadvantaged in the organ allocation systems based
on urgency criteria. In this setting, optimization of the timing of transplantation
makes it possible to achieve graft and patient survivals of approximately 100% after
LDLT, as in our center. Meticulous preoperative planning and surgical expertise
minimize donor risks and guarantee donor safety. The laparoscopic approach in the
donor surgery reduces surgical trauma and increases the safety of the donor
procedure.
References
1. Pham YH, Miloh T. Liver transplantation in children. Clin Liver Dis. 2018;22:807–21.
2. Raia S, Nery J, Mies S. Liver transplantation from live donors. Lancet. 1989;334:497. https://
doi.org/10.1016/S0140-6736(89)92101-6.
3. Strong RW, Lynch SV, Ong TH, et al. Successful liver transplantation from a living donor to
her son. N Engl J Med. 1990;322:1505–7.
4. Broelsch CE, Emond JC, Thistlethwaite JR, et al. Liver transplantation with reduced size
donor organ. Transplantation. 1988;45:519–24.
5. Hsu EK, Mazariegos GV. Global lessons in graft type and pediatric liver allocation: a path
toward improving outcomes and eliminating wait-list mortality. Liver Transpl. 2017;23:86–95.
6. Kasahara M, Umeshita K, Sakamoto S, et al. Living donor liver transplantation for biliary
atresia: an analysis of 2085 cases in the registry of the Japanese liver transplantation society.
Am J Transplant. 2018;18:659–68.
7. Kasahara M, Sakamoto S, Fukuda A. Pediatric living-donor liver transplantation. Semin
Pediatr Surg. 2017;26:224–32.
8. Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2016 annual data report: liver. Am J
Transplant. 2018;18(Suppl 1):172–253.
9. Hackl C, Schlitt HJ, Melter M, et al. Current developments in pediatric liver transplantation.
World J Hepatol. 2015;7:1509–20.
10. Squires RH, Ng V, Romero R, et al. Evaluation of the pediatric patient for liver transplantation:
2014 practice guideline by the American Association for the Study of Liver Diseases, American
Society of Transplantation and the north American Society for Pediatric Gastroenterology.
Hepatology and Nutrition Hepatology. 2014;60:362–98.
11. Nugroho A, Kim OK, Lee KW, et al. Evaluation of donor workups and exclusions in a single-
center experience of living donor liver transplantation. Liver Transpl. 2017;23:614–24.
12. Wahab MA, Hamed H, Salah T, et al. Problem of living liver donation in the absence of
deceased liver transplantation program: Mansoura experience. World J Gastroenterol.
2014;20:13607–14.
13. Trotter JF. The diminishing role of liver biopsy in living donor liver transplantation. Liver
Transpl. 2018;24:457–8.
14. Kiuchi T, Kasahara M, Uryuhara K, et al. Impact of graft size mismatching on graft prognosis
in liver transplantation from living donors. Transplantation. 1999;67:321–7.
15. Spada M, Riva S, Maggiore G, et al. Pediatric liver transplantation. World J Gastroenterol.
2009;15:648–74.
16. Dong Kim J, Lak Choi D, Seok Han Y. Is systemic heparinization necessary during living
donor hepatectomy? Liver Transpl. 2015;21:239–47.
17. Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic left lateral sectionectomy in living donors
safety and reproducibility of the technique in a single center. Ann Surg. 2006;244:815–20.
18. Abu Hilal M, Aldrighetti L, Dagher I, et al. The Southampton consensus guidelines for laparo-
scopic liver surgery: from indication to implementation. Ann Surg. 2018;268:11–8.
19. Park JI, Kim KH, Lee SG. Laparoscopic living donor hepatectomy: a review of current status.
J Hepatobiliary Pancreat Sci. 2015;22:779–88.
20. Kasahara M, Sakamoto S, Sasaki K, et al. Living donor liver transplantation during the first 3
months of life. Liver Transpl. 2017;23:997–8.
21. Hong SK, Suh KS, Kim HS, et al. Pediatric living donor liver transplantation using a mono-
segment procured by pure 3D laparoscopic left lateral sectionectomy and in situ reduction. J
Gastrointest Surg. 2018;22:1135–6.
22. Takayama T, Makuuchi M, Kubota K, et al. Living-related transplantation of left liver plus
caudate lobe. J Am Coll Surg. 2000;190:635–8.
23. Rogiers X, Malagó M, Habib N, Broelsch CE. An easy technique for inferior vena cava control
in pediatric liver transplantation. J Am Coll Surg. 1996;182:555–6.
24. Emond JC, Heffron TG, Whitington PF, et al. Reconstruction of the hepatic vein in reduced
size hepatic transplantation. Surg Gynecol Obstet. 1993;176:11–7.
25. Yagci MA, Tardu A, Karagul S, et al. Living donor liver transplantation with vena cava replace-
ment. Transplant Proc. 2015;47:1453–7.
26. de Magnée C, Bourdeaux C, De Dobbeleer F, et al. Impact of pre-transplant liver hemodynam-
ics and portal reconstruction techniques on post-transplant portal vein complications in pediat-
ric liver transplantation: a retrospective analysis in 197 recipients. Ann Surg. 2011;254:55–61.
27. Nacoti M, Ruggeri GM, Colombo G, et al. Thrombosis prophylaxis in pediatric liver trans-
plantation: a systematic review. World J Hepatol. 2018;10:752–60.
28. Broering DC, Elsheikh Y, Shagrani M, et al. Pure laparoscopic living donor left lateral sectio-
nectomy in pediatric transplantation: a propensity score analysis on 220 consecutive patients.
Liver Transpl. 2018;24:1019–30.
29. Neto JS, Pugliese R, Fonseca EA, et al. Four hundred thirty consecutive pediatric living donor
liver transplants: variables associated with posttransplant patient and graft survival. Liver
Transpl. 2012;18:577–84.
30. Kitajima T, Sakamoto S, Sasaki K, et al. Impact of graft thickness reduction of left lateral
segment on outcomes following pediatric living donor liver transplantation. Am J Transplant.
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31. Honda M, Sugawara Y, Kadohisa M, et al. Long-term outcomes of ABO-incompatible pediat-
ric living donor liver transplantation. Transplantation. 2018;102:1702–9.
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transplantation: a report from studies of Pediatric liver transplantation (SPLIT). Ann Surg.
2007;246:301–10.
Left Split Liver
10
Umberto Cillo and Riccardo Boetto
10.1 Introduction
A wide disparity exists between the number of available donors and the number of
patients on the waiting list for liver transplantation. The practice of split liver pro-
vides grafts for two recipients from one deceased donor, thereby increasing the
number of organs available for transplant (Fig. 10.1). The surgical procedure of
liver division for one adult and one pediatric recipient in a right extended graft and
a left lateral graft is defined as a “conventional” split liver, or true right/left split [1].
Left lateral splitting does not compromise the adult graft pool because right
extended grafts are associated with results basically overlapping those of whole
liver transplantations, and it is usually not involved in a postoperative small-for-size
syndrome [2]. The use of partial livers from deceased donors can relevantly help to
reduce the shortage of grafts needed for the pediatric population.
Split liver transplantation has resulted in a reduction of waiting list mortality for
the pediatric population, with less pressure on parents to become live donors [3].
One donor liver can also be transplanted into two adult recipients by dividing the
parenchyma along the Cantlie line to obtain a right hemiliver (Couinaud segments
5–8) and a left hemiliver (Couinaud segments 1–4); this technique was first described
in 1989 by Bismuth for two recipients with fulminant hepatic failure and named
“full-right full-left” split-liver transplantation [4, 5]. The procedure is technically
demanding because of the larger transection plane, the absence of anatomical
U. Cillo (*)
e-mail: cillo@unipd.it
R. Boetto
e-mail: riccardo.boetto@aopd.veneto.it

98 U. Cillo and R. Boetto
Fig. 10.1 Transection
lines for conventional and
full-right full-left split liver
landmarks to guide transection (such as the falciform ligament), and a major risk of
vascular and biliary injury [6]. For this reason, the conventional split-liver technique
is by far the most frequently adopted procedure.
Split-liver procedures can be performed by means of an in situ (most fre-
quently) or an ex situ approach. The ex situ procedure, first introduced in February
1988 by Pichlmayr’s group, is performed on the explanted whole cadaveric liver
by dividing the parenchyma along the umbilical fissure during bench surgery [7].
Based on their experience with living donor liver transplantations, the Hamburg
group and the UCLA group, in 1996 and 1997, respectively, first described the
liver splitting procedure in heart-beating deceased donors (in situ splitting), claim-
ing this splitting procedure to be superior in view of the shorter cold ischemic
time (avoiding long bench surgery) and the possibility of long-distance graft shar-
ing [8, 9].
10.2 Donor Selection
Based on data from the Organ Procurement and Transplantation Network (OPTN),
more than 10% of all deceased donors and more than 20% of donors less than
35 years old meet the criteria for split-liver transplantation, but only less than 1.5%
of all donor livers have been split since the criteria were adopted [10].
The current donor selection criteria are [6]:
1 . hemodynamically stable patients <55 years

2. duration of ICU treatment <5 days,
3. fatty degeneration of the liver <30%,
4. GGT <50 U/L, GPT <60 U/L, and serum sodium <160 mmol/L.
10 Left Split Liver 99
The split-liver program was established in Italy in 1997 and a specific protocol
of the Italian transplant center (CNT, Centro Nazionale Trapianti), in force since
March 2016 [11] is available to define:
1. general criteria (all donations from donors younger than 50 years are offered to
pediatric centers to evaluate eligibility)
2. donor eligibility (age ≤50, standard risk)
3. allocation criteria.
Donor quality must be evaluated case by case on site by an experienced surgeon

[12].
Interestingly, the last 2 years have seen the introduction of a “mandatory” split
liver in Italy. All donors younger than 50 years are allocated to pediatric centers for
the decision to split. Only if the pediatric center considers the donor ineligible for a
split procedure, is the organ reallocated to an adult center.
In Italy, any right extended split graft offered and shared is considered as a whole
organ to underline that a right split transplantation has the same middle- and long-
term graft and patient survival rates as a whole organ.
10.3 Surgical Technique
The technical details of splitting procedures are based on those principles of liver
partition that have been developed in oncologic hepatobiliary surgery. The most
relevant difference is that in splitting techniques both hemilivers have to be fully
preserved without jeopardizing the two parenchymal surfaces in any way.
Splitting techniques, therefore, represent a clear paradigm of deep interplay
between transplant surgery and hepatobiliary surgery. Liver transplant surgeons per-
forming splits on a regular basis need to have a wide background of liver resections.
In turn, the splitting experience is extremely useful in the training of hepatobiliary
surgeons. Splitting familiarizes surgeons with the importance of anatomical details
and variations, the gentle dissection of small hilar vessels and respect for parenchy-
mal planes and vascular outflow.
10.3.1 Intraoperative Imaging
1. Intraoperative ultrasonography of the liver provides a useful real-time diagnostic

and anatomical evaluation that may result in a better planning of the technical
approach during liver partition; when available in the procurement centers, it is the
best form of guidance for the correct recognition of vascular structures, anatomical
inflow/outflow variations and identification of the correct transection plane [13].
2. Only exceptionally may intraoperative cholangiography, when available, be use-
ful to avoid injury to the biliary plate in the presence of particularly complex
anatomical variations.
The left lobe ligaments (falciform ligament and coronary ligament) are first com-
pletely freed. After interrupting the lesser omentum, with particular attention to the
presence of a significant left replaced hepatic artery arising from the left gastric artery,
the fibrous remnant of the Arantius ductus is interrupted to access the left hepatic vein.
After clear identification of the left lobe outflow, a gentle maneuver to encircle the left
hepatic vein is conducted taking care not to jeopardize the middle hepatic vein. If the
maneuver proves difficult or too dangerous, it can be avoided or delayed to a later
stage of the procedure, namely at the end of parenchymal transection.
After ligation of the Arantius ligament and isolation of the left hepatic vein, a
hanging maneuver can be performed and a vessel loop positioned between the mid-
dle and left hepatic vein.
Subsequently, the hepatoduodenal ligament is approached from the left side to
identify the left hepatic artery and, when possible, to accurately locate and dissect
segment 4 artery (A4). Left portal vein dissection is then accomplished.
10.3.2 Parenchymal Transection
Parenchymal transection may be performed with two different techniques and the
choice is mainly conditioned by individual experience and/or particular case-related
needs [14].
10.3.2.1 Trans-Hilar Technique

According to this approach transection of the liver is performed through segment 4
along a plane running 1 cm to the right of the umbilical fissure. Such an approach
yields a single left duct from segments 2 and 3 in 90% of specimens. The resection
line has to end at the Arantius line (Fig. 10.2). Particular attention has to be paid to
divide the glissonian (portal) pedicle for segment 1 freeing the graft from the cau-
date lobe. At the hilar plate, the division is conducted between the main bifurcation
of the hepatic vascular structures and the umbilical fissure.
One of the major advantages of the technique is that it usually provides a
single duct and a greater liver mass that may be used for larger recipients (usually
up to 25 kg). Furthermore, in the case of post-transplant portal thrombosis, a
meso-Rex shunt may prove easier to perform since the umbilical fissure is better
preserved.
10.3.2.2 Trans-Umbilical Technique

The peritoneum of the umbilical fissure is incised along a line going from the umbil-
ical ligament to the porta hepatis. The Rex recessus is therefore exposed. All venous
branches of the Rex recessus for segment 4 have to be divided between transfixing
sutures (Fig. 10.3).
Special care should be taken to maintain any segment 4 artery with the right
graft. Parenchymal division is conducted along the insertion line of the falciform
ligament to end at the convergence between the left and median hepatic veins.
Posteriorly, it follows the Arantius remnant. At the deep portion of the umbilical
Fig. 10.2 Trans-hilar
technique: hilar plate
divided along the right of
the umbilical fissure line
(0.5–1 cm to the right) and
resection line ends at the
Arantius remnant line
Fig. 10.3 Trans-umbilical
technique: the peritoneum
of the umbilical fissure is
opened from the umbilical
ligament to the porta
hepatis exposing the Rex
recessus; all branches of
the Rex recessus vein
draining into segment 4 are
divided
plate a cold knife transection has to be done to interrupt the left biliary pedicle. The
possibility of finding two or even three ducts is higher if compared with the trans-
hilar technique.
10.3.2.3 Sharing Patterns and Split Policy

There is still a lack of full consensus in sharing patterns of bile ducts and major vessels,
especially when two different centers are involved in the split-liver procurement.
The ideal sharing pattern was described by Bismuth in 1989 [4], based on the
concept of lowering the risk of surgical complications due to complex reconstruc-
tions of multiple small branches.
1. Left lobe has frequently a single branch portal vein, hepatic duct (due to the
greater length of the left branches) and venous outflow.
2. Left graft retains celiac trunk, mainly to avoid the increased risk of a smaller
anastomosis in the pediatric recipient, leaving a single hepatic artery with the
right graft.
3. Right graft maintains main branches (common hepatic duct, main portal vein
and inferior vena cava).
According to the Italian policy, on the basis of segment 4 hepatic artery (A4)
[15], the suggested split-liver technique to be adopted is as follows.
1 . A4 from right hepatic or proper hepatic artery: trans-umbilical.

2. A4 from left hepatic artery: trans-hilar (classic).
3. A4 dual origin, both from right and left hepatic artery: the technique has to be
chosen on the basis of recipient dimensional matching.
10.4 Liver Transection Tools
1. Parenchymal transection may be performed with an ultrasound dissector (porta-

ble Harmonic Scalpel) and radiofrequency dissector, in order to seal the minor
vessels (up to 7 mm) and obtain a dry dissection plane during the donor proce-
dure and graft reperfusion in the recipient, reducing the risk of bleeding and/or
biliary fistula.
2. Monopolar and bipolar cautery with a “handmade” water-drip irrigation may be
available also in small procurement hospitals.
3. Ultrasonic dissection with a Cavitron Ultrasonic Surgical Aspirator (CUSA), if
the device is usually available in secondary or tertiary level hospitals; when the
split-liver procedure is performed in hepatobiliary hub centers, CUSA dissection
may allow the most precise and bloodless parenchymal dissection, with isolation
of the small vessels and biliary branches for clipping or ligation.
4. An argon beam laser and oxidized cellulose, when available, may be useful for
superficial transection plane coagulation.
At the end of the parenchymal transection it is possible to prepare and start the
cold perfusion after cross-clamping. In the cold phase, the vascular section is car-
ried out as follows: the left hepatic vein in close proximity to the middle hepatic
vein and inferior vena cava; the left portal vein and artery according to the decisions
taken with the “adult recipient” team [6].
10.5 Reduced-Size Liver Graft
Size reduction (Fig. 10.4) depends on the relative mismatch between the graft size
and the capacity of the recipient’s abdominal space and the characteristics of the
vascular stumps. Parenchymal reduction is performed at the bench in the cold phase
adopting the technical principles of hepatobiliary surgery with the aim of preserving
vascular inflow/outflow and biliary drainage of the remaining segments.
In a small infant, a left lobe graft may also be too large. Strong et al., faced with
an urgent transplant in a small infant, successfully performed a monosegmental
(segment 3) liver transplant in 1992 with a good postoperative outcome [16].
Monosegmental liver transplantation appears to be a satisfactory option for infants
weighing less than 10 kg [17] (Fig. 10.3) in the presence of a graft weighing more
than 5% of body weight.
10.6 Outcomes
The results of conventional split-liver transplantation are the same as those of whole-
liver transplantation if performed in high volume centers by experienced groups, and
it nowadays represents a standard procedure in pediatric transplant centers [1].
The UCLA Transplant Centre reported a single-center experience (1993–2006)
with a median follow-up of 5 years: the 109 left lateral and 72 right extended grafts
had a 10-year patient survival of 72% and 69% (p = 0.11) and a 10-year graft
Fig. 10.4 Hyper-reduced
liver, ex vivo on bench
(U. Cillo’s experience)
survival of 62% and 65% (p = 0.088), respectively. In children the 10-year graft and
patient survival was similar for all graft types [18].
The specific split-liver transplantation section of the North Italian Transplant
program was established in November 1997: 1449 liver transplants were performed
in 7 transplant centers, using 1304 cadaveric donors. Whole-liver and split-liver
transplantations were performed in 1126 and 323 cases, respectively. The split-liver
procedures were performed in situ as 147 left lateral segments, 154 right trisegment
liver grafts, and 22 modified split livers. After a median post-transplant follow-up of
22 months, split-liver transplantation achieved a 3-year patient and graft survival
not significantly different from the entire series of transplants (79.4 and 72.2% vs.
80.6 and 74.9%, respectively). Recipients receiving a whole liver or a left lateral
segment showed significantly better outcomes than patients receiving a right triseg-
ment liver graft and modified split liver (p < 0.03 for patients and p < 0.04 for graft
survival). At multivariate analysis the factors related to graft failure and signifi-
cantly worse patient survival were:
• donor age >60 years

• right trisegment liver transplant
• center volume of <50 transplants annually
• urgent transplantation, established as UNOS (United Network for Organ Sharing)
status I and IIA
• ischemia time of >7 h
• retransplantation.
Right grafts procured from right trisegment liver grafts like split livers procured
as modified split liver had similar outcomes to marginal whole livers [19].
In 2013, Doyle et al. demonstrated the same outcomes between split- and whole-
liver transplantation in a single-center retrospective analysis of 53 recipients with
95.5%, 89.5% and 89.5% adult patient survival rates at 1, 5 and 10 years, respec-
tively (similar to whole grafts; p = 0.15). In children, overall and graft survival rates
at 1, 5 and 10 years were 96.7%, 80.0% 80.0% and 93.3%, 76.8% and 76.8%,
respectively [20].
Data from a national survey in 2004 evidenced similar results for both the in situ
and ex vivo techniques, in terms of morbidity and mortality, except for a higher rate
of postoperative bleeding with the ex vivo technique [21].
It has to be underlined that Italy has one of the more developed split-liver coop-
erative programs worldwide. Cooperation and trust among professionals, volumes
performed in the last 20 years, capability of expanding the proportion of livers
undergoing splitting procedures (above 10% of all livers procured nationally) are
among the key factors of such a success.
10.7 New Perspectives: Split Liver and Machine Perfusion
Split liver transplantation may be also performed with an ex situ technique during
normothermic or hypothermic machine perfusion [22].
The possible advantages in the future may be:
• expansion of the donor pool (donor after cardiocirculatory death)

• attenuation of cold ischemic injury
• pre-implantation monitoring and testing of the grafts
• complex vascular reconstruction in a “dynamic setting”
• easier logistics of transplanting two grafts in the same center
• complex reduction procedures at the bench (Fig. 10.4).
10.8 Conclusions
The interplay between liver transplantation and hepatobiliary surgery is paradigmatic

in liver splitting techniques. Only surgeons with expertise in hepatic resection and
deep knowledge of anatomical intra- and extraparenchymal details can face a splitting
procedure with a sufficient degree of safety. Similarly, young surgeons trained for
conventional splitting in a liver transplantation setting acquire relevant expertise and
confidence to proceed in their learning path toward more complex liver resection pro-
cedures. Moreover, the tendency to preserve both hemiliver pedicles during the paren-
chymal split, the need to respect correct transection planes and outflow patterns
represent a tremendous advantage in the development of hepatobiliary resection skills.
References
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Recent Prog Med. 2001;92:9–15.
3. Battula NR, Platto M, Anbarasan R, et al. Intention to split policy: a successful strategy in a
combined pediatric and adult liver transplant center. Ann Surg. 2017;265:1009–15.
4. Bismuth H, Morino M, Castaing D, et al. Emergency orthotopic liver transplantation in two
patients using one donor liver. Br J Surg. 1989;76:722–4.
5. Zambelli M, Andorno E, De Carlis L, et al. Full-right-full-left split liver transplantation:
the retrospective analysis of an early multicenter experience including graft sharing. Am J
Transplant. 2012;12:2198–210.
6. Liu H, Li R, Fu J, et al. Technical skills required in split liver transplantation. Ann Transplant.
2016;21:408–15.
7. Broelsch CE, Emond JC, Thistlethwaite JR, et al. Liver transplantation, including the concept
of reduced-size liver transplants in children. Ann Surg. 1988;208:410–20.
8. Rogiers X, Malagó M, Gawad K, et al. In situ splitting of cadaveric livers. The ultimate expan-
sion of a limited donor pool. Ann Surg. 1996;224:331–9. discussion 339–41
9. Goss JA, Yersiz H, Shackleton CR, et al. In situ splitting of the cadaveric liver for transplanta-
tion. Transplantation. 1997;64:871–7.
10. Organ Procurement and Transplantation Network. Split versus whole liver transplantation.
December 2016. https://optn.transplant.hrsa.gov/resources/ethics/split-versus-whole-liver-
transplantation. Accessed 27 Feb 2019.
11. Centro Nazionale Trapianti. Protocollo sulle procedure di split liver convenzionale in ambito
nazionale. March 2016. http://www.trapianti.salute.gov.it/imgs/C_17_cntPubblicazioni_176_
allegato.pdf. Accessed 27 Feb 2019.
12. Maggi U, De Feo TM, Andorno E, et al. Fifteen years and 382 extended right grafts from
in situ split livers in a multicenter study: are these still extended criteria liver grafts? Liver
Transpl. 2015;21:500–11.
13. Kruskal JB, Kane RA. Intraoperative US of the liver: techniques and clinical applications.
Radiographics. 2006;26:1067–84.
14. de Ville de Goyet J, di Francesco F, Sottani V, et al. Splitting livers: trans-hilar or trans-umbilical
division? Technical aspects and comparative outcomes. Pediatr Transplant. 2015;19:517–26.
15. Jin GY, Yu HV, Lim HS, et al. Anatomical variations of the origin of the segment 4 hepatic
artery and their clinical implications. Liver Transpl. 2008;14:1180–4.
16. Strong R, Lynch S, Yamanaka J, et al. Monosegmental liver transplantation. Surgery.

1995;118:904–6.
17. Enne M, Pacheco-Moreira L, Balbi E, et al. Liver transplantation with monosegments.

Technical aspects and outcome: a meta-analysis. Liver Transpl. 2005;11:564–9.
18. Hong JC, Yersiz H, Farmer DG, et al. Long-term outcomes for whole and segmental liver
grafts in adult and pediatric liver transplant recipients: a 10-year comparative analysis of 2,988
cases. J Am Coll Surg. 2009;208:682–9.
19. Cardillo M, De Fazio N, Pedotti P, et al. Split and whole liver transplantation outcomes: a
comparative cohort study. Liver Transpl. 2006;12:402–10.
20. Doyle MB, Maynard E, Lin Y, et al. Outcomes with split liver transplantation are equivalent to
those with whole organ transplantation. J Am Coll Surg. 2013;217:102–12.
21. Renz JF, Emond JC, Yersiz H, et al. Split-liver transplantation in the United States: outcomes
of a national survey. Ann Surg. 2004;239:172–81.
22. Stephenson BTF, Bonney GK, Laing RW, et al. Proof of concept: liver splitting during normo-
thermic machine perfusion. J Surg Case Rep. 2018;2018:rjx218. https://doi.org/10.1093/jscr/
rjx218.
Extended Right Split Liver Graft
11
Giuliano Bottino and Enzo Andorno
11.1 Introduction
In 1902 Carrel described a method of anastomosing blood vessels which enabled

the transplantation of a vascularized organ [1]; in 1963 the first reported liver trans-
plantation (LT) was performed by Starlz; in 1983 the National Institute of Health
Conference established that LT was no longer an experimental procedure but an
effective therapy that deserved broader application [2]. The good results obtained
have led to a wider application and have extended the list of indications [3]. In 1983,
in order to overcome the scarcity of pediatric liver grafts Bismuth et al. introduced
the technique for reduced-size liver graft to transplant an 11-year-old child [4].
Subsequently, the division of a cadaveric liver into two functioning and transplant-
able grafts—split-liver grafts—has been the logical consequence of the technical
development of LT. In 1987 Pichlmayr in Hannover performed the first ex situ split-
ting of a cadaveric liver into a three-segment graft for transplantation of an adult and
a left lateral segment graft (LLSG) to transplant a child [5]. Over the years other
authors developed new experiences in split-liver transplantation (SLT) and con-
firmed the feasibility of the procedure, although patient and graft survival rates were
lower than those for the whole graft and the results were not satisfactory [6–8]. In
1988 Raia et al. performed the first living donor liver transplantation (LDLT) in a
4-year-old girl with biliary atresia who received an LLSG from her mother but
unfortunately died 6 days after the operation [9]. Strong et al. performed the first
pediatric LDLT with long-term success [10], followed by Broelsch et al. in 1991,
who reported a series of LDLT and whole LT in which the patient and graft survival
G. Bottino · E. Andorno (*)

Hepatobiliary Pancreatic Surgery and Transplantation Unit, Policlinico San Martino Hospital,
Genoa, Italy
e-mail: giuliano.bottino@gmail.com; enzo.andorno@hsanmartino.it

108 G. Bottino and E. Andorno
was equal [11]. Since then LDLT was broadly applied in pediatric patients with
excellent results, although concern and ethical issues persisted about the additional
donor risk related to the procedure.
The in situ SLT technique reduces intra-abdominal hemorrhage at the reperfu-
sion of both grafts, because full hemostasis of the two cut surfaces is accomplished
during the donor operation, taking advantage of his normal clotting. Splitting the
liver in the heart-beating cadaveric donor permits the continuous assessment of the
perfusion of segment 4 and evaluation of the real role of an A4 artery arising high
from the left hepatic artery (LHA) for segment 4 vascularization. The technique
includes intermittent clamping, checking directly inflow and variations in segment
4 perfusion, parameters relevant to decide how to share the arterial supply of the two
grafts or, if needed, to plan any re-anastomosis of the A4 or LHA on the back table.
The shorter cold ischemia time related to in situ SLT facilitates the sharing between
centers and enables selection of the most suitable recipients, in order to maximize
the transplant benefit.
The systematic use of in situ SLT in recent years has decreased waiting list time
and related mortality for pediatric recipients, a dramatic improvement achieved
without reducing the organ pool for adult recipients. The complementary use of the
two techniques has enabled a lower utilization of living donation.
Any technical procedure for obtaining partial liver grafts relies on a profound
knowledge of liver anatomy, as described by Couinaud and Bismuth [12, 13].
According to Couinaud’s classical liver terminology, an extended right split liver
graft (ERSLG) consists of segments 1, 4, 5, 6, 7 and 8 of the liver [14] (Fig. 11.1).
Fig. 11.1 In situ splitting of the liver in a heart-beating cadaveric donor resulting in an extended
right split liver graft (ERSLG) and a left lateral segment graft (LLSG). Volume of ERSLG seg-
ments (1 and 4–8) is approximately 1000–1200 mL, corresponding to ~75% of the total liver vol-
ume. Volume of LLSG segments (2 and 3) is approximately 250–300 mL, corresponding to ~25%
of the total liver volume
11 Extended Right Split Liver Graft 109
11.2 Donor Operation
The ideal liver for splitting would be from a young (<50 years), hemodynamically
stable donor with normal liver function tests, normal macroscopic appearance with
no history of liver disease, and short stay in the intensive care unit (ICU <7 days);
in other words, only excellent or very good livers should generally be used for split-
ting [6]. Estimated total donor liver volume using Urata’s algorithm is considered in
order to choose appropriate recipients for the two grafts, as shown in Fig. 11.1 [15].
However, at the end of the procedure the two grafts must be weighed. Donor, intra-
operative, logistic and recipient parameters must be considered carefully before
splitting, and it is crucial to organize a short briefing with the anesthesiological,
cardiopulmonary and other surgical donor teams, who must be informed about the
procedure and the extra time of about 2 h needed to complete the splitting. The
harvesting procedure starts with the conventional steps of whole-liver procurement.
In particular, the supraceliac and infrarenal aorta and vena cava must be freed and
encircled to be ready for rapid cold perfusion in the event of donor instability during
the splitting time. The splitting procedure must be prepared in exactly the same
manner as a major hepatic resection, and blood transfusion must be available. The
first step in performing in situ division to obtain an ERSLG is to assess whether the
procedure is suitable for both recipients, with regard to the division of the parenchy-
mal mass and respective recipient size. Having assessed that, the liver splitting pro-
cedure can be commenced.
Even though liver parenchymal division can be performed either in the middle of
segment 4 (transhilar procedure) or along a line 1 cm to the right of the umbilical
fissure (transumbilical procedure), the latter is more commonly used as it results in
a smaller raw surface. The description below presents the current standard tech-
nique in the case of conventional liver anatomy, resulting in two grafts (ERSLG and
LLSG) and in the appropriate division of hilar structures. The procedure starts and
the surgeon looks for any aberrant hepatic artery. The left lateral segment is mobi-
lized, the falciform ligament is divided down to the suprahepatic vena cava (SHV),
and the left triangular ligament is divided; at this stage, the LHA usually arises from
the left gastric artery but sometimes from the celiac trunk or from the aorta. A
tongue of liver parenchyma often may bridge between segments 3 and 4 and it must
be separated first to expose the left portion of the hepatic pedicle up to Rex recessus.
Dissection of the superior part of the Arantius ligament allows the left SHV to be
prepared with a Ligaloop; great attention must be paid to a possible vein arising
from the falciform ligament. Intraoperative ultrasound can be useful even if is not
mandatory. If it is difficult to control the left SHV due to hemorrhagic risk and pos-
sible hemodynamic instability which could lead to abortion of the procedure, it is
preferable to postpone this maneuver to the end of the parenchymal resection.
The LHA is then isolated by dissecting the left part of the hepatic pedicle leav-
ing untouched the right portion. The presence of an A4 artery for segment 4 arising
distally from the LHA is ruled out and its diameter is inspected carefully to estab-
lish its relevance to hepatic inflow to segment 4, as described above. In our tech-
nique, a standard arterial division provides the LLSG with the celiac trunk, in order
to reduce the risk of arterial thrombosis of the LHA anastomosis. ERSLG arterial
inflow is provided by the right hepatic artery (RHA) which has a bigger diameter.
The left branch of the portal vein (LPV) is isolated; the key for this is to dissect the
whole round ligament up to the Rex recessus and the LPV proceeding from above
to below. The line follows the right margin of the ligament and all the branches for
segment 4 on the right side are ligated and secured by prolene sutures. Special
attention is paid to secure the portal collaterals from the LPV for segment 1, arising
from the posterior wall of the LPV. The line of parenchymal division is marked
approximately 1 cm to the right of the falciform ligament from the confluence of
the middle and left hepatic veins up to the hilar plate. Parenchymal transection
starts from the anterior margin of the liver following the marked line for 3–4 cm
deep up to the hilar plate. Subsequently, the left hilar plate, which contains the left
duct together with its vascular sheets, can be safely transected directly using the
cold knife close to the biliary bifurcation and avoiding the use of electrocoagula-
tion. This safe progression of liver partition (trans-umbilical procedure) allows the
left hepatic duct to be cut between D4 and the D2-D3 biliary bifurcation, thus
avoiding the need for a double biliary reconstruction on the left lateral segment
side and possible damage to the biliary drainage of segment 4 on the ERSLG. The
left ductal stump of the ERSLG must now be sutured by PDS 6/0, taking care of
hemostasis. The liver parenchyma can be transected by electrocoagulation or alter-
natively by kellyclasia if no other devices are available. Exposed vessels and bili-
ary structures are closed by ligature, propene sutures or hem clips, in order to
achieve optimal biliostasis and hemostasis on both raw surfaces, taking advantage
of the clotting function of the heart-beating donor. Liver parenchymal section can
be completed up to the left SHV. Now the two segmental grafts, ERSLG and LLSG,
are separated and perfused. After perfusion, the RHA is divided at its origin and the
LPV and LHV are transected. The LLSG can be retrieved with the celiac axis. The
remaining ERSLG with the main portal trunk, RHA, common bile duct and retro-
hepatic portion of the inferior vena cava (IVC) is then harvested in the usual man-
ner. As in the whole-liver graft, the retrohepatic IVC is included in the graft so that
the right hepatic vein, middle hepatic vein and all accessory veins are preserved to
ensure adequate venous drainage of the graft. Venous and arterial vascular patches
must be as long as possible. An ERSLG needs special attention to arterial graft
procurement since an interposition vascular graft may be required for adequate
arterial vascularization. It is very important to avoid discrepancies between the dif-
ferent diameters of vessels.
11.3 Back Table Procedure
The IVC is treated in the same manner as the whole-liver graft and the orifice of
the left SHV is closed with a continuous 6/0 suture. The portal vein and its right
branch at the level of the left division, is mobilized from behind, avoiding any dis-
section of the biliary and vascular plates; the resulting defect at the junction of the
main and LPV is repaired with a continuous 6/0 prolene suture, avoiding any risk
of stricture. The RHA, divided at its origin during the donor operation, must be
prepared carefully. A short length of the RHA is gently dissected free in order to
obtain as much length as possible to permit direct anastomosis. The hepatic veins
and the structures in the porta hepatis, RHA, portal vein and common hepatic duct
are gently explored with a metal cannula, to identify and confirm the anatomy. The
cut surface of the ERSLG must be carefully inspected by flushing the portal vein
first, then the hepatic artery and common bile duct using preservation solution at
4 °C. Each single site of possible leakage is sutured. As in a whole-liver graft, the
temperature must be monitored by laser thermometer and the graft weighed at the
end of the procedure.
11.4 Recipient Operation
An ERSLG obtained by preserving the donor IVC is well transplantable either in a

traditional fashion with an end-to-end caval anastomosis or after a piggy-back hepa-
tectomy, using any kind of possible anastomoses. These different possibilities help
to avoid problems of outflow obstruction related to graft positioning.
The recipient operation proceeds classically, the porta hepatis must dissected
free including the portal vein and hepatic artery bifurcation in order to obtain suf-
ficient length for subsequent direct anastomosis, avoiding graft interposition.
Most of the time, a sufficient length of recipient RHA allows a direct arterial
anastomosis between the two RHA. If extra lengthening is required, an arterial
homograft is interposed as appropriate; for example, the RHA can be recon-
structed using a segment of donor superior mesenteric artery which offers better
results compared to a PTFE graft. However, an interposition graft presents a
higher rate of vascular complications [16]. Portal vein and biliary reconstruction
does not differ from standard LT. The ERSLG fits easily in the orthotopic posi-
tion, just as a normal liver. Most of the time, both the portal vein and the hepatic
artery have sufficient length to avoid risks related to the interposition graft. In
some selected cases, it is possible to implant the graft by fashioning a face-to-face
cava anastomosis to shorten the gap and positioning the liver below, a solution
that affords enough length for a subsequent tension-free direct anastomosis and
avoids graft interposition. Biliary reconstruction is usually achieved by duct-to-
duct anastomosis with a T-tube in order to decompress the bile duct and minimize
the risk of biliary fistula from the cut surface. If the two ends of the bile duct can
be tailored to meet perfectly without tension or redundancy and are of similar cali-
ber, and the raw liver surface does not present any risk of biliary leak, the recon-
struction can be performed without a T-tube.
At the end of the procedure segment 4 appearance must be carefully evaluated
(Fig. 11.2) and intraoperative Doppler ultrasound must be performed. Hepatic arte-
rial inflow resistance and portal flow as well as the hepatic venous outflow are
explored in order to avoid any risk of ERSLG hyperperfusion and allow the surgeon
to develop an appropriate surgical correction. Hyperperfusion of the ERSLG is,
however, a rare condition [17].
Fig. 11.2 Moderate
congestion of segment 4
after reperfusion, showing
optimal hemostasis of raw
surface previously obtained
during donor operation
11.5 A
natomical Variations Relevant to ERSLG and Related
Surgical Procedures
Variations in the origin and distribution of the arterial branches supplying the
different parts of the liver, in particular segment 4, are quite frequent. The reason
for these variations lies in the embryological origin of the liver [18–20]. The
identification and interpretation of portal, biliary and venous anomalies may
avoid biliary and vascular complications following liver transplant and explain
graft congestion.
Many anatomical variations relevant to the correct partition and vascularization
of the liver may be present. In conventional anatomy a proper hepatic artery (PHA)
originating from the celiac axis divides inside the hepatic pedicle into an RHA sup-
plying the right hemiliver and an LHA that vascularizes the left hemiliver. Sometimes
an RHA and/or LHA originating out of the PHA (aberrant artery) may be present
together with (accessory artery) or in substitution of the normal RHA or LHA,
which are totally replaced. The arterial anatomy of segment 4 has more variations
compared to the other segments so identification of the origin of the arterial supply
is fundamental for performing SLT.
11.6 Postoperative Care
Doppler ultrasound must be performed daily during the first postoperative week.
Should any doubt arise, computed tomography is mandatory to demonstrate any
abnormalities in blood flow. Appropriate treatment will depend on the findings and
may consist of interventional radiology or surgery.
The appropriate standard medical treatment for patients subjected to SLT requir-
ing an interpositional graft or special arterial reconstructions related to the A4 artery
includes low-dose heparin, prostaglandin, and antiplatelet agents.
Hypoperfusion of segment 4 is often related to elevated postoperative transami-

nase levels, which do not necessarily reflect graft dysfunction.
All biliary leakages occur immediately after LT. Biliary leakages from the cut
surface can be treated by percutaneous drainage or by surgical intervention.
References
1. Carrel A. La technique opératoire des anastomoses vasculaires et de la transplantation des
visceres. Lyon Med. 1902;98:859–64.
2. National Institutes of Health Consensus Development Conference Statement: liver transplan-
tation – June 20-23, 1983. Hepatology. 1984;4(Suppl 1):107–10.
3. Keffe EB. Summary of guidelines on organ allocation and patient listing for liver transplanta-
tion. Liver Transpl Surg. 1998;4(Suppl 1):S108–14.
4. Bismuth H, Houssin D. Reduced-sized orthotopic liver graft in hepatic transplantation in chil-
dren. Surgery. 1984;95:367–70.
5. Pichlmayer R, Ringe B, Gubernatis G, et al. Transplantation einer Spenderleber auf zwei
Empfänger (Splitting-Transplantation) - Eine neue Methode in der Weiterentwicklung der
Lebersegmenttransplantation. Langenbecks Arch Chir. 1988;373:127–30.
6. Busuttil RW, Goss JA. Split liver transplantation. Ann Surg. 1999;229:313–21.
7. Rogiers X, Bismuth H, Busuttil RW, et al., editors. Split liver transplantation. Theoretical and
practical aspects. Darmstadt: Steinkopff-Verlag; 2002.
8. Goss JA, Yersiz H, Shackleton CR, et al. In situ splitting of the cadaveric liver for transplanta-
tion. Transplantation. 1997;64:871–7.
9. Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet. 1989;334:497.
10. Strong R, Lynch S, Ong TH, et al. Successful liver transplantation from a living donor to her
son. N Engl J Med. 1990;322:1505–7.
11. Broelsch CE, Whitington PF, Emond JC, et al. Liver transplantation in children from living
related donors. Surgical techniques and results. Ann Surg. 1991;214:428–37; discussion 437–9
12. Yersiz H, Busuttil R, et al. The conventional technique of in-situ split-liver transplantation. J
Hepato-Biliary-Pancreat Surg. 2003;10:11–5.
13. Couinaud C, Houssin D. Partition reglée du foie pour transplantation: contraintes anatomiques.
Paris: Edition Personnelle; 1991.
14. Couinaud C. Segmental and lobar left hepatectomies; studies on anatomical conditions. J Chir
(Paris). 1952;68:697–715. [Article in French]
15. Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and adult standard liver volume
for liver transplantation. Hepatology. 1995;21:1317–21.
16. Maggi U, Caccamo L, Reggiani P, et al. Hypoperfusion of segment 4 in right in situ split-liver
transplantation. Transplant Proc. 2010;42:1240–3.
17. Azoulay D, Astarcioglu I, Bismuth H, et al. Split-liver transplantation. The Paul Brousse pol-
icy. Ann Surg. 1996;224:737–46; discussion 746–8
18. Jin GY, Yu HC, Lim HS, et al. Anatomical variations of the origin of the segment 4 hepatic
artery and their clinical implications. Liver Transpl. 2008;14:1180–4.
19. Ghosh SK. Variations in the origin of middle hepatic artery: a cadaveric study and implications
for living donor liver transplantation. Anat Cell Biol. 2014;47:188–95.
20. Healey JE Jr, Schroy PC, Sørensen RJ. The intrahepatic distribution of the hepatic artery in
man. J Int Coll Surg. 1953;20:133–48.
Full-Left Full-Right Split Liver
Transplantation 12
Stefania Camagni and Michele Colledan
12.1 Introduction
Full-left full-right split liver transplantation (FLFR SLT) is the division of a deceased
donor liver into two similarly sized grafts and the subsequent transplantation of
each of them into two adult-sized recipients.
At present, FLFR SLT represents one of the most advanced steps in the evolution
of segmental liver transplantation. In 1999, 10 years after Bismuth’s extreme but
vain attempt at emergency transplantation by ex situ split liver in two adult patients
[1], our group first reported the long-term successful application of an original in
situ technique for FLFR SLT [2], based on both the excellent outcomes of the initial
experience with adult-to-adult living donor liver transplantation (LDLT) and
advances in resectional liver surgery. FLFR SLT appeared as a promising strategy to
increase the number of adult transplants and to provide otherwise hardly available
size-matched grafts for large children and adolescents. However, early enthusiasm
was not followed by broad diffusion and, despite the encouraging results reported in
the last few years, FLFR SLT still remains an underused resource.
12.2 Donor Selection
Graft quality is one of the key points for the success of FLFR SLT. Consensus exists
on limiting FLFR split liver to optimal donors, generally characterized by the fol-
lowing features: hemodynamic stability, reasonably young age, short intensive care
unit stay, normal or near normal body mass index, normal or near normal liver
S. Camagni · M. Colledan (*)

Department of Organ Failure and Transplantation, ASST Papa Giovanni XXIII,
Bergamo, Italy
e-mail: scamagni@asst-pg23.it; mcolledan@asst-pg23.it

116 S. Camagni and M. Colledan
function tests, and no hypernatremia [3–7]. Graft macrosteatosis should be excluded

by direct evaluation by the donor surgical team or, occasionally, by liver biopsy.
Being macrosteatosis the only proved donor-related risk factor independently asso-
ciated with graft failure [8], we usually accept an upper limit of 10%. The final
decision on graft adequacy should be up to an experienced donor surgeon.
12.3 Size Matching
A fair size matching is crucial to avoid small-for-size syndrome. Unlike LDLT,

SLT can rarely rely on preoperative measurement of graft volume, which can only
be estimated from the donor body weight. The predicted liver mass represents
about 2% of body weight, while the full-left and full-right grafts account for about
40% and 60%, respectively, of the total liver mass. However, great variability and
consequently low predictability exist, especially for the left graft [3, 9], so direct
assessment by the donor surgeon is decisive [7]. The minimal acceptable graft-to-
recipient weight ratio (GRWR) in FLFR SLT is still unknown, but it is agreed that
it must be higher than in LDLT, where a GRWR of at least 0.8% is unanimously
deemed safe [10]. In fact, brain death itself and longer ischemic time may impair
graft function. So, in our opinion, a large safety margin of size matching should
translate into a GRWR of at least 1.2%, even more when transplanting high Model
for End-Stage Liver Disease (MELD) patients with portal hypertension [3, 4]. By
enlarging the pool of potential recipients, graft sharing may facilitate optimal size
matching.
12.4 A
ttribution of Liver Parenchyma and Vascular
and Biliary Supply
The most commonly accepted partition of the donor liver produces a left graft
including Coinaud segments 1 to 4 and a right graft including segments 5 to 8
(Fig. 12.1) [3]. Setting the transection plane at the line of Cantlie is borrowed from
LDLT and is also the result of the evolution from conventional SLT.
Most groups, including ours, usually leave the arterial axis and the main portal vein
with the left graft in order to ensure optimal blood supply to segments 4 and 1.
Conversely, the main bile duct is often left with the right graft in the possible event of a
variant posterior sectoral branch joining the left or common bile duct (Fig. 12.1) [3, 11].
The attribution of the inferior vena cava (IVC) and the middle hepatic vein
(MHV), instead, is a controversial matter. In fact, whichever graft retains both or
either of them, the contralateral one may result in various degrees of compromised
venous outflow, depending on the specific anatomy. Reimplantation of possible
large tributaries of the IVC or the MHV may help preserve venous drainage [3, 4].
Two alternative elegant options for outflow optimization are represented by the
split cava technique and the split of the MHV, both proposed by the Hamburg
12 Full-Left Full-Right Split Liver Transplantation 117
Fig. 12.1 Full-left
full-right split liver,
according to our preferred
practice. The left graft,
consisting of segments 1 to
4, retains the inferior vena
cava with the middle
hepatic vein, the arterial
axis, the main portal vein
and the left bile duct.
Conversely, the right graft,
consisting of segments 5 to
8, retains the right hepatic
vein, right hepatic artery,
right portal vein and main
bile duct. Reproduced with
permission from [3]
group [12, 13]. The former allows the preservation of each graft accessory hepatic
veins, the latter is a further evolution aiming at ensuring an almost physiological
venous drainage from both segment 4 and the right anterior section and is probably
the best strategy.
In conclusion, both parenchymal and vasculobiliary attributions may be adapted
to anatomic variations and specific technical needs on a case by case basis, which
makes FLFR SLT an extremely complex procedure requiring a deep understanding
of liver anatomy.
12.5.1 In Situ Versus Ex Situ Split Liver Technique
Both in situ and ex situ techniques have been successfully used. The in situ tech-
nique, deriving from the experience of living donor liver procurement, offers the
advantages of a shorter ischemic time, which may allow for long-distance graft
sharing, and theoretically easier hemostasis of the raw surfaces of the grafts. The
ex situ technique, on the other hand, significantly reduces the donor operation
time and complexity. No prospective nor controlled studies comparing these two
technical options are available. The in situ technique is our preferred and substan-
tially exclusive choice, the switch to the ex situ procedure being regarded as a
rescue option in case of unexpected hemodynamic instability during the donor
operation. A hybrid approach, partly in situ and partly ex situ, may be adopted
when the split of the MHV is planned. In a near future, dynamic preservation by
machine perfusion may possibly combine the complementary potentials of in situ
and ex situ splitting.
In this section we focus on our technique of FLFR SLT, which combines notions
and skills coming from our experience in both pediatric liver transplantation and
hepatobiliary surgery [3].
12.5.2 Split Liver Procedure
The donor procedure is started in a standard fashion, achieving control of the

aorta for subsequent clamping and flushing. Liver partition can be addressed only
after excluding anatomical contraindications, namely the absence of the extrahe-
patic portal bifurcation [14, 15] and a left-sided gallbladder, which can be associ-
ated with portal and biliary anomalies [16]. After cholecystectomy, hilar dissection
with isolation of the main bile duct, the right hepatic artery (RHA), the right
portal vein (RPV) and the hilar plate containing the left bile duct (LBD) is per-
formed. Afterwards, the right lobe is mobilized by sectioning the right triangular
and coronary ligaments and the accessory hepatic veins. Any possible accessory
vein larger than 5 mm is closed with clips and cut long enough for subsequent
reimplantation on the recipient. The right hepatic vein (RHV) is encircled and an
umbilical tape is passed around it and then caudally between the IVC and the
parenchyma until the inferior face of the liver, where it reappears between the
previously encircled RHA, RPV and left hilar plate on one side and the paren-
chyma on the other side, for the purpose of the hanging maneuver [17]. If a split
cava technique is adopted, the right lobe is mobilized without sectioning any
accessory vein and the umbilical tape is passed between the RHV and the MHV
and then kept on the left of the accessory veins draining the right lobe until the
inferior face of the liver. If the split of the MHV is planned, a completely ex situ
procedure and a hybrid procedure are both possible options. Parenchymal transec-
tion is performed along the line of Cantlie by means of ultrasonic dissection and
bipolar coagulation forceps. Intraoperative ultrasound is recommended to guide
the transection plane and identify the MHV tributaries draining segments 5 and 8.
After parenchymal transection, the liver appears divided into two still perfused
grafts, connected only by their vasculobiliary pedicles (Fig. 12.2). Finally, after
standard aortic cross-clamping and cold flushing, the two grafts are retrieved
separately.
12.5.3 Grafts Implantation
For the left graft, implantation is similar to that of a whole graft. For the right graft,
instead, it is similar to that of a right graft from living donation. Outflow recon-
struction may be accomplished by either the piggyback technique or a double caval
anastomosis for the left graft, while for the right graft a wide end-to-side anasto-
mosis between the graft RHV and the recipient’s IVC is required. If the donor IVC
has been split between the two grafts, a side-to-side anastomosis between the donor
caval patch and the recipient’s IVC is performed. Biliary reconstruction may be
a b
12 Full-Left Full-Right Split Liver Transplantation
Fig. 12.2 (a) At the end of the in situ parenchymal transection, the liver appears divided into two still perfused grafts. (b) The two grafts are still connected by
their vasculobiliary pedicles: the right hepatic artery is encircled by the red vessel-loop, the right portal vein by the blue vessel-loop and the left hilar plate by
the umbilical tape
119
accomplished by either a duct-to-duct or a duct-to-Roux-en-Y anastomosis,

depending on the available graft biliary pedicle and on the surgeon’s choice.
12.6 Outcomes
Since the late 1990s, FLFR SLT has been viewed with both enthusiasm and skepti-
cism. An active debate on its apparently controversial outcomes is still underway.
About 1000 FLFR SLT have been reported so far, most of which in the United
States [18], about 200 in Europe [8, 9, 19–23] and some 50 in Asia [24–27]. Most
of the largest series worldwide have shown comparable survival rates to those
achieved by the most common strategies, namely whole-liver transplantation (WLT)
in Europe and the United States [8, 9, 11, 18, 23, 28, 29] and LDLT in Asia [25].
However, the survival rates reported by few Italian authors appear lower than those
obtained with WLT [30, 31] and a United States monocentric experience described
lower survival rates with FLFR SLT and WLT than with LDLT [28]. Morbidity after
FLFR SLT has been a matter of concern over time. Biliary complications remain the
Achilles’ heel of FLFR SLT, with a reported incidence of up to 32% [29]. However,
the incidence of both vascular complications and small-for-size syndrome is not
striking [8, 9, 11, 19, 23, 25, 29].
Actually, FLFR SLT is a complicated branch of liver transplantation, or better of
segmental liver transplantation, requiring high levels of technical skills, a deep
understanding of liver anatomy and a comprehensive knowledge of all aspects of
liver transplantation. Due to the complexities involved, a more correct evaluation
should take into account the advantage of transplanting two patients on an intention-
to-treat basis, so probably neither WLT nor LDLT are appropriate basis for compari-
son. Moreover, considering that FLFR SLT cannot often rely on preoperative
thorough imaging, we still believe that the reported outcomes are more than encour-
aging and may be further improved through completion of the learning curve, pro-
vided that this procedure is given enough room.
12.7 Conclusions
The interplay of specific key factors is fundamental for the success of FLFR SLT. Since
FLFR SLT deserves only high-quality organs, careful donor selection and a reliable
definitive judgement on graft adequacy are the necessary starting point. The subse-
quent step is represented by an optimal donor-to-recipient matching, which should
consider both size matching and the recipient’s specific conditions, such as the degree
of portal hypertension and severity of illness. Moreover, being both the donor and
transplant procedure considerably demanding, high levels of technical skills are of
paramount importance. That is why FLFR SLT should be performed by centers with
extensive experience in liver transplantation, including segmental liver transplanta-
tion, and hepatobiliary surgery. Finally, a split liver-oriented allocation policy and a
collaborative program of graft sharing are essential to the implementation of FLFR
12 Full-Left Full-Right Split Liver Transplantation 121
SLT with improving outcomes. Not only livers from optimal donors should be
regarded as paired organs, but an active graft-sharing program may allow better donor-
to-recipient matching and distribution of the technical and organizational load.
Indeed, the possible success of FLFR SLT is multifactorial. FLFR SLT may
really become a safe and effective strategy to expand the number of available liver
grafts for adult-sized recipients provided that all the above-mentioned conditions
are fulfilled.
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splitting of the deceased donor liver. Ann Surg. 2005;242:802–13.
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recipients. Liver Transpl. 2000;6:703–6.
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splitting of the liver. Liver Transpl. 2005;11:350–2.
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Small-for-Size Syndrome
13
Umberto Cillo and Francesco Enrico D’Amico
13.1 Introduction
Partial orthotopic liver transplantation (OLT), living donor liver transplantation

(LDLT) and major liver resection are well-consolidated procedures and often repre-
sent the only chance of cure for many patients. Pushing the limits of liver resection,
or protection of the donor in LDLT, can lead to a small remnant graft. In this sce-
nario the patient can face a spectrum of complications determined by a graft that is
too small for the size of his body.
Small-for-size syndrome (SFSS) is a group of signs and symptoms that occur
when, following liver resection, LDLT or partial OLT, an insufficient liver mass is
not capable of sustaining the metabolic demand of the patient. SFSS has been
known since the 1970s, when Thomas E. Starzl described a series of complications,
such as prolonged hyperbilirubinemia, encephalopathy, and coagulopathy, which
occurred in a young patient who underwent a 90% liver resection [1]. Nevertheless,
it was first described as a syndrome in the LDLT field in the late 1990s when the
need to preserve the donor’s liver mass to minimize the risk of liver insufficiency
and postsurgical complications in the donor determined the effect of a relatively
“small” partial graft [2, 3]. However, following LDLT or extended liver resection,
SFSS is often difficult to differentiate from other complications, such as acute rejec-
tion, outflow block, and sepsis, which generally impair liver regeneration and can
thus contribute to liver failure. Because there is a close integration between liver
regeneration, postoperative complications, minimum liver mass and SFSS, in
addressing this topic it is mandatory to keep in mind the process of liver regenera-
tion and liver basic physiology.
U. Cillo (*) · F. E. D’Amico

e-mail: cillo@unipd.it; francescoenrico.damico@unipd.it

124 U. Cillo and F. E. D’Amico
13.2 Definition
There is no full consensus on the definition of SFSS owing to the issues cited
above, such as difficulty differentiating it from other pathological processes like
sepsis or postoperative complications. For the same reasons, the definition of
incidence, prognosis, risk factors and potential treatments can be challenging. An
SFS graft can be generally defined as a graft of a size smaller than the required
liver weight (or volume) necessary to fulfil the metabolic demand of the patient.
As a consequence, SFSS manifests with coagulopathy, intractable ascites, pro-
longed jaundice, encephalopathy and hypoalbuminemia, often complicated by
gastrointestinal bleeding, delayed renal impairment, sepsis and multiorgan fail-
ure [4]. In the literature there are only few detailed definitions of SFSS
(Table 13.1), with assessment of cut-off values and postoperative day (POD) of
manifestation of complications. Soejima et al. defined SFSS by the presence of
cholestasis (total bilirubin >10 mg/dL) on POD 7 and intractable ascites with a
documented daily production of ascites of >1 L on POD 14 or >500 mL on POD
28 without other specific causes [5, 6]. A similar definition was used by Humar
et al.: they considered diagnostic for SFSS the presence of serum bilirubin
>10 mg/dL after POD 7, international normalized ratio (INR) >1.5, and ascites
with drain output >2 L/day, in the absence of an obvious technical problem such
Table 13.1 Definitions of small-for-size syndrome (SFSS)

Author Terminology Definition
Kiuchi SFS graft GRWR <0.8% with postoperative presence of poor bile
et al. [10] production, delayed synthetic function, prolonged
cholestasis, intractable ascites and with subsequent septic
complications and high mortality
Dahm SFS dysfunction Presence of a bilirubin level >100 μmol/L, an INR >2 and
et al. [8] encephalopathy grade 3 or 4, considering diagnostic the
presence of two for 3 consecutive days
SFS nonfunction Failure of a small partial graft (GRWR <0.8%) during the
first postoperative week
Balzan Liver failure Association of PT <50% and serum bilirubin >50 μmol/L
et al. [9] on POD 5
Soejima SFSS Presence of cholestasis (total bilirubin >10 mg/dL) on
et al. [6] POD 7 and intractable ascites with a documented daily
production of ascites of >1 L on POD 14 or >500 mL on
POD 28 without other specific causes
Humar SFSS Serum bilirubin >10 mg/dL after POD 7, (INR) >1.5, and
et al. [7] ascites with drain output >2 L/day, in the absence of an
obvious technical problem such as vascular thrombosis or
stenosis
Ikegami Delayed functional Total bilirubin >20 mg/dL for seven consecutive days
et al. [12] hyperbilirubinemia after POD 7, excluding technical, immunological and
hepatitis factors
GRWR graft-to-recipient weight ratio, INR international normalized ratio, POD postoperative day,
PT prothrombin time
13 Small-for-Size Syndrome 125
Table 13.2 Nomenclature of TLV Total liver volume

liver volumes SLV Standardized liver volume
FRL Future remnant liver
SFRL Standardized future remnant liver
GRWR Graft-to-recipient weight ratio
GWR Graft weight ratio
VR Volume ratio
as vascular thrombosis or stenosis [7]. Dahm et al. presented a more specific defi-
nition [8] which categorized SFSS in two entities: SFS dysfunction and SFS
non-function. SFS dysfunction was defined as a dysfunction of a “small” partial
liver graft (graft-to-recipient weight-ratio [GRWR] <0.8%) during the first post-
operative week after the exclusion of other causes. The graft dysfunction was
defined as the presence of a bilirubin level >100 μmol/L, an INR of more than 2
and encephalopathy grade 3 or 4, considering diagnostic the presence of two for
3 consecutive days. SFS nonfunction was defined as a failure of a small partial
graft (GRWR <0.8%) during the first postoperative week. In resective surgery
another potential definition of SFSS are the so called “50-50 criteria”, which are
defined as the association of prothrombin time <50% and serum bilirubin
>50 μmol/L on POD 5. These simple parameters can accurately predict more
than 50% mortality after hepatectomy [9]. Although useful to predict postopera-
tive mortality, the criteria are not designed to identify preoperative predictive
factors such as an SFS remnant liver.
In the LDLT field some other definitions have been proposed, particularly to
define the size (or the size/weight ratio) of the graft, which are associated with the
development of a SFSS in the recipient. Kiuchi et al. defined SFS graft as a GRWR
<0.8% with postoperative presence of poor bile production, delayed synthetic func-
tion, prolonged cholestasis, intractable ascites and with subsequent septic complica-
tions and high mortality [10]. Similarly, Sugawara et al. reported that a graft volume/
standard liver volume ratio (GV/SLV) <40% was associated with decreased survival
and prolonged recovery of liver function tests [11]. Ikegami et al. defined a similar
entity to SFSS, so-called “delayed functional hyperbilirubinemia”. They defined it
as the presence of a total bilirubin >20 mg/dL for seven consecutive days after POD
7, excluding technical, immunological and hepatitis factors [12]. However, the pro-
spective validation of these criteria in large multicenter studies has been precluded
by the variety of definitions not only for SFSS itself but also for liver volume or size
(Table 13.2) and for surgery settings (resective surgery or LDLT).
13.3 Pathophysiology
The mechanisms of SFSS, particularly in the presence of an underlying liver dis-

ease, remain largely unknown.
The anatomopathological features are characterized by denudation of portal vein
and periportal sinusoidal endothelium, severe congestion with rupture and thrombosis
of the periportal sinusoids, collapse of the space of Disse [13], centrilobular hepatoca-
nalicular cholestasis and centrilobular hepatocyte microvesicular steatosis [14, 15].
SFSS is probably a multifactorial phenomenon, including both the status of the
liver parenchyma and factors related to the patient (recipient in LDLT). The two
major players in the development of this pathologic process appear to be the
impairment of liver regeneration and the increase of portal vein flow (PVF) and
pressure (PVP) [16]. The initiating event is thought to be the hyperdynamic PVF
through a small liver graft, which leads to a shear stress injury of sinusoidal endo-
thelial cells and focal hemorrhage into connective tissue of the portal tract, conse-
quently impairing hepatic microcirculation, causing congestion, and subsequent
hepatocyte necrosis and liver failure [17, 18]. The sinusoidal endothelial and
Kupffer cell injury causes the release of inflammatory cytokines—such as tumor
necrosis factor alpha (TNF-a) [19] and interleukin-6 (IL-6) [20]—which are natu-
rally involved in the process of liver regeneration [21]. Moreover, the upregula-
tion of vasoconstrictive genes secondary to the inflammatory response [22] causes
focal vasospasm which can lead to functional dearterialization, ischemic cholan-
gitis and parenchymal ischemia [23]. Even though an inflammatory cascade
involving acute phase proteins or complement factors is necessary as a trigger
towards liver regeneration, it has been speculated that their excess may contribute
to organ failure in a situation of extensive tissue loss or in the presence of underly-
ing pathological conditions [4]. Others hypothesize that the natural response to
portal hyperperfusion becomes pathological when there is vascular damage, lead-
ing to parenchymal or biliary ischemia [15].
There is another vascular mechanism considered an important player, especially
in LDLT [24, 25], which is closely connected to the liver physiology: the hepatic
artery buffer response [26]. Indeed, the liver does not control the PVF, which is
simply the outflow of the splanchnic organs. In the presence of an excess of PVF,
the whole hepatic blood flow remains constant through a downregulation of the
hepatic arterial flow which in turn affects vascularization of the biliary tree. It has
been shown that after major liver resection, or LDLT with a small graft in a cir-
rhotic recipient, the increased PVF and PVP can lead to a markedly decreased
arterial inflow [27]. On the other hand, previous studies have suggested that eleva-
tion of PVF or shear stress induces liver regeneration, and insufficient PVF induces
hepatic atrophy and liver failure [14, 28]. The “window” of pressure has been
investigated by Yagi et al. who demonstrated that a PVP above 20 mmHg was asso-
ciated with the development of ascites, higher incidences of bacteremia, cholesta-
sis, coagulopathy and hyperbilirubinemia in patients following LDLT [29] but also
that liver function was better with high PVF and a PVP below 15 mmHg [30]. The
concept translates in a condition of high compliance (PVF/PVP) that is particularly
favorable for liver regeneration. Similar findings were documented by Allard et al.
who showed that PVP over 21 mmHg after hepatectomy predicts the progress of
liver failure and mortality in patients undergoing major liver resection [31]. Thus,
according to the described pathophysiology of SFSS, it is possible to say that PVP
and PVF are major contributors to its development rather than the liver remnant (or
graft) size alone.
13.4 Clinical Manifestations
The classical picture of SFSS is characterized by signs and symptoms present also
in posthepatectomy liver failure (PLF): indeed, especially in the literature regarding
extended liver resection, the two definitions often overlap [9, 31, 32]. Clinically, it
is characterized by a combination of prolonged functional cholestasis, intractable
ascites, and delayed recovery of both prothrombin time and encephalopathy [3].
Although the signs and symptoms are often present all together with different
degrees of severity, the clinical evolution can range from prolonged mild cholestasis
to acute liver failure [32]. SFSS often manifest with a subacute evolution character-
ized by increasing jaundice, moderate ascites and hepatic encephalopathy during
the first postoperative week with prolongation to the fourth postoperative week [5,
8, 15]. A poor intraoperative bile production was considered by Edmond et al. as the
first sign, but they acknowledged that the diagnosis should be established clinically
within the first postoperative week [3]. The assessment of encephalopathy, which is
an important marker, can be challenging in the early postoperative period due to
surgical and medical confounding factors such as surgical stress or opiate use [33].
The transaminase levels usually do not increase chronologically and seem to be
higher during the early period after transplantation [34], whereas the bilirubin levels
and daily ascites output begin to increase 3–7 days after surgery and persist for
1–2 months [6, 35]. Other clinical manifestations include sepsis, gastrointestinal
bleeding, decreased bowel movement, gastrointestinal bleeding and prerenal renal
failure because of massive ascites [4, 18]. It is important to clarify that SFSS does
not necessarily lead to patient or graft loss.
The key difference between SFSS after transplantation and following major
resection is the threshold amount of liver tissue below which SFSS develops. In
liver resection a liver/bodyweight ratio of 0.6%, or 20% of the native liver, is usually
adequate for non-cirrhotic patients [36–38], whereas a ratio of at least 0.8% is
required after partial liver transplantation [10, 39]. The reason for this is not com-
pletely known, but it may relate to ischemia reperfusion injury, portal hypertension,
graft denervation and immunosuppression [4].
13.5 Strategies to Prevent or Attenuate SFSS
13.5.1 Graft Volume/Future Remnant Liver Volume Assessment
In the past, preoperative assessment was focused on the volume of liver to be

removed. Currently, there is a shift towards an accurate definition of the minimum
liver volume needed to achieve satisfactory recipient survival following LDLT, or
patient survival following resection. There are different methods to calculate the
volume of the liver before liver resection or LDLT, however none of them is perfect.
The estimated liver volume (ESLV) is usually calculated by computerized tomogra-
phy (CT) scan and measured in mL [40]. It has been assumed that weight and liver
volume are equivalent, but some studies suggest a conversion factor of 1.19 mL/g to
correctly predict it [41]. Moreover, the volume estimated by CT scan was found to
correlate with the real weight resected with a mean absolute error of 64.9 mL [42].
Troisi et al. reported in their study that all grafts were smaller than expected, with a
mean discrepancy of 22% (range 0.2–36%) between estimated graft volume and
actual graft weight [43]. It is also documented that data derived from different races
may not apply to each other [44–46].
In LDLT, a GRWR of ≥0.8% or a graft weight ratio (GWR) of ≥30% are recom-
mended to achieve graft and patient survival of >90% [10, 11]. Even though some
studies have reported successful transplants utilizing grafts with a GRWR of ≥0.6%,
particularly in patients without portal hypertension and Child A [47, 48].
On healthy livers, indications for hepatectomy should be based on future rem-
nant liver (FRL) volume/SLV ratio (where SLV is estimated to be
−794.41 + 1267.28 × body surface area, in m2), and FRL volume/body weight ratio
of liver volume, with 20% and 0.5 as the threshold value, respectively [46, 49, 50].
Recommended minimal functional FRL volume following liver resection is ≥20%
in a normal liver, and ≥40% in an ‘injured’ liver, with moderate to severe steatosis,
cholestasis, fibrosis, cirrhosis, or following chemotherapy [38, 51, 52]. FRL smaller
than 20–30% of total liver volume (TLV) is correlated with higher morbidity and
mortality, particularly due to sepsis and liver failure [53].
13.5.2 Preoperative Strategies to Increase Future Remnant Liver

Volume/Graft Size
Risk assessment for major hepatectomy is dominated by accurate preoperative pre-

diction of postresection hepatic dysfunction. Indeed, even in healthy livers, up to
90% of patients with a FRL <25% of TLV can develop hepatic dysfunction, com-
pared with none with >25% of liver remaining [52]. If the FRL is not sufficient to
meet the supposed future metabolic demand, a number of strategies can be adopted
to increase the liver volume, preventing posthepatectomy SFSS and PLF.
Portal vein embolization (PVE) is the contemporary benchmark to induce FRL
hypertrophy and reduce the risk of SFSS following extended hepatectomy. Initially
described by Makuuchi in 1984 [54], it is a well-tolerated technique allowing hyper-
trophy of FRL by 30–40% in 4–6 weeks in more than 80% of patients, and allowing
surgery about 6 weeks after the procedure [55]. In a range of 70–100% of patients
who underwent PVE, hemi-hepatectomy or extended hepatectomy could be per-
formed safely with reported perioperative morbidity and mortality of less than 15%
and 0–7% [56, 57]. Moreover, failure to proliferate after PVE can be used to select
patients with impaired regenerative capacity in whom major resection would not be
tolerated [58]. The efficiency of surgical ligation of the portal vein (PVL) is broadly
equivalent to that of PVE [59], although there are no controlled studies clearly
showing the superiority of one over the other.
PVL is particularly utilized in patients who are candidate to the two-stage hepa-
tectomy procedure. This therapeutic strategy consists in performing a complete
resection of bilobar tumors in two surgical procedures with the first one consisting
in minor liver resections or ablations in the FRL and PVL of the contralateral hemi-
liver and the second one in an extended hepatectomy. The time frame between the
two procedure is usually 4–6 weeks in which the FRL regenerates [38, 60].
A novel two-step procedure strategy has gained much popularity in liver surgery:
this is the so-called “associating liver partition and portal vein ligation for staged hep-
atectomy”, also known by the acronym ALPPS [61]. It demonstrated and accelerated
hypertrophy by combining right PVL with parenchymal transection without paren-
chymal resection during the first step. The occlusion and ligation of all the portoportal
shunts in segment 4 is the mechanism supposed to boost the liver regeneration which
demonstrated a median increase in volume of about 64% in a short period of time,
with the second surgery usually performed 5–8 days after the first step [62]. Several
variations of this procedure have been described, many of which with the intent of
minimizing the surgical stress particularly of the first step, by utilizing a combination
of laparoscopic surgery and microwave ablation, such as laparoscopic microwave
ablation and portal vein ligation for staged hepatectomy (LAPS) [63, 64].
In LDLT, dual grafts using left lobes from two independent donors [65–67] and
auxiliary transplantation [68–70] (Fig. 13.1) that preserves a part of the recipient
native liver are the only measures available to increase graft size. Both of these
modalities have been reported to be effective but are limited owing to the ethical
problem of putting two donors at risk for one recipient. Auxiliary transplantation,
on the other hand, is gaining new popularity since new indications for OLT are
under investigation, like metastatic colorectal cancer [71]. In this scenario, some
authors have recently explored a solution called the “RAPID concept”: resection
and auxiliary partial liver segment 2–3 transplantation with delayed total hepatec-
tomy after hypertrophy of the auxiliary transplanted liver [72, 73].
Fig. 13.1 Auxiliary left

lobe transplantation
13.5.3 Intraoperative Attenuation of Predicted SFSS
Poor graft outcome has been reported in SFS grafts with PVF >260 mL/min/100 g
and elevated PVP [74, 75]. If the PVF is too high and/or the graft is small (GRWR
<0.8%), several different techniques can be utilized to reduce the PVF (Fig. 13.2)
and overcome graft hyperperfusion, although there is no full consensus about their
indications: hemi-portocaval shunt (HPCS), mesocaval shunt, splenorenal shunt,
splenectomy or splenic artery ligation (SAL) and embolization (SAE). Boillot et al.
first reported a case of LDLT with a GRWR of 0.61% which was successfully
treated by the reduction of PVP with a downstream ligation of the superior mesen-
teric vein and a mesocaval shunt [76]. A laterolateral HPCS has shown in animal
models an improvement in survival (57% vs. 0%) with reduction of PVP and PVF
allowing sinusoidal endothelium preservation. The size of the shunt is critical since
in the case of too large an HPCS shunt, the animals died due to insufficient regen-
eration [77]. Other strategies have been investigated such as construction of an
HPCS connecting a branch of the portal vein of the graft to the circulatory system
[78], or the use of transient portocaval shunts for a few days following surgery [79].
Yamada et al. reported a 100% graft survival utilizing an HPCS in SFS graft (GRWR
~0.6%) with a PVP >20 mmHg [80]. However, the PVF stealing phenomenon from
a graft to the systemic circulation is of concern and some experience indicates that
Fig. 13.2 Examples of

portocaval shunt (a) and a
mesocaval shunt (b) to
reduce portal vein pressure.
PV portal vein, IVC
inferior vena cava, SMV
superior mesenteric vein,
IMV inferior mesenteric
vein
b
HPCS may overcome SFSS in the early period of LDLT and cause graft atrophy and
graft dysfunction in the late period of LDLT [81].
A proportional correlation between PVF and graft-to-recipient spleen size ratio
has been found [82], so that splenectomy, SAL or SAE have been proposed as effec-
tive methods to reduce PVF and PVP. SAL is known to reduce the PVP by 5 mmHg
while reducing the portal flow by 52% on average [83]. This is the most recurrent
and used procedure to obtain inflow control [84]. The decision to add a splenectomy
following SAL depended on an insufficient modulation of the graft inflow [85, 86],
but many authors attempted splenectomy alone as the method of choice to reduce
PVP [86, 87]. Some others reported the usefulness of SAE as a rescue treatment for
post-transplant SFSS [88, 89]. Indeed some studies reported that the effect of SAE
on the reduction of PVP is equivalent to that of SAL [68].
In LDLT, not only the excessive venous inflow but also the outflow may signifi-
cantly reduce hepatic function [24, 25, 90]: reconstruction of accessory hepatic
veins in right lobe LDLT is recommended if >10 mm diameter to maximize venous
outflow (Fig. 13.3) and indirectly liver perfusion [91]. Moreover Chan et al. did not
Fig. 13.3 Small-for-size
graft (a) with venous patch a
(b) to maximize the
outflow
b
observe any correlation between portal inflow and SFSS when outflow was maxi-
mized [92].
There is growing interest in the modulation of portal hypertension in LDLT and
chronic liver disease using novel pharmacological agents [93] that can modulate the
splanchnic blood flow or target intrahepatic endothelial cell dysfunction. Octreotide
has been reported to attenuate the PVP in the early phase after reperfusion in LDLT
[94]. Similarly, in an animal model FK 409, a potent nitric oxide releaser, has dem-
onstrated to ameliorate SFS graft injury by attenuation of portal hypertension and
downregulation of the Egr-1 pathway [23].
13.6 Treatment
There is no definitive treatment for SFSS. The basic strategy is symptomatic or a

wait-and-see policy until the graft regenerates. Massive ascites usually persists for
1–2 months and decreases thereafter, for which aggressive fluid and albumin resus-
citation is mandatory to prevent renal failure. Hyperbilirubinemia without coagu-
lopathy usually resolves within a month. Extracorporeal liver support (ELS) systems
have not been evaluated extensively in patients with SFSS. A meta-analysis and sys-
tematic review showed that ELS may improve survival in patients with acute liver
failure, but none of the studies included patient with postoperative SFSS or PLF [95].
Early enteral feeding is strongly encouraged to decrease the incidence of sepsis [96].
The use of hepatotoxic and nephrotoxic drugs should be avoided, as psychotropic
sedative (except in cases of mechanical ventilation). Regarding symptomatic treat-
ment, the use of lactulose is usually recommended to correct encephalopathy, and
administration of mannitol is possible to reduce intracranial hypertension.
13.7 Conclusions
PLF and SFSS can be viewed as synonyms, since both can lead to an identical pattern
of clinical manifestations, such as cholestasis, impairment of coagulation and devel-
opment of ascites, up to irreversible organ non-function and death of the patient. The
occurrence of SFSS is determined not only by the liver graft volume but also by a
combination of multiple negative factors, in particular portal hyperperfusion.
Although uncommon, SFSS has a high morbidity and mortality rate. Accurate assess-
ment of graft or FRL volume is essential before surgery as well as measurement of
peak PVF and PVP which direct the use of pre-emptive interventions. Ensuring that
surgical technique and vascular inflow/outflow are optimal is critical if extensive
resections are being performed or a small graft is to be implanted. The use of PVF
diversion to protect liver function and avoid damaging hyperperfusion are increas-
ingly being used to avoid SFSS after transplantation but therapeutic pharmacological
perioperative applications remain to be tested outside of the animal models. The
increasing need for grafts for transplantation and new indications, such as metastatic
colorectal cancer, will not only boost the partial small graft transplantation but also
change recipient physiology. Indeed, the metabolic demand and the portal system
pressure of non-cirrhotic patients are different. The knowledge and management of
SFSS will be critical to push the limits of small grafts, avoiding an increase in graft
loss and patient mortality.
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Regeneration Techniques:
TSH and ALPPS 14
Matteo Serenari and Elio Jovine
14.1 Introduction
Tumor burden and/or the future liver remnant (FLR) are the main elements
impairing resectability in liver surgery. When FLR volume is not adequate to
sustain postoperative liver function, portal vein occlusion (PVO) techniques,
such as portal vein embolization (PVE) or portal vein ligation (PVL), can be
performed [1] to increase FLR volume. In healthy livers, the limit for a safe
resection is defined as a standardized future liver remnant (sFLR) ≥20% [2] or
FLR/body weight ratio ≥0.5% [3]. Higher cut-offs have been used if the patients
were considered to have underlying liver disease, such as prolonged chemother-
apy, cholestasis (i.e., total bilirubin >2.9 mg/dL), cirrhosis or liver steatosis
based on preoperative imaging [4].
Especially in cases of bilateral liver disease, a two-stage hepatectomy can be
considered when the FLR is regarded to be insufficient to perform safely a one-
stage hepatectomy. In this context, the two most widely used surgical techniques are
the classical two-stage hepatectomy (TSH) or associating liver partition and portal
vein ligation (ALPPS).
M. Serenari
Department of Surgical and Medical Sciences, Sant’Orsola-Malpighi Hospital,
University of Bologna, Bologna, Italy
e-mail: matteo.serenari@gmail.com
E. Jovine (*)
Department of General Surgery, Maggiore Hospital, AUSL Bologna, Bologna, Italy
e-mail: elio.jovine@ausl.bologna.it

140 M. Serenari and E. Jovine
14.2 Two-Stage Hepatectomy (TSH)
Classical TSH is typically reserved for patients with bilateral tumor involvement
and small FLR. In the first stage, the FLR is usually cleared of tumor and PVO is
performed by means of PVE or intraoperative PVL. PVE is classically performed
through a percutaneous transhepatic ipsilateral approach using computed tomog-
raphy guidance which provides embolization by means of a variety of substances
(histoacryl, lipiodol, gelfoam, and n-butyl cyanoacrylate) of the diseased hemili-
ver including segment 4 branches when a right extended (i.e., including segment
4) hepatectomy is planned [5]. PVO may be also achieved by ligation of the
right/left portal branch, during a first-step laparotomy. Hypertrophy after PVL is
reported to be inferior to PVE, likely due to incomplete vascular interruption of
collaterals between the two hemilivers [6]. Nevertheless, there are no controlled
studies clearly showing the superiority of PVE over PVL. After PVE/PVL, the
second stage of TSH is usually performed 4–8 weeks later [7]. Such a long inter-
val is usually necessary to obtain an adequate FLR hypertrophy, but during this
interval up to 32% of patients is reported to drop out due to progression of dis-
ease or insufficient FLR hypertrophy [8]. Age over 70 years, male gender, larger
lesions >5 cm, serum carcinoembryonic antigen (CEA) level greater than 200 ng/
mL, three or more metastases in the FRL, progression during preoperative che-
motherapy, and presence of extrahepatic disease were demonstrated to be all
significant factors predicting failure to achieve completion of hepatectomy [9]. It
is not clear whether the use of chemotherapy between the first and second stage
can lower tumor progression and dropout rates. What is more likely is that liver
regeneration can be impaired or altered by use of some chemotherapy agents,
thus increasing the risk of posthepatectomy liver failure (PHLF) and overall
morbidity.
14.3 A
ssociating Liver Partition and Portal Vein Ligation
for Staged Hepatectomy (ALPPS)
ALPPS is a novel technique which combines PVL and in situ splitting of the liver
(Fig. 14.1), in order to achieve a more rapid liver hypertrophy than classical TSH,
with almost 100% of completion rate [10]. The ALPPS approach is considered for
patients with an insufficient FLR volume regardless of tumor origin and at least one
of the following [11]:
• a tumor margin close to the FLR or its vascular pedicles;

• a bilobar disease with contraindication for PVE;
• a failure of PVE/PVL;
• an unexpected tumor extension during surgical exploration with a larger than
planned surgical resection;
• the need for a large hypertrophy in an extremely small FLR.
14 Regeneration Techniques: TSH and ALPPS 141
Fig. 14.1 77-year-old patient affected by intrahepatic cholangiocarcinoma. ALPPS was consid-
ered due to a preoperative sFLR (segment 2–3) of 20%. After 10 days the FLR increased from
297 cc to 595 cc (100%) and the patient was subjected to a right trisectionectomy. ALPPS associat-
ing liver partition and portal vein ligation for staged hepatectomy, FLR future liver remnant, sFLR
standardized FLR
In the first stage, besides PVO and in situ splitting, colorectal resection or biliodi-
gestive anastomosis can be performed. During parenchymal transection, ligation of
the small arteries directed to segment 4 should be avoided to prevent necrosis and
consequent biliary leak. For this reason, a partial liver split (3–5 cm) has been
recently advocated [11]. A partial split together with PVE, in place of PVL, namely
“mini-ALPPS”, has been demonstrated to enable a good hypertrophy rate, minimiz-
ing at the same time the impact of stage 1 [12]. PVE is particularly useful in cases
of Klatskin tumor where a no-touch technique has to be preferred to limit potential
tumor spread due to manipulation. Moreover, PVE and partial split can both be
performed laparoscopically, thus reducing even more the impact of stage 1 [13]. In
fact, these modifications were introduced after the first publication of the original
ALPSS technique, as a result of the high morbidity and mortality rates reported
[14]. In particular, the first results from the ALPPS International Registry showed
that 93% of deaths occurred after stage 2 and PHLF was the most important cause
of death. Hyperbilirubinemia or more in general liver dysfunction between stages in
ALPPS has been shown to be associated with higher 90-day mortality after stage 2
[15]. The biological basis for such a dramatic increase in liver volume, registered
already one week after stage 1, is thought to be related to hepatocyte enlargement
without a corresponding increase in liver function. In other words, volumes in
ALPPS overestimate liver function [16], as reported by studies on liver regeneration
and function performed in ALPPS patients. Molecular nuclear imaging techniques
as 99mTc-mebrofenin hepatobiliary scintigraphy and single photon-emission com-
puted tomography (Fig. 14.2) have been used to estimate FLR function and to pre-
dict PHLF and liver-related mortality before the second stage of ALPPS [17]. The
HIBA (Hospital Italiano de Buenos Aires) index described by Serenari et al. seems
to be a promising tool to assess the right timing of the second stage, bearing in mind
142 M. Serenari and E. Jovine
Fig. 14.2 SPECT image

before completion of
ALPPS, showing the
distribution of function
within the deportalized
liver and the future liver
remnant. SPECT single
photon-emission computed
tomography, ALPPS
associating liver partition
and portal vein ligation for
staged hepatectomy
that other well-known risk factors such as the patient’s age, tumor type, occurrence
of liver failure and/or surgical complications between stages should also be taken
into account to guide decision-making in ALPPS. ALPPS is not intended to sup-
plant conventional TSH, but rather to expand the armamentarium for hepatic resec-
tion. The first results from randomized control trials comparing ALPPS versus TSH
have shown a comparable rate of complications (43%) between the two techniques.
However, the oncological results are still awaited.
References
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3. Truant S, Oberlin O, Sergent G, et al. Remnant liver volume to body weight ratio ≥ 0.5%: a
new cut-off to estimate postoperative risks after extended resection in noncirrhotic liver. J Am
Coll Surg. 2007;204:22–33.
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14 Regeneration Techniques: TSH and ALPPS 143
9. Giuliante F, Ardito F, Ferrero A, et al. Tumor progression during preoperative chemotherapy

predicts failure to complete 2-stage hepatectomy for colorectal liver metastases: results of an
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tion for staged hepatectomy offers high oncological feasibility with adequate patient safety: a
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first stage impact: the mini-ALPPS technique. Langenbeck's Arch Surg. 2016;401:557–63.
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approach of laparoscopic-assisted transmesenteric portal vein embolization. J Laparoendosc
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Combined Cardiothoracic
and Abdominal Approach 15
Fabio Ferla, Vincenzo Buscemi, Riccardo De Carlis,
15.1 Introduction
Hepatobiliary procedures are generally performed by laparotomy or laparoscopy,

although in a few patients, a combined cardiothoracic and abdominal approach is
necessary. Most of these cases are technically challenging and require a high
degree of expertise in both liver and cardiothoracic surgery. The aims of the present
chapter are:
• To identify the main indications for the combined approach in liver resection
surgery and liver transplantation (LT)
• To describe the operative technique adopted during combined cardiothoracic-
abdominal procedures
• To analyze the short-term and long-term results of such procedures

F. Ferla (*) · V. Buscemi

e-mail: fabio.ferla@ospedaleniguarda.it; vincenzo.buscemi@ospedaleniguarda.it
R. De Carlis
L. De Carlis

146 F. Ferla et al.
15.2 Indications
The indications for opening the chest as well as the abdomen are different in liver
resection surgery and LT.
15.2.1 Liver Resection Surgery
In liver resection surgery, the combined cardiothoracic and abdominal approach

may be needed in three circumstances, namely, when:
• The liver tumor extends into the hepatic veins.
• The tumor invades the diaphragm.
• A huge tumor requires extensive mobilization of the liver from the inferior vena
cava (IVC) at the hepatocaval confluence.
15.2.1.1 Tumor Extending into the Hepatic Veins

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) tend to invade
and occlude blood vessels with tumor thrombus (TT). HCC with extension into the
IVC or right atrium (RA) is rare and occurs in approximately 3.8% and 2.0% of
patients, respectively [1, 2]; clear data for CCA are not available, but it seems that
CCA is less likely to invade the hepatic veins and to go up to the RA.
In 2013 Li et al. [3] proposed a classification of HCC with TT invading the vena
cava or RA; this classification was intended to guide the surgical approach to
extended HCC but seems to fit with CCA too. Clinically, TT was classified into
three types according to its anatomic location relative to the heart: the inferior
hepatic type (type I), where the TT is in the IVC below the diaphragm; the superior
hepatic type (type II), where the TT is in the IVC above the diaphragm, but still
outside the RA; and the intracardiac type (type III), where the TT is above the dia-
phragm and has entered the RA (Fig. 15.1).
To properly identify the tumor extension in the hepatic veins, vena cava, and RA,
a diagnostic workup should include a contrast-enhanced computed tomography
scan and cardiac ultrasonography.
In type I TT, there is no need for a combined cardiothoracic and abdominal
approach: liver surgery can be safely performed by a standard abdominal approach
and total hepatic vascular exclusion (THVE). In type II TT, it is necessary to control
the intrathoracic vena cava: that can be done safely by dividing the diaphragm from
the abdomen; in type II TT, THVE and liver surgery do not require sternotomy or
thoracotomy. In type III TT, complete access to the heart is mandatory since the RA
has to be incised: to perform a combined cardiac and liver surgery, a cardiopulmo-
nary bypass (CPB) [1] with or without deep hypothermia and circulatory arrest
(DHCA) [4, 5] is needed.
15.2.1.2 Tumor Invading the Diaphragm

When the diaphragm is invaded by liver tumor, the muscle should be resected en
bloc with the tumor itself. In such circumstances three approaches are possible:
15 Combined Cardiothoracic and Abdominal Approach 147
Fig. 15.1 Hepatocellular carcinoma (HCC) with tumor thrombus (TT) is classified into three
types according to its anatomic location relative to the heart: inferior hepatic type (Type I), where
the TT is in the inferior vena cava below the diaphragm; superior hepatic type (Type II), where the
TT is in the inferior vena cava above the diaphragm, but still outside the right atrium; intracardiac
type (Type III), where the TT is above the diaphragm and has entered the right atrium
Fig. 15.2 Tumor invading

the diaphragm: for invasion
less than 2 cm, the
diaphragm can be clamped
above the neoplastic
invasion to allow en bloc
resection without opening
the chest
• For invasion less than 2 cm, the diaphragm can be clamped above the neoplastic
invasion to allow en bloc resection without opening the chest (Fig. 15.2).
• For invasion between 2 and 4 cm, the opening of the diaphragm (and of the chest)
is required to remove the tumor. The subsequent defect in the continuity of the
muscle can be repaired by direct suture [6].
• For invasions greater than 4 cm, the removal of the tumor creates defects that
should be repaired by the interposition of a mesh (when the surgical field is not
contaminated) [6] or a muscle flap (when the field is contaminated) [7].
148 F. Ferla et al.
The greater the diaphragm invasion, the higher the chance to see it at preopera-
tive radiology, so the need for a mesh (needed for big diaphragm defects) can be
generally predicted before surgery.
15.2.1.3 H uge Tumor Requiring Extensive Mobilization of the Liver

from IVC at the Hepatocaval Confluence
Although not universally accepted, the use of a thoraco-phreno-abdominal access
has been proposed as standard approach for huge tumors located in segments 1, 4
superior, 7, and 8 close to the hepatic vein confluence into the IVC [8]. This approach
may allow a better exposure of the hepatocaval confluence, increasing the safety of
the surgery involving this area. Another indication for the thoraco-phreno-abdominal
approach is the patient with severe adhesions because of previous liver surgery or
the patient with a long and narrow thoracic cage. In both circumstances, opening of
the chest enlarges the field to safely operate while minimizing the risk of iatrogenic
injury and providing the chance to repair it, if needed.
15.2.2 Liver Transplantation
In LT, the combined cardiothoracic and abdominal approach may be needed in four
circumstances, namely, when:
• The LT is performed in combination with heart transplantation.
• The LT is performed in combination with lung transplantation.
• Coronary bypass or aortic valve replacement is to be performed in combination
with the LT.
• The upper caval anastomosis is to be performed directly on the RA.
15.2.2.1 Combined Heart and Liver Transplantation

Progressive cardiac dysfunction can cause hypoxic hepatic injury because of con-
gestive hepatopathy leading to hepatic fibrosis [9] and to the need for combined
heart-liver transplantation (CHLT). The most common indication for CHLT is
familial amyloid polyneuropathy (FAP) with associated cardiac cirrhosis [10].
Other indications are familial hypercholesterolemia, β-thalassemia, hemochromato-
sis, alcoholic cardiomyopathy, cryptogenic cirrhosis with underlying cardiomyopa-
thy, and glycogen storage disease. Cardiac-specific causes include hypertrophic
cardiomyopathy, systemic lupus erythematous, and dilated cardiomyopathy.
According the database of OPTN/UNOS (Organ Procurement and Transplantation
Network/United Network for Organ Sharing), 278 CHLTs have been performed in
the United States from 1992 to 2018 [11].
15.2.2.2 Combined Lung and Liver Transplantation

Similar to CHLT, lung disease is the primary driver for combined lung-liver trans-
plantation (CLLT). The most common indication is cystic fibrosis (CF). Hepatic
manifestations associated with CF include liver steatosis and cirrhosis. Other indi-
cations for CLLT include pulmonary hypertension (which is a contraindication for
LT alone) and α1-antitrypsin deficiency. The majority of CLLT recipients without
CF have undergone transplantation for concurrent liver and lung diseases with dis-
tinct causes. According the database of OPTN/UNOS, 106 CHLTs have been per-
formed in the United States from 1994 to 2018 [12].
15.2.2.3 L iver Transplantation and Coronary Bypass or Aortic Valve

Replacement
Patients with end-stage liver disease (ESLD) and coronary artery disease (CAD) or
severe valvular heart disease have been reported with simultaneous LT and coronary
artery bypass grafting or aortic valve replacement (AVR) [13, 14]. The need for a
simultaneous heart-liver procedure resides in the high risk the heart or transplanta-
tion surgery would carry if performed alone. Liver transplantation is precluded to
patients with known CAD since the 3-year mortality after the transplantation varies
between 26% and 50% [15, 16]; at the same time coronary artery bypass is precluded
to Child-Pugh class C patients owing to the high perioperative mortality. Similarly,
LT is precluded to patients with aortic valvulopathies, and AVR is precluded to
Child-Pugh class C patients. In patients in whom severe heart disease and ESLD are
concomitant, the only possible treatment is simultaneous heart and liver surgery.
15.2.2.4 L iver Transplantation with Upper Caval Anastomosis

on the Right Atrium
As for liver resection surgery, all the conditions in which complete control of the
RA is needed for the upper caval anastomosis should be managed by a combined
cardiothoracic and abdominal approach. In particular, Budd-Chiari syndrome
requiring LT, some cases of polycystic liver disease, and some cases of re-
transplantation are just a few of the circumstances in which sternotomy may be
required to perform a safe surgery.
As done for the indications, we will address separately the surgical techniques used
in:
• Liver resection surgery requiring a combined approach
• LT requiring a combined approach
15.3.1 Liver Resection Surgery Requiring a Combined Approach
15.3.1.1 Tumor Extending into the Hepatic Veins

As mentioned above, only type III TT requires complete access to the heart (see
Video 15.1 from the authors’ series).
In type III TT, an intraoperative transesophageal echocardiography is advised
[17] (Fig. 15.3a). Surgery starts with a groin incision and preparation for cannula-
tion of the right common femoral vein. Laparotomy is that performed through an
L-shaped right subcostal incision. Abdominal exploration is performed. The hepatic
pedicle is prepared for a Pringle maneuver, and liver disease extension is confirmed
150 F. Ferla et al.
a b
c d
Fig. 15.3 Intraoperative images of a case from the authors’ series: (a) intraoperative transesopha-
geal echocardiography; (b) the diaphragm is partially divided from the abdomen; (c) a complete
median sternotomy is performed; (d) the superior vena cava is encircled
by intraoperative ultrasound. The diaphragm may be partially dived from the abdo-
men (Fig. 15.3b). Liver parenchyma transection may start at this time or may be
postponed after CPB preparation. A complete median sternotomy is then performed
(Fig. 15.3c). The pericardium is opened, the superior vena cava encircled
(Fig. 15.3d), and the diaphragm division is completed (Fig. 15.4a). The ascending
aorta is cannulated. The superior vena cava and common femoral vein are cannu-
lated to ensure venous drainage of the upper half and lower half of the body
(Fig. 15.4b). The suprarenal vena cava is clamped as well as the hepatic pedicle, and
CPB can be started. When the suprarenal IVC and hepatic pedicle are clamped, the
liver is under THVE. CPB is generally conducted in mild (32–35 °C) to moderate
hypothermia (28–32 °C), although some authors add DHCA to CPB when perform-
ing this kind of surgery [5]. When DHCA is applied, the patient body temperature
is progressively dropped below 28 °C; at 18–20 °C the brain’s electrical activity
stops, and the CPB flow can be reduced to 1–1.5 L/min [4] or stopped [5]. When
DHCA is applied, the hepatic pedicle should not be clamped to ensure hepatic cool-
ing [5]. The reported advantages of DHCA are a bloodless surgical field and a
reduced risk of warm hepatic ischemia. On the other hand, DHCA may be burdened
by postoperative bleeding and coagulopathy.
If CPB is applied without DHCA, the THVE should not last more than 60 min to
avoid postoperative liver failure [18, 19]. If DHCA is performed, it should not last
more than 30 min to avoid brain damage [4].
When CPB (with or without DHCA) starts, the RA is opened, and the resection
surgery can be completed by en bloc removal of the tumor from the heart and from
the abdomen (Fig. 15.4c).
Cava-atrium continuity has to be re-established (a bovine pericardium patch may
be useful in this setting) before the CPB can be stopped (Fig. 15.4d). Once the CPB
a b
c d
Fig. 15.4 Intraoperative images of a case from the authors’ series: (a) the diaphragm division is
completed; (b) the femoral vein is cannulated; (c) the right atrium is cut and the tumor is removed
from the heart; (d) cava-atrium continuity is re-established with a bovine pericardium patch
stops, the cardiothoracic and liver surgeons proceed with a standard technique to
complete the operation.
15.3.1.2 Tumor Invading the Diaphragm

A huge hepatic neoplasm (especially HCC) may invade the diaphragm and require
a large en bloc diaphragm excision. In these cases, the anterior approach is gener-
ally advised to perform the hepatectomy, as described by other authors [20].
When the removal of the tumor determines a diaphragm defect wider than
3–4 cm, muscle reconstruction with a mesh is advised because the diaphragm can-
not be pulled to its original position with too much tension. In our experience a
2-mm Gore-Tex prosthetic mesh can be inserted in the area of the diaphragmatic
defect and sutured with a 1/0 or 2/0 polypropylene running suture with good results.
When the surgical field is contaminated or the patient is at high risk for postop-
erative collection, a latissimus dorsi flap (LDF) can be used for the reconstruction.
Other authors have described the technique, which is performed in three steps [7]:
the LDF is dissected and the thoracodorsal pedicle is identified and preserved; the
flap is brought into the chest through the lateral segment of the third intercostal
space; and the LDF is fixed with separate sutures in order to isolate the pleural and
abdominal cavities.
15.3.1.3 H uge Tumor Requiring Extensive Mobilization of the Liver

from IVC at the Hepatocaval Confluence
The so-called thoraco-phreno-abdominal approach is characterized by an incision
that is first made from the xiphoid process to approximately 4–5 cm above the umbi-
licus and then curves laterally to the right hypochondrium along the ninth intercos-
tal space up to the posterior axillary line. In all patients the xiphoid process is fully
152 F. Ferla et al.
exposed and removed to gain about 3–5 cm of exposure just above the hepatocaval
confluence. The insertions of the external oblique muscle and of the internal oblique
muscle upon the costal arch are carefully detached in order to expose the costal arch
around the ninth intercostal space and enter the thorax. The bone cartilage of the
costal arch is removed, and the intercostal muscles are resected along the superior
border of the tenth rib to avoid injuries of the neurovascular bundle. Such resection
of the intercostal muscles is prolonged posteriorly into the thoracic cavity to prevent
rib fractures and bleeding during retractor pulling. The diaphragm is divided for
10 cm following a line directed to the hepatocaval confluence. Careful dissection
should be carried out to prevent injuries to the phrenic nerve, which usually runs
posteriorly and medially, and to the phrenic veins, which run in the direction of the
right hepatic vein confluence. At this point, the liver can be pushed out by the left
hand of the surgeon. Closure of the thoraco-phreno-abdominal access starts from
the thoracic wall. After placement of a thoracic drain, single large absorbable sutures
are placed between the two adjacent costal margins. Then, the diaphragm is closed
with a running suture that is placed starting from the internal and medial side up to
the costal margin. At this time the single sutures in the thoracic wall are closed.
Finally, the laparotomy is closed using standard techniques.
15.3.2 Liver Transplantation Requiring a Combined Approach
15.3.2.1 Combined Heart and Liver Transplantation

For CHLT, most surgeons follow a standard bicaval technique although on CPB for
heart transplantation. The chest is left open, and the liver is transplanted with selec-
tive use of venovenous bypass. The chest and abdomen are then closed. For FAP, the
domino technique can be used. A piggyback (Belghiti) or standard bicaval technique
is used for whole orthotopic LT. Alternatively, en bloc CHLT has been described for
pediatric cases: donor hilar and retroperitoneal dissections are performed prior to
cross-clamping to minimize heart ischemia. The diaphragm is split at the level of the
IVC, and phrenic veins are ligated. Following cross-clamping, venous venting is
performed through the right atrial appendage and infrarenal vena cava. In the recipi-
ent, the liver is mobilized, and the recipient diaphragm is split. The heart is mobilized
toward the end of the hepatectomy. En bloc organs are then simultaneously implanted
on bypass, and the organs are simultaneously reperfused.
15.3.2.2 Combined Lung and Liver Transplantation

For CLLT, a bilateral thoracosternotomy or bilateral anterolateral thoracotomy is
performed. Venovenous bypass is employed to support hemodynamic instability
and reduce portal or retroperitoneal venous hypertension. Use of CPB is also pos-
sible during lung implant; it is followed by heparinization antagonization and
LT. Ceulemans et al. [21] describe a CLLT in which the liver was transplanted first.
The aim is to prevent coagulopathy, reduce lung edema, and reduce the risk of post-
transplantation biliary strictures. The authors conclude the “sicker organ” should be
transplanted first.
15.3.2.3 L iver Transplantation and Coronary Bypass or Aortic Valve

Replacement
Coronary bypass or aortic valve replacement are performed just before the LT. The
techniques adopted for both heart and liver surgery are the same as for a standard
“single” procedure; the only difference is that the chest is closed before the abdo-
men after the LT is complete.
15.3.2.4 L iver Transplantation with Upper Caval Anastomosis

on the Right Atrium
When the LT requires full access to the RA, the technique is the same as adopted
during liver resection with RA TT previously described.
15.4 Postoperative Outcomes
Liver resection surgery requiring a combined cardiothoracic and abdominal

approach is generally burdened by high postoperative morbidity (40%) and mortal-
ity [22]. Although patients undergoing this kind of surgery have advanced disease
for which the oncologic outlook is dismal at diagnosis, surgery could prolong sur-
vival, which would be very poor otherwise (especially in the case of atrial occlu-
sion, death for cardiac arrest or a rapidly progressive cava syndrome could occur
suddenly).
For HCC patients undergoing HCC and TT resection, Wang et al. and Wakayama
et al. reported a median overall survival of 19.0 and 30.8 months, respectively [23,
24]. Kokudo et al. reported a survival of 16.4 months [25]. A clear prospective on
survival for CCA with TT in IVC or RA is missing, but it could possibly be worse
than that of HCC.
For huge HCC tumors invading the diaphragm, the postoperative morbidity is
20.7% (Clavien grade >2), and the mortality is 1.9% [20]. Long-term survival
depends on the histology and stage of the tumor; for huge HCC involving the dia-
phragm, the reported overall survival at 1, 3, and 5 years is 71.7%, 39.6%, and
27.6%, respectively [20].
Analysis of the 2016 OPTN/UNOS data for adult patients undergoing CHLT
demonstrates 1-, 3-, and 5-year patient survival rates of 87.2%, 83.1%, and 82.0%,
respectively, which is comparable to survival outcomes for liver or heart transplan-
tation alone [26]. Analysis of the 2016 OPTN/UNOS data for adult patients under-
going CLLT demonstrates a 79% 1-year graft survival, which is comparable to the
81.3% reported for isolated lung transplantation [26].
Data on combined LT and coronary bypass or aortic valve replacement are poor.
In a report from Giakoustidis et al. [27], perioperative mortality occurred in 1 case
out of 16 (6%) during LT and coronary bypass and in 2 cases out of 8 (25%) during
LT and AVR.
Organized data on LT requiring cardiac access are missing as well; in our experi-
ence (four cases) both short-term and long-term results seem to be similar to those
of patients transplanted without the need for sternotomy.
154 F. Ferla et al.
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Portal Vein Thrombosis in Liver
Transplantation and in Non-transplant 16
Treatment
Umberto Cillo and Domenico Bassi
16.1 Introduction
The presence of portal vein thrombosis (PVT) represents one of the most relevant
challenges in liver transplantation as well as in the non-transplant treatment of por-
tal hypertension and in some oncologic hepatobiliary operative approaches. A wide
interplay of pathophysiologic, clinical and technical pieces of information among
the different hepatobiliary and transplant disciplines is fundamental to improve
clinical results.
PVT is defined as a partial or complete occlusion of the blood flow within the
portal vein (PV) by an intraluminal thrombus. Cirrhosis represents the most com-
mon etiologic factor, accounting for up to 24–32% of cases [1]. Other common
causes include cancer, inflammation, infection and thrombophilic disorders.
The incidence of PVT in cirrhotic patients usually correlates with the severity of
the underlying liver disease and thus it is a common finding in decompensated cir-
rhotic patients that are waiting for a liver transplantation (LT) [2]. The prevalence
reported in the literature is up to 28% in LT candidates [3]. Cirrhosis itself is now
recognized as a hypercoagulable disease that, combined with a low portal venous
flow in the setting of portal hypertension, is one of the main risks relating to the
onset of PVT [4].
PVT can be described and categorized in different ways: it can be intrahepatic or
extrahepatic, non-occlusive or occlusive, acute or chronic. Although advancements
in knowledge, understanding and treatment of this disease, the clinical impact of
PVT, especially in LT patients, remains still significant. In a retrospective analysis
of 21,673 LT recipients in the United Network for Organ Sharing (UNOS) registry,
U. Cillo (*) · D. Bassi

e-mail: cillo@unipd.it; domenico.bassi@aopd.veneto.it

158 U. Cillo and D. Bassi
the presence of PVT was identified as an independent risk factor for post-
transplantation mortality [5].
Technical skills to manage the extremely relevant portal hypertension associated
with PVT in the transplantation setting prove to be very useful also in non-transplant
scenarios. Viceversa, a huge amount of pathophysiologic and technical details aris-
ing from the experience in portal hypertension surgery represents the backbone of
prophylaxis of the small-for-size syndrome in modern living donor LT [6].
16.2 Classification and Diagnosis of Portal Vein Thrombosis
PVT usually arises within the liver and extends downwards into the extrahepatic
portion of the PV. In some cases, the thrombosis further extends to the mesenteric
branches resulting in a splanchnic venous thrombosis. Following this scheme,
Yerdel et al. classified PVT from grade 1 (<50% thrombosis of the PV) to grade 4
(complete thrombosis of the PV and of the superior mesenteric vein [SMV])
(Fig. 16.1). This classification gained the greatest acceptance and widespread clini-
cal application [2]. Other classifications have been proposed so far and these sys-
tems seem to differ on only minor points, but this may account in part for the wide
variability in the prevalence of PVT reported in the literature [7–9].
a b
c d
Fig. 16.1 The Yerdel classification of portal vein thrombosis. (a) Grade 1: partially thrombosed
PV (≤50% of the lumen), with or without minimal extension into the SMV. (b) Grade 2: throm-
bosed PV (>50% of the lumen, including total occlusion), with or without minimal extension into
the SMV. (c) Grade 3: complete thrombosis of both PV and proximal SMV. (d) Grade 4: complete
thrombosis of both PV and proximal and distal SMV. PV portal vein, SMV superior mesenteric
vein, SV splenic vein
16 Portal Vein Thrombosis in Liver Transplantation and in Non-transplant Treatment 159
The diagnosis of PVT is fundamental in tracing the correct clinical pathway in

transplant evaluation and pretransplant management, and it is critical in the opera-
tive planning of the LT. Similar considerations can be applied in the non-transplant
setting where the location of the neoplastic thrombus has relevant clinical
drawbacks.
Doppler ultrasonography (DUS) has become the most common initial diagnostic
tool for PVT, with a sensitivity and specificity ranging from 60% to 100% [10, 11].
Computed tomography and magnetic resonance imaging with contrast are used to
define the extent of the thrombosis and the nature of the thrombus especially in
patients with hepatocellular carcinoma (HCC), and help in the preoperative assess-
ment for transplantation [12].
Less frequently a fine-needle aspiration cytology may be indicated in the workup
of a suspected unclear neoplastic portal thrombus [13].
16.3 Preoperative Management of Portal Vein Thrombosis
PVT is in the majority of cases asymptomatic and often only routine DUS guides in
the diagnosis. In other cases, the appearance of decompensation symptoms will
alert to a possible PVT.
The correct management of PVT in a pretransplant setting has the goal of reduc-
ing complications and mortality: in fact, PVT has been shown to be independently
associated with a higher risk of variceal bleeding, failure of endoscopic treatment
during bleeding and rebleeding, leading to an increased 6-week mortality (36% in
PVT vs. 16% in non-PVT patients) [14, 15]. In general, in cirrhotic patients listed
for transplantation there is an increased mortality in the presence of occlusive PVT,
independently from transplantation [16]. Again, complete PVT is related to a sig-
nificant increase in 30-day and 1-year mortality after LT when compared to patients
transplanted without PVT [17].
Medical treatment for PVT is based on anticoagulant therapy that must always
be started after implementing an adequate prophylaxis for gastrointestinal bleeding
[18]. Progression of the thrombosis in patients without treatment is evident in
48–70% of individuals at 2-year follow-up [19, 20]. In patients treated with antico-
agulants, the rate of re-permeabilization is around 55–75% with a mean interval
time of about 6 months. The most important factor able to predict the probability of
response to anticoagulant therapy is a time interval less than 6 months between the
diagnosis of PVT and the start of treatment [20]. The recurrence rate of PVT in
patients with re-permeabilization of the vein after withdrawal of anticoagulation
therapy (38%) [21] suggests prolonging the treatment to prevent re-thrombosis
especially in patients waiting for a LT.
In LT candidates, who have progressive PVT not responding to anticoagulation,
it is possible, in specific situations, to consider a percutaneous approach with tran-
sjugular intrahepatic portosystemic shunt (TIPSS) [18].
In the non-transplant setting, when a surgical treatment of portal hypertension
has to be scheduled, as in the presence of idiopathic portal thrombosis, a complete
thrombophilia screening has to be undertaken including protein S, protein C, and

antithrombin levels, Factor V Leiden mutation, prothrombin G20210A gene variant
and antiphospholipid antibodies (APA). Moreover, the workup consists of diagnosis
of inherited and acquired thrombophilia factors, myeloproliferative neoplasms
(JAK2V617F mutation), paroxysmal nocturnal hemoglobinuria and autoimmune
disorders [18].
At the same time, patients need an accurate vascular morphology (angioCT scan or
angioMRI) particularly focused on caliber and distance of the splenic vein (SV) and
left renal vein (RV), if a splenorenal shunt has to be planned, or mesenteric vein and
cava in the case of a mesocaval shunt. Site and caliber of spontaneous portosystemic
shunts, if present, have to be carefully studied to better design the intervention. Such
an accurate morphologic preoperative study is even more relevant in planning a trans-
plantation in the presence of PVT and spontaneous portosystemic shunts which repre-
sent the most relevant cause of portal re-thrombosis after transplantation.
A similar morphologic workup is also needed when scheduling a major resection
for HCC with portal neoplastic thrombosis, since the involvement of portal bifurca-
tion may represent an oncologic contraindication to the resective plan.
Such an attitude to an accurate and detailed preoperative study and knowledge of
venous splanchnic circulation widely overlaps between transplantation and hepato-
biliary surgical scenarios.
16.4 Surgical Approaches to Portal Vein Thrombosis
Surgery of portal hypertension, including cases of PVT, preceded LT, starting in the
1950s and developing until the introduction of TIPSS. Nowadays its role is limited
to the few cases in which endoscopic and/or radiologic approaches have failed. The
technical contents of shunt surgery, however, remain extremely current in that they
represent key background knowledge to be retrieved, for example, in the presence
of portal overflow and a risk of endothelial shear stress after partial LT. In such
cases, it may be useful to perform a portocaval shunt in order to reduce portal pres-
sure to less than 20 mmHg to avoid a small-for-size syndrome, provided, however,
that portal flow remains in normal ranges.
A splenorenal shunt is a technically demanding peripheral shunt to be adopted to
decrease portal hypertension in the specific district of gastroesophageal varices.
Nowadays, even though rarely adopted, it is performed according the Orozco and
Mercado description including a side-to-side rather than end-to-side anastomosis
between the SV and RV [22].
Technical knowledge of this intervention may prove extremely useful when pre-
paring SV and RV to find spontaneous shunts to be ligated after portal thrombec-
tomy during LT in order to increase portal flow and prevent post-transplantation
portal re-thrombosis.
In the pediatric population, the occurrence of a PVT in the presence of a healthy
liver may require a mesoRex shunt connecting the mesenteric vein to the left patent
PV in the Rex recessus in order to reperfuse the intrahepatic portal system [23].
Such a shunt needs an iliac venous graft interposition. Clearly, knowledge of LT
reconstruction techniques is of fundamental help.
The goals of surgical PVT management during LT are: to establish adequate
blood flow into the graft PV; to decompress the splanchnic circulation; to deliver
portal trophic factors to the allograft.
The first successful LT in a patient with PVT was reported in 1985 by the
Pittsburgh group, who described the technique of extensive dissection of the PV to
the confluence of the splenic and mesenteric veins with the use of a free iliac vein
allograft [8]. Since that initial experience, several new techniques have been pro-
posed to solve this problem and provide acceptable results.
Adequate preoperative imaging is critical for correct surgical planning; for
instance, it may help in avoiding wasting time in portal dissection in the presence of
cavernomatous transformation and extensive thrombosis. However, detection of
PVT not infrequently occurs during surgery.
16.4.1 Management of Grade 1–2
The management of grade 1–2 PVT starts with a careful dissection of the porta
hepatis in order to assess the presence and extension of the thrombosis taking
care to avoid injury to the large collateral vessels that often are present. The PV
needs to be dissected to the confluence of SMV and SV behind the head of the
pancreas till a soft patent vessel is encountered at the confluence. The majority
of PVT grade 1–2 are managed with the removal of the thrombus. In cases of a
soft and acute thrombus, this may be removed with a Fogarthy catheter. Care
must be taken during balloon inflation not to lacerate the posterior wall of the
confluence, which is difficult to repair due to its retropancreatic position. Most
cases of PVT are chronic, and in these situations the thrombus is teased out with
the innermost layer of the vessel (thromboendovenectomy) [2]. This is accom-
plished using an endarterectomy spatula under direct vision everting the vessel
wall [24, 25]. Blind extraction of the thrombus is not recommended as it can rip
the vessel causing uncontrollable bleeding. Part of the thrombus especially when
it extends into the SV or SMV may remain adherent to the vessel wall with a
thrombogenic potential. The residual part of the thrombus can be fixed to the
vessel wall. Once the thrombus is removed, the portal flow must be checked and
if it is considered inadequate, a Fogarty catheter can be passed in the SMV and
SV, inflated gently and pulled. Another possibility is to check for spontaneous
portosystemic shunts that have to be ligated in order to reduce the “steal
phenomenon”.
Thrombectomy and thromboendovenectomy are the most frequent techniques
used in presence of PVT and in a large review of 1957 LT recipients with PVT [26]
they were used in 75% of cases with a very low risk of PVT recurrence and
complications.
16.4.2 Management of Grade 3–4
In those situations, in which the thrombus extends beyond the SMV and SV conflu-
ence in the presence of a patent proximal SMV (grade 3 PVT) and thrombectomy is
not feasible, a jump graft bypass may be performed. The SMV is exposed below the
transverse mesocolon at the root of the small bowel mesentery and here the proxi-
mal anastomosis is completed in an end-to-side fashion. The vein graft is tunneled
through the mesentery of the transverse colon and passed anteriorly to the pancreas
in order to avoid disruption of the pancreatic capsule and its associated risks [27].
In the case of extensive portomesenteric thrombosis in the absence of patent
proximal SMV (grade 4 PVT), the only possibility to revascularized the graft is to
connect an alternative inflow to the porta vein. When possible, a coronary vein or an
unnamed collateral vessel can be anastomosed to the donor PV [28]. These vessels
must have a proper diameter (2 cm or more) and adequate flow; sometimes an inter-
position vein graft in used. Great care must be taken when suturing these variceal
structures to the graft PV because these vessels are extremely delicate and will tear
easily and may not hold suture. This is probably the best and more physiological
approach in cases of grade 4 PVT since the blood from the collateral vessel anasto-
mosed to the PV comes directly from the splanchnic system.
Other alternative inflow sources can be the hepatic artery, the gastroduodenal
artery or the aorta with the interposition of a free graft [29]. This technique, called
PV arterialization, is simple but not at all physiological, and the systemic arterial
pressure in the PV bed causes hemorrhage, right heart failure, aneurysmal dilatation
of intrahepatic portal branches, acute and secondary PVT. Moreover, the chronic
elevated pressure in the graft portal system and the consequent modification of the
microcirculation develops graft fibrosis [30, 31]. These complications suggest that
PV arterialization should be used only in exceptional cases.
When an effective portal thrombectomy is impossible, cavoportal hemitransposi-
tion is a further option to restore the inflow to the donor PV. Tsakis et al. in 1998
[32] first described this technique in LT with diffuse PVT consisting of anastomos-
ing the infrahepatic vena cava to the PV in an end-to-end or end-to-side fashion
(Fig. 16.2). In this way al the IVC flow is directed to the PV. In the end-to-side
anastomosis, the IVC is best ligated in order to redirect the systemic vein flow to the
donor PV. In 2007 the same group published their series of 23 patients with long
follow-up [33]: the 1- and 5-year survival rates were 60% and 38%. Postoperative
gastrointestinal variceal bleeding occurred in 30.4%, while ascites and edema of the
bilateral lower extremities were observed in 91% of patients, and usually resolved
with medical therapy in 6–12 weeks. Transitory renal dysfunction is seen in many
patients, and it is usually self-resolving by 3 months postoperatively.
Renoportal anastomosis (RPA) has been proposed as an alternative strategy to
establish a portal inflow to the allograft [34]. This is best done in the presence of
splenorenal shunts that are seen in up to 50% of patients with SVP. This suggests
that almost half of grade 4 thromboses may be suitable for an RPA. After isolation
a b
Fig. 16.2 (a) Computed tomography scan of cavoportal hemitransposition. (b) Scheme of cavo-
portal hemitransposition. C-P thick arrow cavoportal anastomosis, IVC inferior vena cava, PV
portal vein, G iliac vein graft, thin arrow ligation of the IVC
and control of the left RV, it is anastomosed directly or with the interposition of a
vein graft to the PV in an end-to-end fashion. An RPA ensures adequate flow to
the liver, optimal coaxiality, congruence of the anastomosed vessels and preserva-
tion of the retrohepatic inferior vena cava flow. In particular, the left RV flow in
cirrhotic patients with significant splenorenal shunts is more than 1000 mL/min
(55 F). In the systematic review published by D’Amico et al. in 2018 [35], the
all-cause mortality was reported to be 19.6% (13 patients) and the overall patient
and graft survival were each 80%, with a mean follow-up of 35.2 ± 29.7 months.
Overall, 71% of patients developed postoperative complications, the more com-
mon being ascites, transient renal dysfunction, infection, and variceal hemor-
rhage. All cases of postoperative ascites and transient renal dysfunction resolved
within 3 months of LT.
The extreme surgical option in grade 4 PVT is the hepatointestinal or multivis-
ceral transplantation. These techniques allow replacement of the recipients’ entire
splanchnic venous system, but the scarcity of donors causes a very high waiting-list
mortality, up to 50%. Moreover, these techniques are burdened by a high risk of
rejection, infection and surgical complications with a 5-year survival of 49% [36].
Again, the intraoperative management of splanchnic-systemic shunts is a critical
point during transplantation of patients with PVT. They can be left in place during
portions of the hepatectomy to continue to decompress the portal system and then
taken down to improve portal flow if causing PV steal. In cases of splenorenal shunts,
in the presence of a “steal phenomenon” and despite interruption of collaterals, liga-
tion of the left RV can augment portal flow by eliminating the steal from the spleno-
renal shunt. This is accomplished initially by clamping temporarily the RV vein and
then, when the portal flow is confirmed to be improved, with its ligation [37].
16.4.3 Surgical Management in Hepatocellular Carcinoma

Neoplastic Portal Vein Thrombosis
HCC neoplastic PVT represents in the majority of cases a contraindication for

resective surgery. These patients in fact have often a decompensated liver function
and if not, they are best candidates for systemic oncological therapy. In a small
group of patients with compensated liver function and good clinical conditions a
liver resection with PV thrombectomy may be offered with acceptable risks [38].
According to the Liver Cancer Study Group of Japan classification system, PV inva-
sion (Vp) can be classified into four groups [39]:
• Vp1 as an invasion or tumor thrombus distal to the second branch of the PV;
• Vp2 as an invasion or tumor thrombus in the second branch of the PV;
• Vp3 as an invasion or tumor thrombus in the first branch of the PV;
• Vp4 as an invasion or tumor thrombus in the portal trunk or extending to a branch
on the contralateral side.
In the first two groups anatomical or atypical liver resections may be used to
achieve R0 resections. In cases of Vp3 and Vp4 a PV resection is necessary to
ensure radicality and often a reconstruction of part of the vessel wall with a perito-
neal patch or the complete resection of the bifurcation and an end-to-end anastomo-
sis is necessary to allow an adequate portal flow.
16.5 Conclusions
Management of PVT both in the setting of LT and in the hepatobiliary surgical

patient requires knowledge of the diseases and their pathophysiology as well as
technical skills that overlap in the field of LT and hepatobiliary oncological surgery.
In both situations a careful selection of candidates for surgery and preoperative
assessment are critical.
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APOLT and RAPID Techniques
17
Umberto Cillo
17.1 Introduction
The auxiliary partial orthotopic liver transplantation (APOLT) and resection and
partial liver segment 2–3 transplantation with delayed total hepatectomy (RAPID)
techniques are two of the most relevant paradigms of the interplay between liver
transplantation and hepatobiliary surgery. In both techniques, the complex concepts
of liver partition are merged with the articulated issues related to graft implantation.
In both, the key factors implied in liver regeneration and the clinician’s ability to
modulate and influence it are of paramount importance for the postoperative results.
Owing to the complexity of the techniques and the large number of variables
involved in the clinical outcomes, realizing an APOLT or a RAPID technique is a
major achievement for a hepatobiliary and liver transplant surgeon.
Such an achievement is the result of a full technical and conceptual maturity
reached through massive exposure to both live resection and liver transplantation
surgery.
The Padua center performed both the first APOLT in Italy in 2007 (and is still the
only Italian center to perform APOLT) and the first Italian RAPID technique in
2018.

U. Cillo (*)
e-mail: cillo@unipd.it

168 U. Cillo
17.2 APOLT Technique
Auxiliary partial orthotopic liver transplantation (APOLT) is a particularly complex

technique that includes a major hepatectomy realized to create enough room to
implant a partial liver graft in the orthotopic position. The procedure never gained
wide diffusion in the transplant community due to extreme technical complexity
and a somewhat problematic reproducibility. The concept, however, represents one
of the most fascinating in surgery. On one hand, it maintains the native liver in place
allowing a future reversal in the event of a full recovery from the underlying disease
and, on the other, it enables the “addition” of functioning liver parenchyma to sup-
port metabolic processes in the recipient. The orthotopic position of the graft guar-
antees a perfectly physiologic inflow and outflow.
APOLT was initially offered to children with metabolic liver disease without cir-
rhosis, as a sort of gene therapy. Even small amounts of liver parenchyma can effi-
ciently correct single enzyme-related metabolic disorders. Additionally, in the event
that a future gene therapy becomes available, the APOLT can be removed with
withdrawal of immunosuppression [1]. It is extremely interesting that even very
small parts of liver, namely a left lateral segment (LLS) graft, can be enough to sup-
port the metabolic deficit. This can be provided by a standard LLS split graft in a
deceased donor liver transplantation setting or a left lateral segmentectomy in a
living donor setting. Moreover, in the living donor liver transplantation (LDLT) set-
ting donor safety is much better preserved with APOLT than with a classical trans-
plantation procedure due to the much smaller amount of liver parenchyma needed.
A further important indication for APOLT has historically been fulminant hepatic
failure. In particular, in the pediatric population, the idea was to support the native
liver recovery during a phase of acute life-threatening insufficiency by means of an
“extra metabolically functioning parenchyma”. Such an extra parenchyma could
have been subsequently removed (or just let undergo atrophy without immunosup-
pression) once native liver function had recovered fully [2].
Recently, both conditions—non-cirrhotic metabolic disease and acute liver fail-
ure—are gaining acceptance as standard indications for the adoption of APOLT in
selected cases. In particular, in the case of acute liver failure the concept of a poten-
tial bridge to native liver function recovery gives the patient the possibility of an
immunosuppression-free survival.
Among the most important technical issues presented by APOLT is the potential
for a portal steal. After transplantation the graft implanted in the orthotopic position
is almost invariably associated with inflammatory events that may increase intrapa-
renchymal resistance to blood flow. This generates a difference in resistance to portal
flow between the graft and the native liver where resistances are classically normal.
In turn, this may result in a diversion of portal flow in the direction of the native liver
where resistances are low. As a result, the graft may undergo a relative ischemia lead-
ing to progressive atrophy. In addition, potential rejection episodes may further
increase intragraft resistance to portal flow thereby worsening the relative ischemia.
Some techniques have been developed to overcome the problem. Portal modula-
tion consists in reducing the caliber of the portal branch going to the native liver.
17 APOLT and RAPID Techniques 169
A complete portal diversion may be needed in some cases (complete ligation of the
native liver portal vein) [3]. This decision, however, is irreversible since the native
liver function cannot recover after complete portal ligation. Broering et al. sug-
gested inducing venous congestion in part of the native remnant by ligating the
middle hepatic vein close to its outflow in the vena cava in order to prevent portal
flow competition between both livers [4].
If portal steal is detected or suspected in the postoperative phase a radiological
segmental portal embolization can be performed to increase native portal vein resis-
tance and rebalance portal flow.
17.3 RAPID Technique
According to Line et al., the acronym RAPID stands for “resection and partial liver
segment 2–3 transplantation with delayed total hepatectomy” [5].
The concept includes elements deriving from classical APOLT, on the one hand,
and, on the other, from two-stage hepatectomy. It is indeed an auxiliary liver trans-
plantation where a small partial liver graft (namely an LLS graft) is implanted
orthotopically after a left hepatectomy of the native liver.
Subsequently, in order to promote a fast regeneration of the transplanted seg-
ments, a portal flow diversion is operated in the direction of the future remnant as in
the ALPSS (associating liver partitioning and portal vein ligation for staged hepatec-
tomy) technique. Once a fast regeneration of the auxiliary future remnant has been
obtained, the native liver hepatectomy is completed as in a two-stage hepatectomy.
The RAPID technique meets some major clinical and pathophysiologic demands:
1. It provides “extra donor resources” to allow transplantation for “unconventional

indications” for transplantation: LLSs are easily obtainable either by means of a
cadaveric split (once served the pediatric population) or by LDLT with an
extremely low risk for the donor;
2. It overcomes the problem of an insufficient metabolic mass typical of LLSs
(with the aim of supporting life);
3. It prevents the shear stress on the portal endothelium associated with an excess
of portal pressure related to the small vascular bed of a small graft;
4. It promotes a fast future remnant regeneration allowing completion of the native
hepatectomy in the context of a safe two-stage hepatectomy.
17.3.1 The Technique According to the Description of the First

Italian Case in Padua
We performed the first case of RAPID technique in Italy in December 2018. It was
the sixth RAPID procedure ever, the second case worldwide using a living donor
[6], and the first case with a minimally invasive approach for the second stage hepa-
tectomy (Videos 17.1, 17.2 and Figs. 17.1, 17.2 and 17.3).
170 U. Cillo
Fig. 17.1 RAPID
technique: diagram of step 1
Fig. 17.2 RAPID
technique: diagram of step 2
Fig. 17.3 RAPID
technique: intraoperative
picture (personal
experience)
A 47-year-old patient affected by more than 20 colorectal liver metastases

(CRLM) was considered not resectable by the Padua multidisciplinary oncologic
meeting. The unresectability was subsequently confirmed by an international multi-
disciplinary board. The patient had undergone a full course of Folfox evacizumab
therapy with a partial response.
After ethics committee approval, two potential donors were evaluated. The
patient’s brother-in-law agreed to provide his LLSs, for a total liver weight of 400 g.
The donor operation was totally uneventful and the donor was discharged on the
sixth postoperative day after a regular postoperative course.
The recipient operation started with a full left hepatectomy (segments 1–4)
extended to the left hepatic vein. Subsequently, the donor LLSs were implanted
orthotopically. The graft left hepatic vein was anastomosed on the stump of the
middle and left hepatic veins. The graft left portal vein was then anastomosed end-
to-end with the recipient’s left portal vein. Similarly, the left hepatic artery was
anastomosed end-to-end with the recipient’s stump of a replaced left hepatic artery
from left gastric artery by means of a microsurgical technique and the use of opera-
tive microscope. Portal pressure and flows were repeatedly measured. After right
portal vein ligation, left portal vein pressure remained stable below 20 mmHg. The
left biliary stump was anastomosed on a Roux-en-Y loop.
The postoperative increase in graft volume was tightly monitored. After 15 days,
the volume reached a graft-to-body weight ratio (GRWR) of 1. A hepatobiliary imi-
nodiacetic acid (HIDA) scan was also completed. We then decided to proceed with
the second stage hepatectomy. The native right hepatectomy was performed laparo-
scopically and the native liver was extracted through a 10-cm incision. The patient
is well and disease-free 2 months after the procedure.
17.3.2 Providing Extra Donor Resources
Even after the introduction of direct antiviral agents for the treatment of HCV infec-
tion leading to a dramatic drop in the demand for liver transplantation for these
patients, the waiting list pressure for liver transplantation remains severe.
Furthermore, new indications have arisen in recent years with particular reference
to CRLM. The incidence of colorectal cancer (CRC) is about 700 cases per million
population. Among the new cases, about 50% will develop metastases in the liver,
which represent the major cause of morbidity and mortality in these patients.
Systemic chemotherapy associated with radical surgical resection is the milestone
of treatment in these patients. However, only 20% of patients are resectable in the
course of the disease.
The Oslo group has shown how liver transplantation in selected patients with
CRLM is associated with good survivals rates in the middle and long term (well
above 50% at 5 years). These survival rates are significantly greater if compared
with similar patients undergoing only systemic chemotherapy (less than 20% at
5 years). Even though recurrence-free survival is relatively low (10 months median
recurrence-free survival), recurrences are more frequently in the lung and are
172 U. Cillo
associated with a relatively mild outcome only marginally impacting survival. It has
been shown that lung metastases are slow-growing and that their growth rate is not
significantly influenced by immunosuppressants. When patients with partial
response or stable disease after chemotherapy, CEA <80, maximum diameter
5.5 cm and prolonged time after CRC diagnosis (more than 2 years) are selected, the
results post-transplantation are even more encouraging [7].
Several prospective studies are ongoing at the moment. In particular, Adam et al.
are leading a randomized clinical trial comparing liver transplantation + chemo-
therapy vs. conventional chemotherapy in patients with BRAF wild-type tumors in
the absence of extrahepatic metastases and partial response or stable disease at che-
motherapy [8].
Independently from the results of the ongoing studies, it is already clear that liver
transplantation will be part of the therapeutic armamentarium available for
CRLM. In Italy, the waiting list mortality is still around 5–7% of cases, so that new
donor sources are needed.
LDLT has never really taken off in Europe due to cultural and logistic reasons. In
particular, the donor risk of about 1% mortality is seen as a major negative draw-
back. The patients themselves often refuse the LDLT option so as not to endanger
the life of a relative. In turn, the donor morbidity and mortality risk are associated
with the large liver mass needed, which often exceeds 60% of the liver
parenchyma.
In the RAPID concept, the donor source may be a conventional (LLS) split liver
from a cadaveric donor or a live donor. In Italy, donors younger than 50 years are
offered to pediatric centers to cover the pediatric national waiting list. However,
selected donors older than 50 years may provide excellent LLS splits available for
RAPID without impacting the scarce donor pool. Extended right livers from split-
ting techniques have been widely associated with results comparable to whole-liver
transplant in the past [9].
As far as living donors are concerned, it has been widely demonstrated that the
donation of LLSs carries an extremely low risk of morbidity whereas mortality is
close to 0%. In terms of outcomes, risks and ethical equipoise, LLS living donation
has been compared to kidney living donation. In this sense, the RAPID technique
represents a potential breakthrough that opens liver transplantation to a virtually
infinite donor pool. Furthermore, the LDLT option has also the advantage of bring-
ing this complex procedure in the context of an elective setting.
17.3.3 Preventing the Small-for-Size Syndrome
In LDLT, a GRWR of at least 0.8 is needed to avoid a small-for-size syndrome after

transplantation. For this reason, an LLS graft is never used to transplant an adult
recipient. The only condition in which a GRWR lower than 0.8 is tolerated is when
portal pressure is reduced to less than 20 mmHg to avoid endothelial shear stress
and intrahepatic portoarterial buffer alteration. Many techniques to achieve such a
pressure reduction have been described to date. Among them, splenic artery ligation
and partial portocaval shunt are the most important.
After LLS implantation in the orthotopic position, an accurate measurement of
portal pressure and flow is completed. Measurements have to be performed with and
without clamping of the portal vein to the native liver. If, after clamping the portal
vein to the native liver, the pressure rises above 20 mmHg, a splenic artery ligation
or a different portal modulation flow has to be put in place.
In the case described by Line et al. [5], the RAPID technique allowed transplan-
tation with an astonishing and unprecedented GRWR of 0.36.
17.3.4 Promoting a Quick Regeneration of the Auxiliary Graft
Regeneration of the graft implanted in the orthotopic position is promoted by portal

flow diversion to the graft after ligation of the portal vein to the native liver. The
principle has been diffusely tested and demonstrated in the context of the ALPSS
procedure. It is possible that the major cytokine release induced by parenchymal
transection plays a role in inducing a rapid regeneration, as shown by Shlegel et al.
[10]. In the Oslo case [7] the interval between auxiliary transplantation and the
second-stage hepatectomy was 30 days.
17.3.5 Oncologic Aspects of the RAPID Technique
It is not known if the coexistence of the graft and diseased native liver for 20–30 days
may be detrimental from an oncologic point of view. A numerically larger experience
as well as studies on circulating cells in the auxiliary phase are needed. The favorable
biology of CRC is fundamental to obtain acceptable long-term results [11]. A more
precise biologic-molecular stratification of patients is needed to better address the
complex issue of patient selection.
References
1. Kasahara M, Sakamoto S, Horikawa R, Fukuda A. Auxiliary partial orthotopic liver transplan-
tation for noncirrhotic metabolic liver disease: reigniting interest in an old but new technique.
Liver Transpl. 2019;25:12–3.
2. Rammohan A, Reddy MS, Narasimhan G, et al. Auxiliary partial orthotopic liver transplanta-
tion for selected noncirrhotic metabolic liver disease. Liver Transpl. 2019;25:111–8.
3. Yabe S, Nishizawa H, Egawa H, Tanaka K. Portal blood flow and liver regeneration in auxil-
iary partial orthotopic liver transplantation in a canine model. Eur Surg Res. 1999;31:83–92.
4. Broering DC, Walter J, Bassas AF. Overcoming the portal steal phenomenon in auxiliary par-
tial orthotopic liver transplantation by modulation of the venous outflow of the native liver.
5. Line PD, Hagness M, Berstad AE, et al. Novel concept for partial liver transplantation in non-
resectable colorectal liver metastases: the RAPID concept. Ann Surg. 2015;262:e5–9.
174 U. Cillo
6. Königsrainer A, Templin S, Capobianco I, et al. Paradigm shift in the management of irre-

sectable colorectal liver metastases: living donor auxiliary partial orthotopic liver transplanta-
tion in combination with two-stage hepatectomy (LD-RAPID). Ann Surg. 2018. https://doi.
org/10.1097/SLA.0000000000002861 . Epub ahead of print.
7. Dueland S, Hagness M, Line PD, et al. Is liver transplantation an option in colorectal cancer
patients with nonresectable liver metastases and progression on all lines of standard chemo-
therapy? Ann Surg Oncol. 2015;22:2195–200.
8. Liver transplantation in patients with unresectable colorectal liver metastases treated by che-
motherapy (TRANSMET). ClinicalTrials.gov Identifier: NCT02597348. https://clinicaltrials.
gov/ct2/show/NCT02597348. Accessed 26 Mar 2019.
9. Herrero A, Nadalin S, Panaro F. Liver transplantation for irresectable colorectal liver metasta-
ses: still a contraindication? Hepatobiliary Surg Nutr. 2018;7:475–8.
10. Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated
and novel mechanisms of liver regeneration. Ann Surg. 2014;260:839–46.
11. Bjørnelv GMW, Dueland S, Line PD, et al. Cost-effectiveness of liver transplantation in
patients with colorectal metastases confined to the liver. Br J Surg. 2019;106:132–41.
Robotic Surgery in Liver Transplantation
and Resection 18
Fabrizio Di Benedetto, Giuseppe Tarantino,
Gian Piero Guerrini, Roberto Ballarin, and Paolo Magistri
18.1 Introduction
Minimally invasive approaches are spreading worldwide in every field of surgery as

well as in liver surgery. In particular, the use of robotic assistance in performing
surgical tasks has been developed over the last decade, and current robotic systems
are quickly penetrating the surgical realm [1]. Minimally invasive liver surgery pro-
vides more favorable perioperative outcomes compared to open liver resection, with
significantly less intraoperative blood loss, shorter hospital stay, and less postopera-
tive morbidity, without affecting the oncological result [2]. Moreover, the clinical
aspects are comparable to standard laparoscopy, while there are technical advan-
tages of the robotic platform that make for a more comfortable approach for the
surgeon, even to complex procedures that classically required an extremely skilled
laparoscopic surgeon.
18.2 Robotic Approach for Liver Surgery: State of the Art
It has been demonstrated that robotic hepatectomy is related to less postoperative

pain and a shorter hospital stay, with a similar oncological outcome compared to
open resection [3]. Several studies assessed that robotic surgery is as safe as open and
laparoscopic approaches in terms of complications and post-operative morbidity for
both minor and major hepatectomies [4–8]. Currently, indications and contraindica-
tions to robotic liver resections do not differ from those of the laparoscopic approach.
Some benefits have been described in cirrhotic patients thanks to more precise
F. Di Benedetto (*) · G. Tarantino · G. P. Guerrini · R. Ballarin · P. Magistri

Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Policlinico University
Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy
e-mail: fabrizio.dibenedetto@unimore.it; tarantino.giuseppe@aou.mo.it;
guerrini.gianpiero@aou.mo.it; ballarin.roberto@aou.mo.it; paolo.magistri@unimore.it

176 F. Di Benedetto et al.
bleeding control [9]. The use of the daVinci (Intuitive Surgical Inc., Sunnyvale, CA,
USA) robot in liver surgery allows an easier access to liver segments that are difficult
to access using the laparoscopic approach, such as the caudate lobe and right poste-
rior section [4, 10]. This is mainly due to better movement precision, seven degrees
of instrument freedom, 3D stable view and better ergonomics compared to classical
laparoscopy [11, 12]. The 1-, 3-, and 5-year disease-free survival rates after robotic
resection for hepatocellular carcinoma (HCC) have been reported in large series to be
similar to those of the open and laparoscopic approaches, as well as the 1-year, 3-year
and 5-year overall survival [13, 14]. Similarly, survival rates after robotic resection
for colorectal metastasis are similar to those of the laparoscopic approach [15]. The
largest review on robotic liver surgery published so far reported acceptable conver-
sion and complication rates of 5.9% and 17.6%, respectively [16].
18.3 Technical Considerations
The daVinci platform includes a surgeon’s console, a patient-side cart and a vision
system. Patients are usually positioned supine, 20° to 30° anti-Trendelemburg and
can be slightly rotated to the left to allow an easier access to right and posterior seg-
ments. The pneumoperitoneum is usually induced with the Verres needle technique,
from the left upper abdominal quadrant (Palmer’s point), in patients not presenting
with splenomegaly or suspect for abdominal adherences from previous surgery. An
open approach to induce the pneumoperitoneum is preferred in those cases (Hasson’s
technique). Constant endoabdominal pressure can be kept with the use of the auto-
mated insufflator AirSeal (Surgiquest Inc., Conmed, Utica, NY, USA). Exploratory
laparoscopy should always be performed before docking the patient cart to assess
the resectability and to safely insert the trocars. The disposition of the trocars varies
according to each patient’s peculiar conformation and lesion localization, and to the
robotic platform in use. As a general rule, trocars should be positioned very high
subcostal and lateral for the posterior-superior segments or closer to the transverse
umbilical line for the anterior segments, shifting toward the left or the right depend-
ing on the lesion location. The goal is to create an adequate triangulation with
enough space (8 cm on average) between the ports [17] (Fig. 18.1). The fourth
robotic arm is generally positioned on the left side. Trocar placement and docking
have been considered a crucial and time-consuming step at the beginning of the
robotic experience [18], mainly due to the rigidity of the system that did not allow
changing the position of the patient after having docked the cart. Nowadays, using
the fourth generation of the robotic platform, we can find novel features such as a
laser targeting system that makes the robotic arm set-up easier, and integrated Table
Motion that allows dynamic repositioning of the patient while the surgeon operates
without undocking. Other novel features are the integrated Firefly fluorescence
imaging and the possibility to move the endoscope on any of the four arms.
Visualization of the biliary tree anatomy, evaluation of organ and tissue perfusion,
recognition of vascular anatomy, lymph node identification and the distinction
between tumor cells and normal liver parenchyma are some of the real-time
18 Robotic Surgery in Liver Transplantation and Resection 177
Fig. 18.1 Trocar
disposition and docking for
a left hepatectomy with a
daVinci Si platform
Fig. 18.2 Intraoperative
view of the TilePro
function, an image fusion
technique between the
ultrasound probe and the
endoscope, during a
segment 5 resection for
hepatocarcinoma
information that the surgeon can obtain thanks to the integrated fluorescence detec-
tion with indocyanine green (ICG). Tumor cells are usually hypo-fluorescent lesions
with no ICG uptake [19]. Intraoperative ultrasound (US) should always be per-
formed to better define tumor size and position, and to assess the correct transection
plane with image-fusion between the scope and the US [20] (Fig. 18.2). The TilePro
function on the robotic console is one of the most important resources of the plat-
form and displays at the same time the classical endoscopic view and imaging
sources such as the US, computed tomography (CT) scan, magnetic resonance
(MR) images or 3D reconstructed models [21]. Up to three different images can be
viewed at the same time by the console surgeon and the operating room personnel.
This represents a valuable improvement compared to standard laparoscopy since
switching from one screen to another to visualize pre- and intraoperative imaging is
no longer required. Another option to assess the correct transection line is to tempo-
rarily close the portal branch with a minimally invasive vascular clamp (Bulldog) to
identify the vascular demarcation (Fig. 18.3). Parenchymal transection can be per-
formed with a combination of monopolar and bipolar energy, and with the use of
daVinci Harmonic ACE (Ethicon, Somerville, NJ, USA) for deeper layers. Although
Fig. 18.3 To assess the

correct resection plane a
temporary vascular
clamping can be performed
the robotic platform still does not support liver-specific articulated devices for
parenchyma dissection such as the Cavitron Ultrasonic Surgical Aspirator (CUSA),
the correct use of the available tools allows a safe dissection. For example, the
Maryland forceps can be used as a right-angle to precisely dissect small vessels in
the parenchyma thanks to the 7 degrees of freedom of the robotic instruments
(Fig. 18.4). The use of the bipolar electrosurgical instrument, daVinci Vessel Sealer,
is another option for vascular control. The management of the left hepatic vein dur-
ing left lobectomies and hepatectomies may benefit from a selective dissection by
lifting the left lobe to avoid tractions on the vena cava and the middle hepatic vein
(Fig. 18.5); however, trans-parenchymal control with a laparoscopic or robotic sta-
pler is recommended at the beginning of the minimally invasive experience.
Hemostasis and biliostasis should be checked with the pneumoperitoneum off, with
the help of a surgical pad or Valsalva maneuver. We usually extract the specimen
through a Pfannenstiel incision and re-evaluate the transection plane after having
induced the pneumoperitoneum again.
18.4 Role of Robotics in Liver Transplantation
The treatment of patients affected by HCC outside the Milan Criteria should be
adapted case by case after a multidisciplinary evaluation involving surgeons, hepa-
tologists and radiologists [22]. However, it is useful to remember that strategies for
bridging or downstaging patients to a “Milan-in” condition may benefit from a
robotic approach, in particular, in those patients who are not suitable to be treated
with a locoregional therapy [22, 23]. While the role of a robotic approach in kidney
procurement and transplantation for living donation is now well developed and
accepted in dedicated centers [24], few reports have been published regarding robotic
liver procurement. Conversely, laparoscopic donor hepatectomy has been success-
fully applied to both left and right procurement from living donors and has been
Fig. 18.4 Detail of hilar

(a) and intraparenchymal a
(b) vascular dissections
using Maryland bipolar
forceps
Fig. 18.5 Isolation of the

left hepatic vein during a
robotic left lobectomy. The
left lobe is lifted to the
right, and the vena cava is
under control. In the figure
a tie is being passed around
the vein by Maryland
bipolar forceps
proven safe, effective and related to fast return to daily activities in expert centers
[25]. Several reasons can be advocated: firstly, as above mentioned, dedicated tools
specific to robotic liver surgery are still lacking; secondly, no strong evidence on
indications have been produced yet, and while some literature has shown comparable
results when robotic hepatectomies are compared to laparoscopic hepatic surgery,
these results and these outcomes may not be generalized [1, 19]; thirdly, the robotic
platform remains somewhat cumbersome, making undocking and gaining access to
the patient potentially difficult in emergency settings [26]. This increases the con-
cerns with regards to the safety of performing procedures in completely healthy sub-
jects such as donors, in whom there is no room for error [27]. While robotic
hepatopancreatobiliary surgery is growing in popularity globally, robotic donor hep-
atectomy is still in its infancy. In 2016 Chen and colleagues reported their experience
with 13 patients undergoing living donor right hepatectomy for liver transplantation
with the robotic approach [28]. Compared to the open group, the robotic living donor
hepatectomy required a longer operative time, but there were no differences in the
rate of complications and blood loss. No conversions were needed, and the mean
warm ischemia time was 9.5 min (range 8–15). Postoperatively, the robotic group
showed better pain control and faster return to work.
18.5 Conclusions
According to the report from the second international consensus conference held in
Morioka [29], robotic surgery is considered to be IDEAL stage 2a (Development)
[30], especially in regard to instrumentation. In other words, it requires both ongoing
institutional ethical approval and a reporting registry of all cases before beginning to
perform this procedure. Experience on the daVinci platform is growing among many
surgeons, but the learning curve for proficiency has yet to be defined. Therefore, we
believe that a robotic approach for hepatobiliary disease should be reserved for high-
volume tertiary referral centers. Recently published data concluded that the develop-
ment of robotic surgery for complex operations should be encouraged, but high
quality standards and safety-driven surgical growth must be guaranteed [31].
References
1. Szold A, Bergamaschi R, Broeders I, et al. European Association of Endoscopic Surgeons
(EAES) consensus statement on the use of robotics in general surgery. Surg Endosc.
2015;29:253–88.
2. Han DH, Choi SH, Park EJ, et al. Surgical outcomes after laparoscopic or robotic liver resec-
tion in hepatocellular carcinoma: a propensity-score matched analysis with conventional open
liver resection. Int J Med Robot. 2016;12:735–42.
3. Wang W-H, Kuo K-K, Wang S-N, Lee K-T. Oncological and surgical result of hepatoma after
robot surgery. Surg Endosc. 2018;32:3918–24.
4. Spampinato MG, Coratti A, Bianco L, et al. Perioperative outcomes of laparoscopic and robot-
assisted major hepatectomies: an Italian multi-institutional comparative study. Surg Endosc.
2014;28:2973–9.
5. Venturini M, Angeli E, Maffi P, et al. Technique, complications, and therapeutic efficacy of

percutaneous transplantation of human pancreatic islet cells in type 1 diabetes: the role of
US. Radiology. 2005;234:617–24.
6. Yu YD, Kim KH, Jung DH, et al. Robotic versus laparoscopic liver resection: a comparative
study from a single center. Langenbeck’s Arch Surg. 2014;399:1039–45.
7. Lee KF, Cheung YS, Chong CCN, et al. Laparoscopic and robotic hepatectomy: experience
from a single centre. ANZ J Surg. 2016;86:122–6.
8. Boggi U, Caniglia F, Amorese G. Laparoscopic robot-assisted major hepatectomy. J
Hepatobiliary-Pancreat Sci. 2014;21:3–10.
9. Magistri P, Tarantino G, Ballarin R, et al. Robotic liver surgery is the optimal approach as
bridge to transplantation. World J Hepatol. 2017;9:224–6.
10. Di Benedetto F, Ballarin R, Tarantino G. Totally robotic isolated caudate-lobe liver resection
for hydatid disease: report of a case. Int J Med Robot. 2016;12:254–61.
11. Felli E, Santoro R, Colasanti M, et al. Robotic liver surgery: preliminary experience in a ter-
tiary hepato-biliary unit. Updat Surg. 2015;67:27–32.
12. Montalti R, Scuderi V, Patriti A, et al. Robotic versus laparoscopic resections of postero-
superior segments of the liver: a propensity score-matched comparison. Surg Endosc.
2016;30:1004–13.
13. Chen PD, Wu CY, Hu RH, et al. Robotic versus open hepatectomy for hepatocellular carci-
noma: a matched comparison. Ann Surg Oncol. 2017;24:1021–8.
14. Lai ECH, Yang GPC, Tang CN. Robot-assisted laparoscopic liver resection for hepatocellular
carcinoma: short-term outcome. Am J Surg. 2013;205:697–702.
15. Troisi RI, Patriti A, Montalti R, Casciola L. Robot assistance in liver surgery: a real advantage
over a fully laparoscopic approach? Results of a comparative bi-institutional analysis. Int J
Med Robot. 2013;9:160–6.
16. Tsilimigras DI, Moris D, Vagios S, et al. Safety and oncologic outcomes of robotic liver resec-
tions: a systematic review. J Surg Oncol. 2018;117:1517–30.
17. Giulianotti PC, Bianco FM, Daskalaki D, et al. Robotic liver surgery: technical aspects and
review of the literature. Hepatobiliary Surg Nutr. 2016;5:311–21.
18. Di Benedetto F, Magistri P, Ballarin R, et al. Ultrasound-guided robotic enucleation of pancre-
atic neuroendocrine tumors. Surg Innov. 2019;26:37–45.
19. Gonzalez-Ciccarelli LF, Quadri P, Daskalaki D, et al. Robotic approach to hepatobiliary sur-
gery. Chirurg. 2017;88(Suppl 1):19–28.
20. Magistri P, Tarantino G, Guidetti C, et al. Laparoscopic versus robotic surgery for hepatocel-
lular carcinoma: the first 46 consecutive cases. J Surg Res. 2017;217:92–9.
21. Woo Y, Choi GH, Min BS, Hyung WJ. Novel application of simultaneous multi-image dis-
play during complex robotic abdominal procedures. BMC Surg. 2014;14:13. https://doi.
org/10.1186/1471-2482-14-13.
22. Magistri P, Rosenblatt R, Halazun KJ. Liver transplantation for HCC beyond Milan. Curr
Transpl Rep. 2018;5:319–26.
23. Magistri P, Tarantino G, Ballarin R, et al. The evolving role of local treatments for HCC in the
third millennium. Anticancer Res. 2017;37:389–401.
24. Tzvetanov I, Bejarano-Pineda L, Giulianotti PC, et al. State of the art of robotic surgery in
organ transplantation. World J Surg. 2013;37:2791–9.
25. Samstein B, Griesemer A, Cherqui D, et al. Fully laparoscopic left-sided donor hepatectomy is
safe and associated with shorter hospital stay and earlier return to work: a comparative study.
26. Di Benedetto F, Magistri P, Halazun KJ. Use of robotics in liver donor right hepatectomy.
Hepatobiliary Surg Nutr. 2018;7:231–2.
27. Miller C. Preparing for the inevitable: the death of a living liver donor. Liver Transpl.
2014;20(Suppl 2):S47–51.
28. Chen PD, Wu CY, Hu RH, et al. Robotic liver donor right hepatectomy: a pure, minimally
invasive approach. Liver Transpl. 2016;22:1509–18.
2015;261:619–29.
30. McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation: the
IDEAL recommendations. Lancet. 2009;374:1105–12.
31. Magistri P, Tarantino G, Ballarin R, et al. Robotic liver donor right hepatectomy: a pure, mini-
mally invasive approach. Liver Transpl. 2017;23:857–8.
Other “Bridge” Therapies for Liver
Transplantation: RFA, TACE, and TARE 19
Giuseppe Maria Ettorre and Andrea Laurenzi
19.1 Introduction
Hepatocellular carcinoma (HCC) is the sixth cause of death among all cancers with
an incidence of over 800,000 new cases/year [1]. The majority of cases arise on a
background of liver cirrhosis. For this reason, liver transplantation (LT) is one of the
best treatments since it simultaneously treats the HCC and the underlying liver cir-
rhosis, reducing the risk of new HCC developing on the remnant liver [2]. However,
the great disproportion between patients requiring LT and the availability of liver
grafts calls for an accurate selection of possible LT candidates in order to identify
the patients likely to benefit from the procedure and to have a long-term outcome
comparable to those transplanted for reasons other than HCC (e.g., liver cirrhosis).
Different criteria for determining HCC suitability for LT have been proposed
over the last 20 years (e.g., Milan Criteria, University of San Francisco, Up-to-
seven, AFP score) [3–6]. The Milan criteria, which were described by Mazzaferro
et al. in 1996, are still among the most used criteria worldwide for HCC patients
prior to LT. An HCC is considered within the Milan criteria if the nodule is single
and <5 cm in size or if there are maximum 3 nodules, none of them larger than 3 cm
without macrovascular invasion. If the patient meets such criteria, the 5-year overall
survival (OS) is 75%.
The main concern of HCC patients is the time elapsed between the HCC diagno-
sis and LT. This interval is extremely variable and depends on different factors such
as country, number of available grafts, organ allocation policy, etc. During this inter-
val, if not treated, the HCC can progress and exceed the above-mentioned criteria
and become no longer suitable for LT. A consensus statement for LT for HCC has
recommended locoregional treatments (LRTs) if the anticipated waiting time for an
G. M. Ettorre (*) · A. Laurenzi

Transplantation Department, S. Camillo-Forlanini Hospital, Rome, Italy
e-mail: gmettorre@scamilloforlanini.rm.it; alaurenzi@scamilloforlanini.rm.it

184 G. M. Ettorre and A. Laurenzi
organ to become available exceeds 6 months [7]. For this reason, in order to avoid
drop-out of the patient from the LT waiting list, a treatment that can cure or slow
down tumor progression should be undertaken to act as a bridge until LT. Moreover,
it has been demonstrated that reducing the amount of viable tumor in the liver
improves the survival post-LT [8]. Response to LRTs can be evaluated by preopera-
tive radiological assessment and serum alpha-fetoprotein (AFP) changes [9–16].
The main LRTs available nowadays are: radiofrequency ablation (RFA), transar-
terial chemoembolization (TACE) and transarterial radioembolization (TARE). The
bridging treatment must take into account two different factors in order to be effi-
cient and safe: tumor characteristics (number of nodules, size, proximity to vascular
and biliary structures, etc.) and liver function. The efficacy of different treatments
according to tumor characteristics will be discussed in the following sections. As
concerns liver function, all the bridging treatments should be performed in patients
with preserved liver function or with a mild decompensation, such as Child-Pugh A,
B 7–8, low MELD (model for end-stage liver disease) score, no or slight portal
hypertension. This is due to the liver toxicity associated with each treatment, which
can induce liver decompensation and the need for an urgent LT.
19.2 Radiofrequency Ablation
RFA is now the first-line technique for ablation [17]. The goal of RFA is to induce,
through an electrode introduced inside the HCC, an increase of the temperature up to
50–60 °C for a period of 4–6 min that causes irreversible cellular damage. Nowadays,
RFA is considered an effective treatment for patients with an HCC <3 cm in size
[18–21]. This treatment has also been validated as a bridge for patients on the waiting
list for LT. Different studies have demonstrated that RFA may reduce the drop-out
rate of HCC patients on the waiting list for liver transplantation up to 25% [22, 23].
The results of RFA are strongly influenced by tumor location (central vs. periph-
eral, distance from the gallbladder, main bile ducts, bowel loops), patient’s body
habitus (lean vs. overweight) and presence of portal hypertension [24, 25]. Nodules
that are neither subcapsular nor close to the main biliary structures are the ideal
target for RFA, especially if less than 2 cm in size. In such cases the complete
response rate approaches 97% and the 5-year survival rates are 65–68% [26]. In a
large study on RFA of very early and early HCC, based on a 10-year consecutive
case series, complete tumor ablation was achieved in 99.4% of treatments per-
formed for the 1170 primary HCC patients. With a median follow-up of 38.2 months,
5- and 10-year survival rates were 60% and 27%, respectively. Multivariate analysis
demonstrated that age, HCV infection, Child-Pugh class, tumor size, tumor number,
serum des-gamma-carboxy prothrombin level, and serum leptin-reactive alpha-
fetoprotein level were significantly related to survival. The 5- and 10-year local
tumor progression rates were both 3.2% (95% confidence intervals 2.1–4.3%) [27].
In a recent study on RFA as a bridge to LT the intention-to-treat analysis showed
that the 5- and 10-year OS rates were 63.5% and 41.2%, and recurrence-free sur-
vival rates were 60.8% and 37.7%, respectively [23].
19 Other “Bridge” Therapies for Liver Transplantation: RFA, TACE, and TARE 185
The main limitations of RFA relate to the tumor characteristics. More than 90%
of the patients treated with RFA have 1–2 HCC [23, 27], as multiple HCC >2 are not
usually considered good candidates for RFA, and a tumor size >3 cm is known to
increase the failure rate [18, 19]. Moreover, tumor location within the liver paren-
chyma also influences the decision to perform RFA. Subcapsular or partially exo-
phytic HCC are not considered for RFA due to the risk of tumor rupture or seeding.
On the other hand, deeply located tumors should be far from both vascular and bili-
ary structures: in the first case, to avoid the blood flow-related cooling effect that
would reduce the efficacy of RFA; in the second case, to avoid biliary injury (i.e.,
necrosis and subsequent stenosis) due to the high temperature generated by
RFA. The presence of mild ascites represents another contraindication for RFA for
two reasons. Ascites is a sign of portal hypertension and partial liver dysfunction
that can worsen after RFA; moreover, from the technical point of view, the presence
of ascites can contribute to postoperative bleeding at the site of puncture since the
liver is no longer compressed toward the abdominal wall and the diaphragm.
Other two main issues in the setting of RFA are the visualization of the HCC at
the time of treatment under ultrasound (US) guidance and the evaluation of the
treated nodule.
Patients with increased body mass index and deep nodule are known to be at high
risk of missing the nodule due to the difficult visualization of the HCC [24, 27].
Nowadays, real-time fusion of US and whichever imaging modality—computed
tomography (CT), magnetic resonance imaging (MRI), or positron-emission
tomography-CT (PET-CT)—best depicts the single target lesion and makes it pos-
sible to reach and precisely ablate almost any target anywhere in the liver while
performing US [28, 29].
Evaluation of tumor necrosis with conventional US is not reliable, but the routine
use of US contrast agents (microbubbles) immediately at the end of the procedure
allows assessment of the amount and location of necrosis achieved and, if needed,
can guide retreatments of partially ablated tumors in the same interventional session
[30, 31]. In addition, specific software enabling one to spatially co-register and
overlap pre- and postablation CT or MRI scans is currently being introduced in
clinical practice, to allow extremely precise assessment of the volumes of necrosis
compared to the original tumors as well as of the thickness and regularity of ablative
margins in 3D [32].
19.3 Transarterial Chemoembolization
TACE is nowadays considered the standard of care for patients with an intermediate
HCC (class B) according the Barcelona Clinic Liver Cancer (BCLC) staging system
[33]. The efficacy of this procedure is supported by robust evidence [34, 35]. TACE
relies on the arterial supply of the HCC, which is predominant. The goal of the pro-
cedure is to deliver a cytotoxic chemotherapy agent (i.e., doxorubicin) through the
hepatic artery to the HCC nodule(s). The treatment can be delivered to the liver in
different fashion (whole liver, lobar, selective, superselective) in order to better
distribute the drug and reduce the rate of liver decompensation. TACE is the most
commonly used bridging treatment for patients on the LT waiting list, with a low
major complication rate [36, 37]. Tumor necrosis after selective/superselective
TACE can be up to 90%. In terms of tumor size, TACE is more effective in HCC
<5 cm in size [37]. Complete or partial response of the HCC positively impact the
OS rate [38]. The drop-out rate in patients on the LT waiting-list undergoing TACE
is estimated at 5–20% [39]. The use of TACE as a bridge before LT does not impact
adversely the morbidity and mortality post-LT [40].
In terms of cytotoxic agents used during TACE, doxorubicin remains the drug of
choice, although in a recent comparative study from Liu et al. the use mitomycin C
and gemcitabine combined with doxorubicin seemed to improve survival and tumor
response [41]. Moreover, in recent years doxorubicin-loaded drug-eluting beads
TACE (DEB-TACE) have been proposed as a novel drug delivery embolization sys-
tem. DEB-TACE is able to deliver higher doses of the chemotherapeutic agent to the
tumor, to prolong the contact time of the drug with neoplastic cells and to reduce its
systemic release.
Different studies have compared conventional TACE to DEB-TACE. In terms of
adverse events, hospital stay, post-TACE syndrome and liver toxicity, DEB-TACE
seems to have better results than conventional TACE [42, 43], while results are dis-
cordant as regards the long-term outcomes [43–45].
The main drawback of TACE is the risk of liver decompensation after the proce-
dure. Patients undergoing TACE have normally multifocal-bilobar HCC with pre-
served or mildly compromised liver function (Child-Pugh A-B7). In order to
minimize the risk of liver decompensation, single whole-liver treatments have been
progressively abandoned in favor of multiple selective/superselective TACE [37].
19.4 Transarterial Radioembolization
TARE is one of the most recent LRTs for liver tumors (primary and metastatic). The
goal is to selectively target a very high radiation dose of yttrium-90 (90Y) to all
tumors within the liver, regardless of their cell of origin or location, while maintain-
ing a low radiation dose to the normal liver tissue. As with TACE, 90Y—contained
within beta-emitting microspheres—is infused through the hepatic artery to the
liver tumors. The procedure is carried out in two different phases. The first one is a
diagnostic phase where all the extrahepatic vessels are occluded in order to avoid
90
Y diffusion in the gut and technetium-99 m macroaggregated albumin (99mTc-
MAA) is injected to evaluate lung shunting, which is one of the contraindications to
TARE if the dose to the lung is >30 Gy. In the second phase, which is performed
1–4 weeks later, the 90Y microspheres are injected. If compared to TACE, TARE
reduces the effect of embolization since the microspheres occlude only the distal
small vessels reducing the toxic effect on normal liver. Like TACE, TARE is indi-
cated in patients with single or multiple HCC with preserved or mildly compro-
mised liver function (Child-Pugh A-B7).
A multicentric European study showed the safety and feasibility of the procedure
with robust evidence of a survival benefit among all the BCLC stages. Interestingly,
patients with a portal branch macrovascular invasion treated with TARE had a sur-
vival comparable to the other patients [46]. For this reason, in the early period,
TARE was widely adopted in patients with advanced BCLC stages as an alternative
to sorafenib [47]. After having shown a better efficacy than TACE in downstaging
HCC to LT [48], TARE has progressively been used in BCLC-B patients, showing
to be an effective strategy in bridging patients to LT [49] and achieving a longer
time-to-progression and a reduced drop-out from the LT waiting list when com-
pared to TACE [50].
Moreover, in terms of safety, TARE has shown to have a reduced rate of adverse
events if compared to TACE [51]. In a phase II randomized clinical trial comparing
TARE and TACE, radioembolization had a better overall response rate than TACE
with a reduced number of procedures and the same quality of life [52]. Radiological
response to TARE positively impacts long-term survival [53]. In all patients treated
with a bridging intent TARE proved to be an efficient LRT, with an effective bridg-
ing rate at pathological examination of 66%, and no cases of microvascular invasion
on the specimen [49].
19.5 Discussion
The introduction of the Milan Criteria in 1996 followed by MELD prioritization of

HCC recipients has increased LT for HCC sixfold over the last decade [54].
However, there is an increasing recognition that MELD prioritization of HCC recip-
ients needs to be revised to take into account the variable rates of tumor progression,
waiting list drop-out, and post-LT recurrence [55]. Pretransplant LRTs including
transarterial modalities (TACE and TARE) and RFA have been widely adopted by
transplant programs to bridge HCC recipients to LT. LRT mediates its effect by
achieving pathologic tumor necrosis and potentially improves post-LT outcomes.
Reported rates of complete pathologic response vary from 27% to 75% according to
the procedure [37, 55–59], while HCC recurrence is estimated at 10–15% after LT
[60–62].
Pathologic response strongly impacts OS and disease-free survival (DFS).
Complete pathologic response, if achieved, can reduce the risk of recurrence up to
2% with better 5-year OS and DFS [62, 63]. In terms of treatments, best responses
are achieved in patients with fewer pre-LT procedures (≤2) [61, 62], probably as a
result of the fact that patients requiring multiple treatments have persistent or de
novo lesions that indicate aggressive tumor biology. The combination of transarte-
rial and percutaneous treatments has been proposed to increase the complete
response rate [61, 64], but this concept has been refuted by a larger multicentric
study [62]. Surprisingly, in a recent review and metanalysis, LRTs were associated
with a non-significant trend toward improved waiting list and post-LT outcomes,
even though the evidence level seems to be low.
If compared, TACE and RFA seem to have similar outcomes in terms of effi-
cacy and tumor control [37, 55–59]; however, there are different selection biases
due to tumor heterogeneity (i.e., single vs. multiple) in all retrospective series.
TARE has increasingly been used in recent years in the setting of pre-LT proce-
dures for the treatment of BCLC B. The procedure is well tolerated and different
studies with heterogeneous populations suggest it may provide survival rates
similar to TACE [46, 50] with improved tumor control [50]. However, random-
ized controlled trials are needed to definitely consolidate its role in the treatment
of HCC.
Bridging treatments are a heterogeneous scenario in the setting of HCC, and
LRTs must be tailored to the patient, the tumor characteristics and organ availability
to improve HCC control and maximize long-term outcomes.
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Interplay Between General Surgery
and Liver Transplantation 20
Alfonso W. Avolio, Marco M. Pascale, and Salvatore Agnes
20.1 Introduction
Transplantation is the natural extension of general surgery and could not exist with-
out the realization of the intuitions of general surgeons throughout centuries of
medical history. The prehistory of transplantation dates back to the third century, as
stated by the imaginative paintings in which Sts. Cosmas and Damian are trans-
planting a leg harvested from a deceased black slave donor; however, the complete
realization of the transplantation idea only occurred in 1954, when surgical knowl-
edge reached a higher level of awareness, allowing the first kidney transplant [1].
The solution to surgical problems was achieved before full knowledge of the mech-
anisms playing a role in the immune response. This dynamic process became clearer
almost 10 years later when the first liver transplant was performed [2]. General
surgery has inherited from transplantation not only the technical solutions, but also
the capability to cope with various organ failures (liver, kidney, lung) which may
occur even in the same patient. Early dysfunction of the graft, technical complica-
tions, drug toxicity often coexist in several challenging scenarios. The history of
transplantation shows that complexity may be solved by adopting a multiperspec-
tive approach. Today, the problems observed in the postoperative course of the criti-
cal surgical patient can successfully be faced and solved using a transplant-aligned
approach.
A. W. Avolio (*) · S. Agnes

Catholic University of the Sacred Heart, Rome, Italy
Division of General Surgery and Liver Transplantation, Department of Surgical Sciences,
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
e-mail: alfonso.avolio@unicatt.it; salvatore.agnes@unicatt.it
M. M. Pascale
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
e-mail: marcomaria.pascale01@icatt.it

194 A. W. Avolio et al.
20.2 Liver Transplantation and General Surgery
The first generation of transplant surgeons were general surgeons who transferred
all their experience to this new field, giving birth to many practical techniques still
used today. The surgical technique of liver transplantation is the result of major
innovations introduced by a few liver surgeons who performed extensive liver resec-
tions and liver transplantation, perfecting them at the same time [3]. For this reason,
other surgical specialties, including vascular surgery and gastrointestinal surgery
developed together, valorizing common progress, each in its own field [4].
Collaboration among surgeons during the development of the different surgical spe-
cialties favored the growth of technical knowledge [5].
It is not by chance that transplant surgery grew alongside vascular surgery, which
contributed with its techniques for vascular anastomosis, and digestive surgery, with
its techniques for managing small bowel reconstruction in cases of bilioenteric
anastomoses. On the other hand, transplant surgeons have contributed to the devel-
opment of general surgery in many respects. Thanks to their unique skills, they typi-
cally master complex situations when operating on patients with gastrointestinal,
vascular or retroperitoneal disorders, achieving oncological proficiency. Moreover,
the precarious conditions of transplant patients allow testing of the different surgical
strategies for the most common intraoperative and postoperative complications,
such as bleeding, venous congestion, ileus or infections, all contributing to the
development of the best protocols to be used in other surgical settings, and espe-
cially in emergencies.
The interplay between general surgery and liver transplantation is also justified
by the need to classify diseases across different points of view (scientific, economic,
and administrative). Today, the interplay remains at the basis of each multidisci-
plinary management that aims at taking complete care of the patient.
20.3 E
mergency and Elective Surgery in Patients
Awaiting Liver Transplantation
Patients with end-stage liver disease represent complex cases, just as they did before
their inclusion on the waiting list. It is universally recognized that cirrhotic patients
undergoing non-hepatic surgery have an increased postoperative risk, with overall
mortality rates as high as 45% [6]. This estimated high risk often induces to avoid
surgery for this particular group of patients unless absolutely necessary. Avoiding
elective surgery for patients with cirrhosis, however, can result in a high rate of
emergency surgery, which is associated with higher morbidity and mortality and
longer postoperative hospitalization for this group of frail patients [7, 8].
In the emergency surgery area, several considerations should be made. Cirrhotic
patients undergo emergency surgery more often than patients without cirrhosis. About
10% of all cirrhotic patients require surgery, both elective and emergency in the last
few years of their life [9]. The estimated risk varies greatly, depending on the severity
of the cirrhosis, according to cardiovascular, portal, renal, coagulative, and immune
20 Interplay Between General Surgery and Liver Transplantation 195
complications as well as to the type of surgical procedure [9, 10]. The cirrhotic patient,
already operated on in an emergency condition due to the procrastination of an elec-
tive indication or to the late presentation of a pre-existing disease, shows high rates of
morbidity and mortality [11]. Emergency colorectal surgery is one of these cases, with
a high mortality rate of 21% for cirrhotic patients and 36% for those patients with cir-
rhosis and portal hypertension. Also, umbilical hernia repair in an emergency setting
is associated with higher complication rates compared to elective repair in cirrhotic
patients [12]. Moreover, high risks are reported for patients with Child-Pugh B/C cir-
rhosis undergoing trauma surgery, particularly those with abdominal or vascular inju-
ries, so that it is recommended that all cirrhotic trauma patients undergoing laparotomy
should be admitted to the ICU irrespective of the severity of their injuries. For thoracic
surgical procedures, it is demonstrated that patients with Child-Pugh A cirrhosis toler-
ate cardiac operations rather well, but for patients with Child-Pugh B/C cirrhosis, this
practice should be considered unsafe [11].
Regarding elective surgery, the most common conditions are cholelithiasis and
abdominal hernia [12]. The incidence of gall stones and hernia is higher in the cir-
rhotic than in the non-cirrhotic population. Gallstones are present in one-third of
patients with cirrhosis because of the increased secretion of unconjugated bilirubin,
hydrolysis of conjugated bilirubin in the bile, reduced secretion of bile acids and the
presence of phospholipids in bile [13]. Gallbladder hypomotility also contributes to
lithogenesis [13]. Abdominal hernia, instead, may be favored by the increased intra-
abdominal pressure due to ascites [12]. Cholecystectomy and hernia repair are the
most frequently described surgical procedures in cirrhosis [14, 15]. The laparo-
scopic approach allows lower morbidity rates, fewer bleeding complications, shorter
operating times and reduced hospital stay. Moreover, it reduces morbidities such as
surgical site infection and hemorrhage [15, 16]. A high degree of portal hyperten-
sion represents a relative contraindication to all surgical procedures. Portal hyper-
tension can be successfully managed by endoscopic ligatures of varices and by
transjugular intrahepatic placement of a portal systemic shunt (TIPS); however, if
TIPS placement is technically not feasible, shunt surgery remains the best available
choice. The surgical approach should only be reserved for Child-Pugh A/B patients;
however, shunt surgery still shows better results in terms of reduced recurrence of
hemorrhage and fewer occlusive complications [6]. If possible, a partial shunting of
the portal flow is recommended to minimize the risk of severe encephalopathy.
20.4 Emergency Surgery in Liver Transplant Patients
Fever, diarrhea and abdominal pain are relatively common in liver transplant recipi-
ents, leading to admission to the emergency department. However, because of a
complex underlying condition, these disorders may be related to real problems or to
the side effects of the immunosuppressive treatment [16, 17]. When specialized
teams are not reachable, these patients may be managed by a group of non-trans-
plant physicians, with a high risk of misdiagnosis, delayed treatment and, in the
case of surgical abdominal conditions, poor outcomes.
Epidemiologic data suggests that transplant recipients present a greater rate of

common acute complications than non-transplant patients (Table 20.1) [18–23].
In particular, the most frequent conditions observed are bowel obstruction, acute
appendicitis, diverticulitis, acute pancreatitis, peptic ulcer, and ischemic colitis.
All these conditions may lead to acute peritonitis. The most frequent disorder
among these is the bowel obstruction, which should be considered in the early
postoperative period. The etiology of obstruction includes adhesions, abdominal
wall hernias, and internal herniation. In abdominal wall hernia (umbilical, ingui-
nal, and incisional), clinical evaluation is mandatory for diagnosis while, for
internal hernias and adhesions, imaging may play a key role in the diagnosis. As
for non-transplanted patients, surgery is necessary in cases of acute bowel isch-
emia. Delayed surgical management could be advocated in cases of uncompli-
cated abdominal wall hernias. Today, the laparoscopic approach is considered a
safe and feasible alternative to the open approach, showing better outcomes
expressed in shorter hospital stay, lower recurrence rate, and lower complication
rate [14–16]. A small and intermittent hernia that spontaneously regresses at the
beginning may gradually involve longer herniated segments of small bowel, and
those may twist, become obstructed and/or ischemic. Surgical management is
mandatory, and at the time of surgery for internal hernia, most patients present
with small bowel volvulus, and bowel ischemia. Moreover, post-transplant lym-
phoproliferative disease (PTLD) is a rare cause of small bowel obstruction but,
specifically in transplant recipients, it should be mentioned. PTLD should be con-
sidered in patients that fail to respond to medical therapy and/or have an unclear
diagnosis of the obstruction.
Regarding acute diverticulitis after liver transplantation, the incidence is increas-
ing in Western populations. Most patients have an uncomplicated disease while per-
foration is uncommon but associated with high mortality rates [24]. These patients
require urgent surgery, and morbidity and mortality are significantly worse than for
immunocompetent patients, especially when acute episodes occur in the immediate
post-transplantation period. In elective resections, the postoperative outcome after
an elective procedure was no different from that in immunocompetent patients. The
severity of sigmoid diverticulitis among transplant recipients has prompted consid-
eration of pre-transplant prophylactic surgery for patients with sigmoid diverticulo-
sis proven by colonoscopy, but this is a feasible approach only for kidney transplant
candidates, as patients awaiting heart, lung, or liver transplant are generally too sick
to tolerate any major surgical procedures.
Acute appendicitis after transplantation has been reported to have a very low
incidence (2%) [23, 25]. However, there was a high percentage of misdiagnosis with
a markedly high incidence of complicated appendicitis. Clinical presentation is
similar to non-immunocompromised patients, while laboratory findings show
mostly white blood cells <10 × 109/L. Emergency surgical management is usually
the treatment of choice, with a preference for the minimally invasive qualities of the
laparoscopic approach. Acute pancreatitis is rare (the incidence ranges from 3% to
8%) but more aggressive in liver transplant recipients [26]. The etiology can be dif-
ferent from the common population: manipulation and injury to the peripancreatic
Table 20.1 General surgery in liver transplant patients
Number Number
of Number of of
Authors patients transplants Follow-up Complications Treatments Outcomes citations
Merhav 155 89 (in 57 5 years Arterovenous occlusion; Elective surgery (60%); 21% permanent damage to 3
et al. [18] patients) nephrectomy; duodenal emergency surgery (40%) the transplanted organ
perforation; cholecystectomy;
femorofemoral bypass; bowel
occlusion
Catena et al. 1611 46 2 years Gastrointestinal perforation in Not reported 24% died as direct result of 15
[19] kidney transplantation gastrointestinal perforation
Reshef et al. 5329 51 9 years Diverticulitis Emergency surgery Morbidity and mortality 22
[20] (Hartmann) 28; worse in emergency surgery
sigmoidectomy + ileostomy 8;
ileostomy 1; elective surgery
(sigmoidectomy + ileostomy)
9; sigmodectomy 5
Cruz et al. 5677 36 8 years gastrointestinal; post- Surgical 16; non-surgical 20 High early mortality 12
[21] transplant lymphoproliferative
disease
20 Interplay Between General Surgery and Liver Transplantation
Fikatas et al. 810 77 21 months Incisional hernia Surgical Risk factors similar to 13
[22] patients without
immunosuppression
Sommacale 1211 183 (in 161 1 year Incisional hernia; digestive Surgical Surgical procedures on 1
et al. [23] patients) surgery; HPB transplanted patients have a
significantly high risk of
complications
197
tissue (especially in the case of aortohepatic interposition grafts); virus infections

(CMV, HSV, HBV); iatrogenic (endoscopic retrograde cholangiography for the
treatment of biliary leaks post liver transplant). The prognosis of early pancreatitis
is poor, with high mortality rates (38–63%), whereas late pancreatitis seems to have
better outcomes with mortality rates of 11% [26]. Emergency surgical management
is not required as conservative management was successful in 58–65% of cases.
Only 34–42% of liver transplant recipients require a surgical procedure and 22–25%
of patients developing pseudocysts. In conclusion, abdominal surgery in liver trans-
plant candidates is not a limiting factor for transplantation [27].
20.5 Incisional Hernia in Liver Transplant Patients
In the field of elective surgery, the most frequent general surgical transplant-related
complication is incisional hernia, with an incidence between 4% and 20% [28]. In par-
ticular, hernia formation after liver transplantation tends to be as high as 32% [29], with
strong evidence for a bilateral subcostal incision with upper midline extension (Mercedes
incision) being a risk factor [30, 31]. Many studies have reported various predisposing
factors for incisional hernia after abdominal transplant, including advanced age, obesity,
wound infection, pulmonary complications, ascites, steroid use, diabetes, surgical tech-
niques, immunosuppressive agents such as mTOR inhibitors and mycophenolate
mofetil, although with less evidence among studies about the last one [28–32].
The benefit of mesh hernioplasty in transplanted patients is assumed. However, it is
also assumed that transplant patients are potentially more susceptible to incisional and
mesh infections after hernia repairs, especially as a result of post-transplant immuno-
suppression [32]. The risk of hernia recurrence after repair without using a mesh is as
high as 63%, but mesh use has reduced the recurrence rate to approximately half of that
seen with suture repair [33]. Nevertheless, the use of prosthetic mesh for incisional
hernia repair may be associated with serious complications such as small bowel
obstruction, fistula formation and mesh infection in up to 17% of cases [28–32].
The preferred material for prostheses remains polypropylene mesh, which is widely
described in the literature in the treatment of non-infected incisional hernia. On the
other hand, there is an increasing consensus on the use of biological material, such as
porcine dermal collagen, in the treatment of contaminated incisional hernia [31, 33].
20.6 Obesity and Liver Transplantation
Obesity is one of the diseases of the future, a true pandemic that continues unabated
and is accompanied by a plethora of chronic conditions. Non-alcoholic fatty liver
disease (NAFLD), represents a spectrum of conditions, of which one of the more
severe subsets is non-alcoholic steatohepatitis (NASH), which may progress to cir-
rhosis and lead to the development of hepatocellular carcinoma.
With increasing recognition of efficacy in treating obesity and obesity-related dis-
eases, bariatric surgery has been increasingly performed worldwide. However, the
right timing between bariatric surgery and liver transplant remains an object of debate.
Liver transplantation in the obese patient presents some elements of complexity [34].
Hepatectomy is more complex due to the deeper position of the liver and particularly
of the vena cava. Furthermore, the vena cava anastomosis is also challenging because
of its depth and the restricted space available between the liver and diaphragm. In
addition, postoperative care in the obese patient may be more complicated due to the
longer ventilation period necessary. Although morbidity in the obese non-diabetic
patient is higher than in the non-obese one, the mortality rate is not significantly
affected [34, 35]. It could be logical to reduce weight in transplant candidates, but this
approach determines limitations in operating on cirrhotic patients [36].
In the literature, studies are beginning to appear concerning the relationships
between bariatric surgery and organ transplantation [37, 38]. Only few data from
small series on the effects of bariatric surgery in the setting of liver transplantation
are available. Two major approaches have been proposed. They include gastric
bypass and sleeve gastrectomy. Both of them can theoretically be performed before,
during or after liver transplantation. However, substantial effects on graft function
and post-transplant survival have not been reported so far. Most surgeons prefer
sleeve gastrectomy to gastric bypass because of shorter operative time, lower techni-
cal complexity and the preservation of access to the biliary tree, together with unclear
effects of gastric bypass on the absorption of immunosuppressants. As regards tim-
ing, any surgical procedure under general anesthesia, except liver transplantation
itself, has a considerable risk of death in patients with decompensated cirrhosis.
Consequently, advanced liver diseases with the presence of portal hypertension are
usually considered contraindications for any elective surgery [37]. Therefore, any
bariatric surgery has to be carefully balanced against its risks in cirrhotic patients.
The few reports of concomitant bariatric surgery at the time of transplantation show
high rates of complications and significant risks of initial poor organ function, so that
a combined procedure cannot be routinely recommended. After successful liver
transplantation, obese recipients have a high potential to further gain weight.
International experience with bariatric surgery after liver transplantation shows good
weight control and lower rate of side effects when performing of sleeve gastrectomy.
First, gastric bypass excludes the feasibility of an easy retrograde access to the bili-
ary system in some patients. Further, the extent of dissection after liver transplanta-
tion determines, in gastric bypass, a higher surgical risk for the transplanted patient
compared to a sleeve gastrectomy, which, however, does not seem to translate in
higher complication rates. Finally, transplanted patients treated with gastric bypass
could present changes in the kinetics of the enteral absorption of immunosuppressive
drugs, even if no relevant effects on the immunosuppressive levels in the blood have
been reported [38].
20.7 Neoplasms in Liver Transplant Patients
Cancer is a major source of morbidity and mortality following solid organ transplan-
tation. Surgical resection of neoplasm remains the main modality for treating liver
transplant patients [18, 21, 23]. In fact, a potential oncologic factor is the continuous
administration of immunosuppressive drugs. In vitro studies suggest that
cyclosporine and tacrolimus may promote carcinogenesis. However, in view of the

higher cancer incidence and poorer prognoses, prevention and screening may play an
important role in reducing the burden of cancer in liver transplant recipients. Routine
cancer screening is recommended for all transplanted individuals. Recommendations
for cancer screening in transplant recipients are mostly extrapolated from general
population, with the exception of cervical, skin, colorectal, and renal cancers, where
a strict surveillance program is advisable. Moreover, surgical resection, radiotherapy
and chemotherapy remain the preferred treatments for most early-stage and locally
invasive tumors among transplanted patients. Although there is a lack of trial-based
evidence, judicious reduction of immunosuppression with regular monitoring of dis-
ease progression and graft function may be warranted, particularly in patients with
advanced disease [39].
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Liver Transplantation as a Challenge
for the Anesthesiologist: Preoperative 21
Cardiac Assessment to Orient
the Perioperative Period
Andrea De Gasperi, Gianni Biancofiore, Ernestina Mazza,

and Pietro Molinari
21.1 Introduction
Liver surgery has made enormous strides in the last 10–15 years. So-called extreme
surgery, impossible only a few years ago, is now possible and poses new challenges
to be faced, managed and solved. New frontiers are opening up for anesthesia and
perioperative medicine, whose main commitment is to keep pace with the innova-
tions to support surgeons’ activity: adapting to and managing the changes intro-
duced by the physiologic repercussions of the new surgical techniques are the next
tasks to be faced by the anesthesiologists as perioperative physicians. In effect, the
pre-, intra- and postoperative aspects of liver surgery are a continuum and have to
be solved as a continuum: liver transplantation (LT) as a whole is perhaps the best
example in advanced liver surgery. According to the United Network for Organ
Sharing (UNOS) [1], LT anesthesia deserves specific competence and relevant skills
for the appropriate management of the pretransplant evaluation, sometimes turbu-
lent intraoperative period and potentially extremely complex postoperative course.
In this chapter we will discuss, among the many perioperative aspects of LT, the
preoperative cardiac assessment, key for the success of an extremely challenging
procedure now performed more and more frequently in elderly candidates. LT is the
best example of a very complex surgery in which multidisciplinary approach and
close cooperation between the surgeon and the anesthesiologist are essential for the
success of the procedure.
A. De Gasperi (*) · E. Mazza · P. Molinari

Division of Anesthesia and Intensive Care 2, Niguarda Hospital, Milan, Italy
e-mail: andrea.degasperi@mpcnet.it; ernestina.mazza@alice.it;
pietro.molinari@ospedaleniguarda.it
G. Biancofiore
Unit of Anesthesia and Critical Care for General, Vascular and Transplantation Surgery,
Pisa University Hospital, Pisa, Italy
e-mail: g.biancofiore@med.unipi.it

204 A. De Gasperi et al.
With more than 1300 LTs performed in 2017 [2], a well-established LT program
is now being run in Italy. The results and outcomes of this extremely demanding
procedure, able to treat or even cure patients with end-stage liver disease (ESLD) or
suffering from acute liver failure (ALF) or acute-on-chronic liver failure (ACLF),
have markedly improved in the last 20 years, with a 1- and 5-year survival rate of
about 87% and 75%, respectively (Italian data 2003–2015) [3]. Transplantation of
the liver—whether whole or split—from living or deceased donors (i.e., donors
after brain death and, since 2015 also in Italy, after cardiac death) is the second most
commonly performed solid organ transplant procedure worldwide and in Italy [2,
4]. Advances in surgical technique, immunosuppression and perioperative care have
contributed to the excellent medium- and long-term results: accordingly, LT indica-
tions are now expanding, as proposed and endorsed by the most recent guidelines of
the American Association for the Study of Liver Diseases (AASLD) and European
Association for the Study of the Liver (EASL) [5–7] and also by the Società Italiana
dei Trapianti d’Organo (SITO) (http://www.societaitalianatrapiantidiorgano.com).
No formal age limit is nowadays suggested in the absence of major contraindica-
tions [5, 6], and the transplant procedure, when appropriately managed as a whole
(or better, as a continuum), may extend life expectancy beyond what the natural
history of the underlying liver disease would predict. As expected, elderly candi-
dates (aged well beyond 65 years old) are now very often proposed for the trans-
plant procedure and in spite of comorbidities, sicker candidates are now accepted
for LT candidacy. Even though not formally a contraindication, older age is associ-
ated with increased comorbidities and in particular with a higher cardiovascular
risk, amplified by manifestations associated with a long-standing cirrhosis (the most
common ESLD in LT candidates) and portal hypertension [4–8]. Unique problems
associated with cardiac, pulmonary, renal and central nervous system conditions
could significantly impact on the entire perioperative course. As assessed by Kang
et al. [9] (and experienced by a large part of LT anesthesiologists), during the LT
procedure the potential candidate has to tolerate minutes (or even hours) of tachy-
cardia, critical hypotension, severe anemia, and acidosis. These conditions can be
even worse than the frequently reported comparison (LT being for the patient akin
to “running a marathon” [10]) and can be tolerated only by patients with a compe-
tent cardiac status (to survive this scenario unscathed). This is why preoperative
evaluation, and particularly cardiac assessment and its functional aspects, are piv-
otal for the entire perioperative period [5, 6, 8, 10–13].
21.2 Preoperative Anesthesiological Consultation
The role of the anesthesiologist in the preoperative evaluation is crucial: an accurate

preoperative assessment is mandatory to stratify the risk of the candidate and to coop-
erate in the multidisciplinary process aiming at the most appropriate allocation of a
limited resource (the graft) to an ever-increasing number of possible recipients [4].
From the anesthesiological point of view, the pretransplant evaluation should rule out
conditions/comorbidities which might render the candidate unable to adapt or respond
21 Liver Transplantation as a Challenge for the Anesthesiologist: Preoperative… 205
to sudden and severe cardiorespiratory and metabolic changes [5, 6, 11, 12]. Among
them are severe hypotension (sometimes associated with acute blood loss), critical
hypoperfusion, extreme anemia, markedly reduced venous return, prolonged and
resistant vasoplegia after graft reperfusion, renal hypoperfusion and acute kidney
injury, or, on the contrary, massive transfusion and acute right or left ventricular over-
load immediately before or after reperfusion [5, 6, 11, 12]. Knowing the risks or the
conditions able to negatively impact on the perioperative course should start a multi-
disciplinary discussion to define actions/strategies able to improve the indexed condi-
tions with appropriate measures (if and when possible), and to predispose, at least
theoretically, a rational intraoperative anesthesia approach. Candidates too sick to be
transplanted are to be recognized and removed from the list to avoid a futile transplan-
tation and the waste of a very limited resource [1, 4–7]: among them are severe car-
diopulmonary dysfunction(s) (scope of the chapter) but also, as an example, multiple
organ dysfunctions whether or not associated with active and uncontrolled bacterial
and fungal infections outside the liver (no antibiotics able to control the infection as is
the case of infections sustained by multidrug-resistant microorganisms). In fact, in the
case of infection within the liver, hepatectomy and transplantation or re-transplanta-
tion should be considered as a form of source control (removal of the diseased liver)
when not associated with multiple organ dysfunction. This cutting-edge item, para-
mount for the outcome of LT candidates, deserves an ample dedicated space, which is
beyond the scope of this chapter.
21.3 Cardiovascular Evaluation
The main tasks of a preoperative cardiac evaluation before LT are:
(a) to identify known or suspected cardiovascular diseases associated with ESLD,

for the proper assessment of the perioperative cardiovascular risk of the candi-
date: cirrhotic cardiomyopathy, coronary artery disease (CAD), valvular heart
disease, portopulmonary hypertension, hepatopulmonary syndrome, patent
foramen ovale are conditions able to negatively impact on the intraoperative
period and early postoperative course [5–13];
(b) to understand whether or not the patient is able to survive an invasive and
demanding surgical procedure as is LT.
Basic cardiac assessment for all LT candidates should include history and physi-
cal examination, presence of clinical major and minor risk factors, estimated func-
tional cardiac reserve (vide infra), electrocardiography (EKG), chest X-ray, and 2D
transthoracic echocardiography (TTE) [6, 10–14].
The rising age and the increased prevalence of metabolic diseases (diabetes and
nonalcoholic steatohepatitis, among them) in LT candidates increase the individual
risk [6, 10–13]. Prediction of the risk or identification of the disease should ideally
start a “rehabilitative” program to optimize cardiac function (prehabilitation) [13].
In a very recent and comprehensive review of cardiac events after LT [8], major
complications (myocardial infarction, heart failure, acute coronary syndrome, pul-

monary embolism) occurred in 10% of the transplanted population within 90 days
after LT. Many of the adverse events were non-coronary in origin and significantly
associated with perioperative atrial fibrillation (not uncommon in ESLD patients)
and stroke. As evident from the literature (surprisingly and in spite of many efforts),
no standardized recommendations for the preoperative cardiac assessment are
available; differences, sometimes significant, might be present between centers
and in published guidelines [6, 7, 11]. In fact, in spite of the relevance of cardiac
complications in the perioperative LT period, no consensus exists on the optimal
preoperative cardiovascular risk stratification. In 2012 an expert consensus docu-
ment from the American College of Cardiology (ACC)/American Heart Association
(AHA) suggested noninvasive testing in LT candidates based on the presence of
multiple CAD risk factors (≥2), regardless of functional status and in spite of the
absence of active cardiac conditions [11]. In 2013, the AASLD and the American
Society of Transplantation recommended noninvasive cardiac testing (either exer-
cise stress testing or pharmacologic stress testing) for all LT candidates [6].
However, even though a general consensus could be found in the stepwise para-
digms of the AHA/ACC guidelines [6, 11–13], both exercise and pharmacological
stress tests have suboptimal predictive values in LT candidates, (but with a very
high negative predictive value, estimated over 90%) [13, 15–18]. According to the
most recent revisions of the problem, stress test (in particular dobutamine stress
echocardiography [DSE]) should be reserved for candidates at high risk for CAD
[15–18]. In line with the recommendations [6, 11], since 2011 at our Center
(Niguarda Hospital, Milan, Italy) we have developed and updated a stepwise flow-
chart [14] (Fig. 21.1; Tables 21.1 and 21.2) for general cardiac risk stratification:
the aim is the identification and management of CAD in high risk LT candidates
(see below). It has to be anticipated that alternative diagnostic techniques are now
available: among them are cardiac computed tomography (CT), stress cardiac
magnetic resonance imaging (MRI) or positron-emission tomography (PET), the
two latter quoted in the literature, but so far with very few specific studies [19–22].
Whether the new technologies have a much better yield than DSE or perfusion
imaging is still hotly debated among the experts.
To summarize, the goals of risk stratification are:
1. To identify patients at extremely high risk in whom transplant surgery should be

cancelled.
2. To identify patients in whom the optimization of medical therapy or (in the case
of CAD) a coronary revascularization before transplant surgery might reduce the
risk of the surgical procedure.
3. To identify patients in whom ad hoc invasive and intensive monitoring might
reduce the risk of perioperative events.
4. To assess the long-term risk of a future cardiac event. The available literature
data show that clinical stratification models in patients undergoing LT have a
relatively low prognostic power. Noninvasive testing (both functional and perfu-
sion imaging) has been proved to be effective in risk stratification: however,
Potential candidate
for liver transplantation
Risk factor assessment CAD risk factors

• Clinical history, physical see Table 21.1
examination, functional
cardiac reserve estimation
• METs or DASI score
• CPET or 6MWT 1 major ≥2 minor
EKG risk factor risk factors
• Prolonged QTc
• Atrial fibrillation
Stress test Cardiac CT
Chest X-ray Positive • Echocardiography • CCTA
2D TEE • MPS • Calcium score
see Table 21.2
Valvular Negative Negative Positive

heart disease
Expert opinion CA + Expert opinion

Liver
for possible for possible
transplantation
liver transplantation liver transplantation
Fig. 21.1 Stepwise flow chart for the cardiovascular assessment of orthotopic liver transplanta-
tion candidates. METs metabolic equivalent of tasks, DASI Duke Activity Status Index, CPET
cardiopulmonary exercise test, 6MWT six-minute walk test, EKG electrocardiography, 2D TTE
two-dimensional transthoracic echocardiography, CAD coronary artery disease, MPS myocardial
perfusion scan, CT computed tomography, CCTA coronary computed tomography angiography,
CA coronary angiography
there are no prospective randomized trials addressing this clinical issue. Recently,
stress echocardiography has been shown to be a reliable tool in this setting, but
only when patients at high clinical risk were tested.
21.3.1 Cirrhotic Cardiomyopathy
Cirrhotic cardiomyopathy describes the well-known pathological changes associ-

ated with ESLD: low arterial blood pressure, high cardiac output and decreased
systemic vascular resistances (the latter considered to be the reason for the hypoten-
sion and the reduced response to vasopressors). Relevant features are prolonged
QTc interval on EKG (>440 ms), stress-induced systolic dysfunction, diastolic dys-
function, atrial enlargement, ventricular hypertrophy (best evaluated using TTE, see
also [23]), chronotropic dysfunction (less common), altered cardiac biomarkers
Table 21.1 Coronary artery disease (CAD) major and minor risk factors
CAD major risk factors
• Diabetes mellitus
• Age > 60 years
• Severe peripheral vasculopathy
• Cerebrovascular pathology (stroke/TIA)
• Kidney failure
– s-Creatinine >2 mg/dL
– Creatinine clearance <30 mL/min
– Hemodialysis
• Ischemic EKG changes
• NASH
• Previous CAD (coronary angiography evaluation)
CAD minor risk factors
• Arterial hypertension
• EKG alterations
– LVH with ST changes
– LBBB
• Obesity, dyslipidemia (LDL cholesterol >180 mg/dL)
• Smoke (>15 cigarettes/day)
• Cardiac hypertrophy
• Prolonged drug abuse (>2 years)
• Familiarity with CAD (family history of ischemic heart disease in first degree relatives)
TIA transient ischemic attack, EKG electrocardiography, NASH non-alcoholic steatohepatitis, LVH
left ventricular hypertrophy, LBBB left bundle branch block, LDL low-density lipoprotein
Table 21.2 Two-dimensional transthoracic echocardiographic (2D TTE) evaluation

• Morphology
• Valvular heart disease and severity
– mild
– moderate
– severe
• Atrial dilatation
• Left ventricular ejection fraction (LVEF)
– contraindication with resting LVEF <50%
• Diastolic (dys)function
– E/A ratio < 1
• Right ventricular size and function supported by TAPSE
• Pulmonary artery systolic pressure (PASP) (indirect estimation)
– right heart catheterization mandatory if estimated PASP >45 mmHg, to rule out PoPH
• Left ventricular outflow tract (LVOT) occlusion
• Intracardiac R-L shunts (bubbling test)
TAPSE tricuspidal annular planar systolic excursion, PoPH portopulmonary hypertension
(troponin I and brain natriuretic peptide [BNP]). Autonomic dysfunction has also
been described [12]. Impaired diastolic function (diastolic dysfunction [DD]) can
be detected using left ventricular inflow velocities (E/A ratio) and tissue Doppler
(E/E0 ratio, velocity of myocardial displacement) [13, 21]. Reported in close to
15% of the candidates, DD is graded as mild, moderate and severe [21]: pretrans-
plant moderate and severe DD were recently associated with a risk of rejection,
graft failure and mortality, further stressing the relevance of preoperative echocar-
diography in the pretransplant cardiac evaluation [21]. From a functional point of
view, in cases of moderate or severe DD, an impaired aerobic capacity, unveiled by
cardiopulmonary tests, could help to identify candidates at further increased risk for
poor post-transplant outcomes [13]. According to VanWagener et al. [13], while left
ventricular ejection fraction (LVEF) <50% constitutes a relative contraindication,
figures <40% are to be considered an absolute contraindication.
21.3.2 Coronary Artery Disease
With increased age (over 50 years old, according to the EASL and AASLD guide-
lines) [5–7] the prevalence of CAD is raising among LT candidates: below 5% in
Italy (2–4%) [14, 24], it is higher (7–25%) in the rest of Europe and USA [6,
10–13]. CAD is defined as significant when at least one coronary artery stenosis
is ≥50%, while is considered critical when a coronary artery stenosis is ≥70%
(with the indication of correction). Older candidates might have increased cardio-
vascular risk factors (heavy smoking, diabetes, arterial hypertension, chronic
renal failure, metabolic syndrome in its various presentations, including nonalco-
holic steatohepatitis) [22], all able to negatively impact on the course of the early
perioperative period. Postoperative outcomes after adequate treatment before LT
(including coronary artery stenting when appropriate) are comparable to non-
CAD patients [13]. Silent CAD should be ruled out during the preoperative
assessment to avoid major perioperative cardiovascular complications and critical
coronary artery stenosis are to be treated before LT. Management options to treat
CAD include medical treatment, percutaneous transluminal coronary angioplasty
(PCTA), coronary artery stenting with appropriate double antiplatelet therapy
(1–3 months vs. 6–9 months) [13]. Dual antiplatelet therapy (DAPT), the combi-
nation of aspirin and an oral inhibitor of the platelet P2Y12 receptor for adenos-
ine, remains a highly effective therapy to prevent coronary artery stent thrombosis
in the period at major thrombotic risk after stent implantation. Irrespective of the
type of the implanted stent (bare metal stent [BMS] now less and less used, poly-
mer-free drug coated stents [PF-DCS], and newer generation drug-eluting stents
[DES]), a minimum of 1 month of DAPT should be considered when surgery can-
not be postponed for longer [13, 25]. This is particularly true if aspirin can be
maintained in the perioperative period. Coronary artery stenting allows candi-
dates, otherwise rejected, to be considered for LT and transplanted with extremely
positive results. If PCTA is not indicated, the possible options are pre-LT coronary
artery bypass surgery (CABG), feasible in Child-Pugh A patients with good out-
come (one-year survival rate of 80%) and simultaneous CABG and LT. The com-
bined procedure of CABG and LT has been scarcely reported in the literature and
should be reserved for Child-Pugh B or C patients: in a case series of ESLD
patients with severe triple-vessel disease, at 25 months of follow-up, graft and
patient survival was 80% (one death due to hepatitis C recurrence [26–29]). One
case (severe triple-vessel disease in a MELD 30 candidate) was recently
performed at our center with very good results (5-month follow-up at the time of
writing). By contrast, the single CABG procedure in Child-Pugh B and C candi-
dates has a survival rate of 45% and 16%, respectively [26–29].
21.3.3 CAD Screening
As mentioned above, no consensus exists on the best approach to stratify cardiovas-

cular risk and, in particular, to screen CAD in ESLD patients [6, 12, 13, 15–17, 19,
30–33]. After EKG and basal TTE, mandatory in every candidate [13], the cardio-
vascular evaluation prior to LT in candidates at “high risk” for CAD (still great
uncertainty exists on the definition of “high risk”) [15–17, 19], should include, even
in asymptomatic patients, exercise or pharmacological stress tests, coronary CT
angiography (CCTA), noninvasive imaging alternative to stress tests, and coronary
angiography (CA), the invasive gold standard to rule out significant CAD in case of
doubts [19]. Recently, stress cardiac MRI has been reported as deserving interest in
a small series of LT candidates [20]. Very controversial evidence is present even in
the most recent literature on the best screening test (stress test or imaging or a com-
bination of stress and imaging) [15–20], and its utility in predicting postoperative
outcomes [13, 29, 34]. Interestingly, the choice of noninvasive stress imaging is left
to the local expertise by the AHA/ACC guidelines [6]. In the presence of regional
wall motion abnormalities at TTE, in cases of reduced contractility (ejection frac-
tion <50%) or in the presence of one major or ≥2 minor cardiovascular risk factors
(Fig. 21.1; Tables 21.1 and 21.2) further tests are required to rule out silent
CAD. Among them are [6, 11, 13, 19, 31–33]:
• Exercise stress tests: stress EKG or stress echocardiography;

• Pharmacological stress tests: usually myocardial perfusion scanning (MPS),
stress myocardial perfusion imaging, or DSE;
• Noninvasive imaging: CCTA and calcium score, stress cardiac MRI or PET;
• Invasive imaging: CA (still the gold standard).
Exercise stress testing has poor predictive value due to the (not infrequent) limited
ability of the LT candidates to reach the target heart rate. The pharmacologic stress
test might be problematic owing to low sensitivity and a negative predictive value
<80% even in the presence of critical obstruction (when documented afterwards with
CA) [5, 6, 10–13, 15–19, 34, 35]. On the contrary, Safadi et al. [30] using DSE were
able to document a very high negative predictive value (>90%) in cases of normal
tests in liver-transplanted patients, ruling out significant stenosis when the test was
normal. According to the current guidelines [6, 11], in cases of a positive stress test
(reversible defect), CA is mandatory (Fig. 21.1): the incidence of false positive tests
ranges between 5% and 15% (6% in our unpublished series) [14]. Single-photon
emission CT (SPECT) or MPS, when used, are able to identify patients at very low
risk [19]. According to Hachamovich et al. [31], the rate of major cardiac adverse
events with normal perfusion should be 1% over 2–3 years: in other words,
noninvasive stress testing or stress imaging, when negative, would be relevant to rule
out CAD (high negative predictive value) [13, 19]: instead, the low rate of positive
yield documented after CA (by definition the presence of critical stenosis) might
demonstrate quite a high rate of false positive results [6, 12, 13, 15–19, 30–35]. Same
concerns (if not negative conclusions) are drawn by Soldera et al. in their very recent
systematic review and meta-analysis on DSE, MPS and CA in LT candidates [34].
Among the newer and more sophisticated noninvasive cardiac imaging modali-
ties is cardiac CT [13, 17, 19, 34]. The two major types of cardiac CT are coronary
artery imaging for the calculation of the calcium score (CACS, Agatston score) and
the CCTA.
CCTA with contrast allows for imaging of the heart chambers, coronary arteries,
and pulmonary vessels in three dimensions and could be considered an alternative,
noninvasive tool to identify atherosclerotic disease in silent CAD. CACS correlates
with the risk of CAD: CACS values are generally classified as absent (0), minimal
(1–10), mild (11–100), moderate (101–400), or extensive (>400). A CACS <10
documents the absence of any (significant) coronary obstructive lesion: the quanti-
fication of coronary artery calcium on CT is correlated with the severity of luminal
narrowing, stenosis severity, and total plaque burden in the arteries secondary to the
atherosclerotic disease [19]. A CACS >400 (extensive) is significantly associated
with the presence of significant (≥50%) or critical (≥70%) coronary artery stenosis
on CA in asymptomatic patients and LT candidates. As very recently assessed by
VanWagner et al. [13], noninvasive CCTA, due to a sensitivity close to 90% and a
negative predictive value close to 95% for excluding significant CAD, may be con-
sidered an acceptable alternative to invasive CA in “low risk” patients with regular
non-tachycardic rhythm, able to lie still and to perform breath-holding maneuvers.
CA has to be performed in patients with coronary artery stenosis ≥50% on CCTA
or in cases of CACS >400 [19]: should it be the case, the incidence of critical CAD
requiring revascularization is high. Major limitations to CCTA in ESLD patients are
nephrotoxicity and the need for relative bradycardia.
According to Reddy et al. [20], cardiac MRI could allow a so-called “one-stop
shop” to evaluate cardiac function, structure, coronary disease and viability while
studying thoracoabdominal vasculature and liver anatomy [18–20]. Even if promis-
ing, results from wide-scale studies are still lacking and gadolinium is not free of
nephrotoxicity [19]. An idea worth to be considered could be Parikh’s proposal
[19]: patients with low baseline heart rate (secondary to autonomic dysfunction or
beta-blockade) could benefit more from cardiac CT or MPS rather than DSE, while
in candidates with concomitant renal dysfunction MPS or DSE may be preferred
over cardiac CT (or MRI).
21.3.4 Coronary Angiography
CA is the gold standard to assess CAD in LT candidates when other tests (noninva-
sive static imaging such as CCTA/CACS or stress tests) are positive and “true posi-
tivity” (presence or absence of critical stenosis requiring to be treated) has to be
confirmed: CA allows simultaneous diagnosis and treatment of the lesions with

minimal risk (particularly with the transradial approach) in spite of altered hemosta-
sis. In a very recent authoritative viewpoint, it was admitted that “it remains unclear
when to proceed with invasive coronary angiography” [10]. Quite surprisingly, a
standardized protocol for assessing (and managing) CAD in LT recipients is, as yet,
lacking, even though long awaited and eagerly needed [6, 12, 13, 15–22, 30–35].
21.3.5 Portopulmonary Hypertension
Portopulmonary hypertension (PoPH), reported in less than 2–5% of the candidates

(<1% in our series), is a serious complication of portal hypertension [13, 36–40].
Physical signs and symptoms may be absent or mild and nonspecific (dyspnea,
chest pain, mild hypoxia). Diagnostic criteria include mean pulmonary artery pres-
sure (mPAP) >25 mmHg and pulmonary vascular resistance (PVR) >240 dyne/s/
cm5 documented on right heart catheterization (RHC): central venous pressure
(CVP) and pulmonary wedge pressure (PWP) should be in the normal range (in
particular PWP should be <15 mmHg) [13]. In fact, pulmonary hypertension sec-
ondary to volume overload (CVP and PWP above normal range) has to be ruled out.
RHC is mandatory in case of TTE-estimated pulmonary artery systolic pressure
(PASP) >45–50 mmHg (a very conservative approach was recently proposed by
Raevens et al. [37] with a right ventricular systolic pressure > 38 mmHg). The com-
bination of main pulmonary artery diameter at CT and TTE might improve the
diagnostic accuracy [38]. Interestingly enough, TTE false positive results (estimated
PASP >45 mmHg) even in case of normal values at RHC are possible. PoPH is clas-
sified according to mPAP at RHC as mild (25–35 mmHg), moderate (35–45 mmHg),
and severe (>45 mmHg). According to very recent guidelines, while mild PoPH
does not constitute a contraindication to LT, patients with moderate PoPH should be
temporarily delisted, treated (pulmonary vasodilators; prostacyclin analogs, phos-
phodiesterase inhibitors, endothelin receptor antagonists), reassessed (RHC and
TTE) to evaluate the hemodynamic improvement (mPAP <35 mmHg, PVR
<400 dyne/s/cm5, good right ventricular function), and relisted [13, 36–39]. Instead,
persistent severe PoPH is considered a contraindication to LT, because of a high risk
of post-LT right ventricular failure and mortality [36]. In cases of appropriate indi-
cation, survival after LT is good.
21.3.6 Hepatopulmonary Syndrome
Even though not strictly a “cardiac” problem, we will shortly discuss hepatopulmo-
nary syndrome (HPS) [13, 36]. Characterized by a decreased O2 saturation
(SaO2 < 96% or PaO2 < 70 mmHg) in ESLD patients and secondary to an intrapul-
monary vascular dilatation in the presence of ESLD, HPS is found in 5–30% of LT
candidates [36, 40]. Unlike in PoPH, PVR are normal, and cardiac output is high.
Portal hypertension is responsible for pulmonary capillary vasodilation and
arteriovenous shunts, leading to a reduced capillary transit time and diminished

oxygen diffusion. Hypoxia (particularly mild) might be quite common in ESLD
patients (10–30%), is usually considered present in the case of increased alveolar–
arterial oxygen gradient equal to or greater than 15 mmHg in room air and in the
sitting position, and mandates a thorough evaluation for a differential diagnosis
between HPS and obstructive or restrictive forms (pleural effusions, or hydrothorax,
atelectasis caused by ascites or diaphragmatic dysfunction, aspiration secondary to
encephalopathy, forms of COPD). Hypoxemia in HPS might be from mild (PaO2
70 mmHg and above) to very severe (PaO2 50 mmHg). Diagnosis of HPS should be
confirmed by contrast TTE. After intravenous injection of agitated saline, contrast
microbubbles appear in the left heart after a delay of 3–6 heart beats in normal indi-
viduals, while in HPS the microbubbles move from the right to left heart immedi-
ately, due to the presence of intracardiac shunts. A high brain shunt (>6%) with 99Tc
macroaggregated albumin perfusion could constitute a further confirmation of HPS
[36]: hypoxemia caused by other intrinsic lung disorders has normal brain uptake.
Clinical signs in patients with HPS are digital clubbing, cyanosis, platypnea (dys-
pnea that worsens moving from supine to upright position) and orthodeoxia
(improved SaO2 moving from upright to supine position). Oxygenation improves
dramatically with a high inspired oxygen concentration (true shunt), unlike in other
pulmonary diseases: the high alveolar concentration of oxygen exceeds the reduced
diffusing capacity, thus increasing the oxygenation of erythrocytes in the center of
the bloodstream. High inspiratory O2 concentration is the first line measure during
transplant surgery in the case of hypoxemia: the response to high O2 concentration
should be evaluated before surgery. Methylene blue might be considered an option
in refractory hypoxia, before considering ECMO support [13, 36, 40]. Patients diag-
nosed with HPS might have an increased risk of postoperative respiratory complica-
tions compared with cirrhotic patients without HPS, but medium-term outcome is
now considered similar [36, 40]. They are granted MELD exception points for
higher waiting list priority. There is currently no medical treatment for HPS and LT
is the option: time to hypoxia resolution might last months [37].
21.3.7 Valvular Heart Disease
Among the scopes of pre-transplantation TTE, assessing valvular heart disease and its
severity is pivotal [6, 12, 13, 30, 40–46]. Mild to moderate valvular heart diseases are
usually well tolerated during the LT procedure and do not constitute a contraindication
to transplant surgery [6, 12, 13]. Mild or moderate tricuspid and mitral regurgitation
may be associated with cirrhotic cardiomyopathy together with ventricular remodel-
ing. Valvular surgery before LT can be proposed only in Child-Pugh A patients, due to
the severe prognosis in Child-Pugh B or C patients admitted to valve replacement sur-
gery [41, 45, 46]. Few cases of simultaneous valve replacement with Child-Pugh B and
LT have been reported, but the procedure is extremely challenging and should be
reserved for very selected cases [45, 46]. Small series of combined LT and aortic valve
replacement are reported when cardiac surgery prior to LT was not possible: the results
are encouraging [41]. Alternatives in cases of moderate-severe and severe forms of

aortic valve stenosis are percutaneous balloon angioplasty or transaortic valve implan-
tation (TAVI), after an extensive multidisciplinary approach: in cases of severe aortic
stenosis or regurgitation, TAVI could be a feasible option (personal experience in three
cases, with good perioperative results, reported as an abstract) [43–45]. TAVI requires
a short (one month) DAPT period. Instead, combined LT and mitral valve replacement
is reported in very few cases and the medium-term results are poor [45, 46].
21.3.8 Cardiac Dysrhythmias
Supraventicular or ventricular dysrhythmias may be encountered in the LT candidate:

atrial fibrillation is the most common atrial tachyarrhythmia (prevalence ranging
between 1% and 6%), while complex ventricular dysrhythmias are much rarer [13, 47].
If and when present, and particularly in the case of peculiar conditions (long QT syn-
drome or Brugada syndrome are examples) dysrhythmias mandate a thorough investiga-
tion and an appropriate and proactive perioperative strategy planned with the cardiologist:
the perioperative strategy should include availability of appropriate antiarrhythmic
drugs and/or temporary or implanted electrical devices for cardioversion and defibrilla-
tion [13]. Recently, a candidate with Brugada syndrome was successfully treated by our
group implementing such a multimodal/multidisciplinary strategy (unpublished case).
Atrial fibrillation has been associated with an increased rate of perioperative cardiovas-
cular complications and deserves, when symptomatic and/or associated with uncon-
trolled ventricular response, a thorough cardiological investigation and an appropriate
management. Among the many aspects to be discussed and planned with the cardiolo-
gist are the need for anticoagulation while on the waiting list (oral or parenteral antico-
agulants, and if oral, whether warfarin or the direct oral anticoagulants) [25] and a
precise, proactive plan to manage their reversal on the occasion of LT: availability of the
most recent guidelines on this item is mandatory [48], as is, if and when in doubt, con-
sultation with a cardiologist or an expert in coagulation [13, 25, 48].
21.4 F
unctional Tests and Their Role in Preoperative
Cardiac Assessment
Among the components of risk assessment for major surgical procedures, func-
tional capacity plays a relevant role. Metabolic equivalent of tasks (METs), the
6-minute walk test (6MWT) and the cardiopulmonary exercise test (CPET) have
long been recognized as able to reliably predict perioperative cardiac events in non-
cardiac surgery and quite recently also in LT [10].
21.4.1 Metabolic Equivalent of Tasks
METs are frequently used to assess functional status [49]. One MET is the equiva-
lent of the resting oxygen consumption of an average 40 years old, 70 kg male
subject. Candidates unable to perform at least a work equivalent to 4 METs (climb

two flights of stairs is the usual reference) are at increased risk of perioperative
cardiac events [49–52]. Recently, to define the ability to predict death or complica-
tions after major elective non-cardiac surgery, subjective assessment (defined as
“not accurate”) was compared to cardiopulmonary exercise testing (CPET), DASI
score (Duke Activity Status Index, based on a well-defined questionnaire), and a
serum cardiac biomarker (N-terminal prohormone of brain natriuretic peptide
[NT-BNP]) [49]. The DASI score based on the questionnaire, but not the simple
subjective assessment, was associated with the prediction of primary outcome:
functional capacity assessed by subjective assessment only failed to accurately
identify patients at increased risks of major cardiac events. Quite surprisingly, a
very good correlation was also demonstrated with the measured peak oxygen con-
sumption at CPET [49].
21.4.2 Cardiopulmonary Exercise Test
Able to provide diagnostic and prognostic information in patients with cardiac or

respiratory disease, CPET is a symptom-limited exercise test [53–56], able to mea-
sure cardiac, respiratory and metabolic functions [8, 51]. Among others, maximum
aerobic capacity (VO2 peak) and anaerobic threshold (AT) are the standard mea-
sures obtained with CPET. Reduced aerobic capacity has been demonstrated to pre-
dict mortality while on the waiting list and also to predict 90- and 100-day outcome
after LT. Low AT (<9 mL/min/kg) was associated with reduced 90-day survival
rates [52–54]. Even though limited in some candidates by sarcopenia and decon-
ditioning, the test should be used to gauge the increase of the functional status after
prehabilitation and appropriate nutrition in sarcopenic candidates and to objectively
document the improvement.
21.4.3 Six-Minute Walk Test
Only recently introduced in the preoperative assessment of LT candidates, the

6MWT is a simple, easy and reproducible test to measure functional capacity [10,
23, 56, 57]: a distance <250 m is associated with increased morbidity and mortality
after LT. Further confirmation is needed to introduce this test as a routine tool in the
preoperative assessment of LT candidates.
21.5 Conclusions
Eagerly waiting for a multidisciplinary consensus to define the optimal paradigm to

guide the cardiovascular assessment of LT candidates, extensive worldwide clinical
experience and favorable clinical results suggest as a good, feasible and practical
solution the combination of risk stratification and functional assessment for a ratio-
nal stepwise pathway. In low-risk patients, the risks from the tests and treatments
may offset the potential benefit of evaluation, addressing the relevance of a balance
between effectiveness and risk. We dare propose, together with the many solutions
indicated in this chapter [5, 6, 10–13, 16, 17, 19, 49–54] our stepwise flowchart
(Fig. 21.1; Tables 21.1 and 21.2), first released in 2011 and regularly updated
according to the most recent guidelines, including the crucial points of stress tests,
noninvasive imaging and the assessment of CAD [14].
As stated by Hogan et al. [10], even though different forms of testing are used in
different centers or countries, the relevant “pillars” sustaining their rationale are
common to the various stepwise paradigms (and we dare include ours) and are
“broadly and successfully applied to the LT population”: noninvasive imaging
(stress echocardiography or CCTA) or, in the near future, new forms of stress imag-
ing (stress MRI), will take the more appropriate and logical place in stepwise algo-
rithms. The first commitment of this effort is to optimize the pathway, eliminating
useless, time-wasting tests while concentrating resources and attention on the “true”
candidates at high risk for cardiac complications.
At the very end of the process, the main aim is to select the right candidate for
the LT, a procedure which involves a precious but finite resource, the graft, able to
save and change lives.
Acknowledgements Thanks to Rosa Sicari, MD, PhD, for the fruitful discussion and the compe-
tent and useful suggestions.
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Liver Resection and Transplantation
for Metastases 22
from Gastroenteropancreatic
Neuroendocrine Tumors
Michele Droz dit Busset, Matteo Virdis,
Christian Cotsoglou, Jorgelina Coppa, Roberta Rossi,
and Vincenzo Mazzaferro
22.1 Introduction
Neuroendocrine tumors (NETs) are rare tumors with a growing incidence slightly
above 5 new cases per 100,000 population/year. Gastroenteropancreatic NETs
(GEP-NETs) account for approximately 2% of all tumors of the gastroenteropan-
creatic system. They are characterized by heterogeneous biological behavior and a
generally indolent, slow-progressing clinical course. NETs can be classified as
functioning (secreting a variety of peptide hormones with corresponding clinical
pictures) and non-functioning tumors.
According to the recent WHO (World Health Organization) 2010 classification,
NETs are divided into three classes with different biological behavior: low grade
(G1), with a proliferation Ki-67 index ≤2%, intermediate grade (G2), with a Ki-67
index of 3–20%, and high-grade neuroendocrine carcinomas (NEC, G3), with a
Ki-67 index >20%.
Between 60% and 80% of GEP-NETs are metastatic at the time of diagnosis. The
liver is the most frequent site of metastases and the sole distant site of metastatic
M. Droz dit Busset · M. Virdis · C. Cotsoglou · J. Coppa · R. Rossi

Hepatopancreatobiliary Surgery, Gastroenterology, and Liver Transplantation,
Istituto Nazionale dei Tumori, Milan, Italy
e-mail: michele.drozditbusset@istitutotumori.mi.it; matteo.virdis@istitutotumori.mi.it;
christian.cotsoglou@istitutotumori.mi.it; jorgelina.coppa@istitutotumori.mi.it;
roberta.rossi@istitutotumori.mi.it
V. Mazzaferro (*)
Hepatopancreatobiliary Surgery, Gastroenterology, and Liver Transplantation,
Istituto Nazionale dei Tumori, Milan, Italy
University of Milan, Milan, Italy
e-mail: vincenzo.mazzaferro@istitutotumori.mi.it

222 M. Droz dit Busset et al.
spread in up to 60% of cases. The overall survival (OS) of patients with NETs is
related to tumor staging, the presence of liver and bone metastases being the worst
prognostic factor.
Therapeutic options for neuroendocrine liver metastases (NELM) include sur-
gery, locoregional therapies (i.e., ablation, transarterial embolization [TAE], trans-
arterial chemoembolization [TACE] and transarterial radioembolization [TARE]),
medical systemic treatments (i.e., chemotherapy, somatostatin analogues and inter-
feron, molecular targeted therapies such as everolimus and sunitinib) and systemic
peptide receptor radionuclide therapy (PRRT). In carefully selected patients with
diffuse, unresectable, liver-limited metastases, liver transplantation (LT) can also be
considered [1].
22.2 Role of Primary Tumor Resection
As reported in the algorithm of NELM treatment (Fig. 22.1), the first issue to be

addressed is the convenience of primary tumor removal. In patients with resectable
NELM of intermediate-low grade of differentiation (G1–G2), simultaneous or
staged removal of the primary tumor and possible minimal metastatic extrahepatic
disease is recommended, as this is associated with improved long-term survival in
retrospective series [2].
This may be true also in patients affected by unresectable liver disease, although
resection of primary tumor in the case of unresectable NELM is controversial in
asymptomatic patients. Similarly, NEC G3 with unresectable liver metastases are
best managed with systemic treatment. Evaluation of the therapeutic impact of the
primary tumor removal is, however, hindered by the long natural history of the dis-
ease, with a need for long follow-up intervals to demonstrate any benefit in
survival.
In our experience, surgical removal of the primary tumor in G1 and G2 function-
ing NETs has been associated with a significant survival advantage, regardless of
the location and independent from hepatic tumor load, chromogranin-A levels and
surgical treatment of liver disease. Such increase in survival could only be explained
by some slowdown in disease progression and tumor growth elicited by the primary
tumor removal and to possible easier liver-directed therapies favored by the erase-
ment of any extrahepatic tumor deposit [2].
Despite several signals supporting the use of primary tumor removal in NELM,
the decision has to be weighed against surgical risks, location of the primary, dis-
ease extent, liver function, access to subsequent liver-directed treatment options,
age, comorbidities, previous surgical history and the patient’s preferences. For
tumors metastatic to the liver and located in the pancreatic head, resection of the
primary tumor through pancreatoduodenectomy can only be considered for young,
fit patients with resectable NELM or with the prospect of LT—if meeting transplant
criteria or carrying reasonable chances of downstaging.
In all other G1 and G2 NELM, resection of the primary tumor should be consid-
ered only if an eradication of all the extrahepatic tumor deposits is possible, thus
Liver metastases
from GEP-NETs
Chemotherapy G3 * G1-G2 *
Treatment response Resection of primary tumor with Tumor burden assessment

assessment † radical lymphadenectomy ** of intrahepatic disease
Resectable Resectable Borderline resectable Unresectable Unresectable

Single lesion Multifocal Liver remnant <25-30% within Milan NET criteria beyond Milan NET criteria
≤2 segments to be resected >2 segments to be resected >1 hepatic vein involved
Intraoperative ablation added
Bridging Downstaging
Low risk of recurrence High risk of recurrence High risk of recurrence Systemic treatment, TACE, TARE, PRRT
Palliative approach
Neoadjuvant approach Cytoreductive surgery ‡
Systemic treatment, TACE, TARE Systemic treatment
Risk-benefit assessment
Age, performance status, presence of carcinoid syndrome, comorbidities
Observation period (3-6 months)
Advanced liver resection

Conventional liver resection § Liver transplantation
Staged hepatectomy / ALPPS
Fig. 22.1 Treatment algorithm for patients affected by liver metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs). ∗Grading (G) should
be assessed on metastatic lesions. In case of heterogeneity of grading in different liver metastases, the highest grade should be considered. ∗∗Resection of pri-
mary tumor should adhere to principles of surgical oncology with curative lymphadenectomy. In selected cases, limited extrahepatic deposits can be resected
in order to clear all the extrahepatic disease. For NETs of the pancreatic head, a risk-benefit assessment is necessary, as in the case of unresectable liver metas-
tases pancreatoduodenectomy is not usually indicated. †In selected patients with G3 liver metastases from NETs deemed resectable with conventional surgical
22 Liver Resection and Transplantation for Metastases from Gastroenteropancreatic… 223
procedures, responsive to medical treatment, resection of primary and metastatic disease can be considered. ‡Patients with carcinoid syndrome are the elective
subgroup for cytoreductive surgery. §Consider laparoscopic approach to liver resection. TACE transarterial chemoembolization, TARE transarterial radioembo-
lization, PRRT peptide receptor radionuclide therapy, ALPPS associating liver partition with portal vein ligation and staged hepatectomy
allowing for the best liver-directed treatment planning. Presence of extensive lymph
node involvement or peritoneal carcinomatosis is a contraindication to surgical
resection of NELM and these patients—with the exception of those with impending
symptoms from intestinal obstruction or bleeding—are better served with systemic
medical treatment or PRRT. It should be noted, however, that limited peritoneal
involvement or resectable lymph nodal involvement may be considered for aggres-
sive surgical protocols relying on the fact that cytoreduction—if clinically sound
and complication-free—is in NETs an accepted option with a potential for improved
survival and symptom control.
22.3 L
iver Resection: Current Standard
of Surgical Indications
As the concept of “resectability” of liver metastases is largely dependent on techni-

cal skills, center volume and expertise, patients with NELM should be managed in
referral centers, also considering the subset of patients who may benefit from
advanced, complex LR and LT.
According to the European Neuroendocrine Tumor Society (ENETS) guidelines
[1], LR with curative intent is considered the benchmark treatment of G1 and G2
NELM with no extrahepatic tumor spread, any tumor involvement of the hepatic
hilar lymph nodes not being a contraindication. In order to assist the strategic plan-
ning, three subgroups of NELM have been described [3]:
• Type I: single metastasis;

• Type II: isolated metastatic bulk with smaller deposits;
• Type III: disseminated metastases.
Types I–II should primarily undergo LR. Although type III is usually more suit-
able for systemic locoregional therapies, in selected cases of multifocal but resect-
able disease, radical LR can represent, when feasible, the most efficient strategy as
compared to non-surgical treatments. Several reports demonstrated the benefit in
terms of prolonged survival following concurrent or staged resection of the primary
tumor and NELM, with 5-year OS rates up to 80%. However, median 5-year
recurrence-free survival (RFS) is below 40% in most series. Thus, despite the sig-
nificant survival advantage as compared to non-surgical treatments, LR offers a
chance of definitive cure only in a selected proportion of patients.
In unresectable NELM, cytoreductive tumor-debulking surgical resection has
been advocated, if at least 70–80% of the tumor burden can be removed. Very
selected cases of multifocal NELM with insufficient anticipated future liver rem-
nant (FLR) following resection may benefit from advanced surgical techniques
allowing for a more extensive LR. Such an option has to be considered after the
evaluation of response to neoadjuvant systemic or locoregional treatments, aimed at
assessing tumor biology in order to avoid demanding procedures with significant
morbidity in patients with a marginal oncological benefit due to a very high risk of
recurrence. In patients with extensive and multifocal liver involvement, advanced

surgical options also have to be weighed against the possibility of LT, which can
represent a more radical treatment in metastatic disease confined to the liver [4].
With respect to the advanced procedures of LR described in other chapters of this
book, NELM might represent a reference population for
• 2-stage hepatectomy or
• associating liver partitioning and portal vein ligation for staged hepatectomy.
22.3.1 Staged Hepatectomy
Ideally, any metastatic patient can be considered resectable if a FLR ≥25% of total
liver volume and a remnant volume-to-body weight ratio ≥ 0.6 are retained, with
preserved vascular inflow, outflow and biliary drainage.
The major limitation in many patients is the inability to clear all metastatic dis-
ease in a single operation while preserving an adequate FLR. For these patients a
2-stage hepatectomy approach has been advocated. This procedure is described in
other parts of this book and in brief consists in a first step in which, through portal
vein ligation or embolization, a compensatory increased portal flow is generated in
the FLR, thus increasing its functional volume. Once that is achieved—usually
within 4–8 weeks—the second step consisting of a major hepatectomy is completed.
The selected use of this approach has increased the number of patients able to
achieve surgical clearance of metastatic disease. However, the rate of successful
completion of the second stage is around 70%.
22.3.2 Associating Liver Partitioning and Portal Vein Ligation

for Staged Hepatectomy (ALPPS)
With the aim of reducing the number of drop-out patients whose FLR does not
regenerate enough after the portal vein flow redistribution consequent to the first
step of staged hepatectomies, a new regeneration technique has been introduced
in the last decade. The association of ALPPS has significantly increased regen-
erative potentials of the FLR as compared to conventional staged hepatectomies.
In fact, ALPPS is able to increase the parenchymal regeneration by more than
30% in one-quarter of the time, even though a tradeoff consisting of high morbid-
ity (50–60%) and significant mortality (10–12%) has been described in most of
the series.
The use of ALPPS in NELM raises considerable doubts considering the inherent
indolent, slow-growing nature of these tumors and their responsiveness to a large
spectrum of treatments. However, in extremely selected patients with NELM
responsive to neoadjuvant treatments not amenable to LT, and after a careful risk-
benefit assessment, advanced surgical techniques may be valuable treatment options
able to clear the metastatic disease, possibly providing a survival advantage [5].
22.4 M
ultimodal Modern Surgical Approach to Treatment
of Neuroendocrine Liver Metastases
Treatment options for NELM from GEP-NETs mainly depend on the disease bur-
den (number and size of nodules), tumor biology and aggressiveness (well described
by the Ki-67 index) and response to neoadjuvant therapies. Except for NEC G3 and
those originating from the pancreatic head, the removal of the primary tumor is an
option to be considered in the large majority of patients (see above).
Based on our experience, five clinical presentations of NELM can be identified,
each directed to a specific area of curative or palliative treatment (Fig. 22.1):
1. Single NELM: single metastasis involving no more than two liver segments.
LR applied to this group is associated to significant prolongation of disease-free
survival. Curative resection is usually possible with conventional surgical proce-
dures (i.e., atypical resections, anatomical segmental resections).
2. Multifocal NELM: two or more hepatic lesions involving three or more liver
segments. This presentation is at higher risk of recurrence, but still resectable with
conventional surgery (anatomical segmental resections, left or right hepatectomy,
extended hepatectomies with sufficient FLR). Neoadjuvant strategies (systemic
therapy, TACE, TARE) may help in patient selection, especially if more extensive
disease spread is present. In selected cases of resectable multifocal disease, deemed
at prohibitively high risk of recurrence, LT may also be considered.
3. Borderline resectable NELM: the metastatic burden of this category is high
and LR may suffer from technical limitations as in cases with either an anticipated
FLR <25–30% or more than one hepatic vein tumor invasion or in which intraopera-
tive ablation has to be added to control otherwise unresectable lesions. These
patients may be potential candidates for complex surgical procedures such as staged
hepatectomy or ALPPS, with the aim of eradicating the metastatic disease. Due to
the high surgical risk related to such procedures, neoadjuvant treatments are usually
indicated to assess tumor biology and control progression prior to major surgical
resection. In selected patients with borderline resectable NELM with liver replace-
ment not exceeding 50% of the total parenchymal volume, LT may also be consid-
ered. In this category of patients advanced LR, when feasible, achieves better
outcome than locoregional and systemic treatments alone.
4. Unresectable bilobar NELM (within the Milan-NET Criteria, described in
Table 22.1) are good candidates to LT with demonstrated long-term benefit
(Fig. 22.2) [6, 7].
5. Unresectable bilobar/diffuse NELM, involving >50% of the liver paren-
chyma, the arterial or portal branches bilaterally, or the hepatocaval confluence.
These are patients beyond surgical options who should be considered for PRRT and
locoregional treatment strategies in combination with systemic treatments [8]. In
selected cases, tumor downstaging to within the Milan-NET criteria (Table 22.1)
can be achieved, with possible access to LT. Debulking surgery may play a role in
controlling carcinoid syndrome.
Table 22.1 Milan-NET selection criteria for liver transplantation in patients with liver metastases
from GEP-NETs [2, 3]
1. Confirmed histology of carcinoid tumor (low-grade neuroendocrine tumors, Ki-67 < 10%)
with or without syndrome.
2. Primary tumor drained by the portal system (pancreas and intermediate gut: from distal
stomach to sigmoid colon) removed with a curative resection (pre-transplant removal of all
extrahepatic tumor deposits) through surgical procedures different and separate from
transplantation.
3. Metastatic diffusion to liver parenchyma ≤50%.
4. Good response or stable disease for at least 6 months during the pre-transplantation period.
5. Age ≤ 55 years
GEP gastroenteropancreatic, NET neuroendocrine tumor
22.5 L
iver Transplantation for Unresectable Neuroendocrine
Liver Metastases: An Update
In carefully selected patients with inoperable metastases limited to the liver, LT

should be considered [1]. Given the worldwide donor scarcity, the availability of
alternative therapeutic options for these tumors and their long natural history even
if untreated, the option of LT should be carefully balanced, taking into account both
tumor and patient features.
Clear evidence of the role of LT for NETs as compared to other therapeutic
options is scanty. Only one study reflecting prospective application of the Milan-
NET criteria yielded a significant survival benefit in NET patients with respect to
non-transplant options. The transplant survival benefit in NET patients was found to
significantly increase over time with respect to non-transplant options [7]. Reported
outcomes for LT in the neuroendocrine setting, summarized in Table 22.2, are quite
heterogeneous, partially due to differences in selection criteria among transplant
centers. Although the post-transplant survival in selected GEP-NETs can be as high
as 90%, both OS and RFS are described mostly in the 40–90% and 20–80% inter-
vals, respectively [9]. Although there is still controversy regarding the optimal
selection of candidates, the strict application of the Milan-NET criteria by
Mazzaferro et al. (Table 22.1) is associated with a 5- and 10-year OS of 97.2% and
88.8%, respectively [6, 7]. These criteria, which have been incorporated in the
UNOS (United Network for Organ Sharing) exceptions for LT candidacy, can be
summarized as follows:
1. Remove primary tumor and all the extrahepatic disease with surgical oncology
curative operations before considering LT. Simultaneous resection of the pri-
mary tumor at the time of LT should be avoided, as it has been associated with
poor short- and long-term outcomes, due to a high perioperative mortality of
10%. Demanding procedures on the pancreas or distant lymph nodes or other
tumor locations should be reserved for different operations performed ahead of
228
Fig. 22.2 Example of a patient meeting the Milan-NET criteria at explant pathology. Fifty-four-year-old male with progressive weight loss, mitral valve pro-
lapse and severe hypertension. In 2012 a diagnosis of pancreatic neuroendocrine tumor (pNET) with unresectable neuroendocrine liver metastases (NELM)
(Ki-67 10% on biopsy) was established. The patient was started on somatostatin analogues. In 2013 a distal pancreatectomy was performed. Histology con-
firmed a pNET, G1, pT2N1(5/13)M1, R0. MIB-1/Ki-67 on primary tumor 2%, vascular and neural invasion present. After surgery four cycles of transarterial
chemoembolization (TACE) were performed with stable intrahepatic disease. No signs of extrahepatic spread were found at repeated 68Ga positron-emission
tomography-computed tomography (PET-CT) and endoscopic ultrasound lymph node and pancreatic sampling. In 2014 liver transplantation with a marginal
donor graft with severe steatosis was performed. At pathology 45 tumor nodules were identified, ranging from 2 to 50 mm (see figure). Histology confirmed
NELM of pancreatic origin, G1, replacing 40–50% of the liver parenchyma, MIB-1/Ki-67: 7.8%. The patient is alive with no signs of recurrence at 4 years. The
ruler below the specimens measures 6 in = 15.24 cm
M. Droz dit Busset et al.
Table 22.2 Literature review of liver transplantation for metastases from NETs (series reporting at least 10 patients)
Median
Number OS/DFS 5-year/10-year 5-year/10- Adverse prognostic
Authors Design of pts Inclusion criteria (months) OS year RFS factors
Mazzaferro Prospective, 42 NELM from primary drained by portal – 97.2%/88.8% 86.9%/86.9% Age (<42 and >54)∗,
et al. [7] single center system, previous resection of site of primary∗,
extrahepatic disease, ≤50% liver WHO grading, MIB-1
parenchyma involved, G1/G2, age
<60 years, PR/SD for 6 months
(histology confirmed)
Sher et al. Retrospective, 85 NELM from GEP-NETs or other/ – 52%/– – Macrovascular
[12] multicenter unknown primary ± multivisceral invasion∗, grading,
transplant or visceral resection extent of resection
added to LT∗
Grąt et al. Retrospective, 12 NELM from GEP-NETs, G1/G2 – 78.6%/78.6% 51.6%/15.5% Ki-67>2%, G2,
[13] single center (9 y RFS) PRBC transfusions,
Le Treut Retrospective, 213 NELM from bronchial or GEP-NETs ± 67/24 52%/– 30%/– Major resection
et al. [14] registry-based visceral resection added to LT∗, G3∗,
hepatomegaly∗
Gedaly Retrospective, 150 NELM from GEP-NETs or other/ – 48%/– 32%/– Wait time to
et al. [15] registry-based unknown primary ± multivisceral LT < 2 months∗
transplant
Nguyen Retrospective, 110 NELM 58.6/– 57.8%/– – Higher bilirubin∗,
et al. [16] registry-based higher donor
creatinine∗, lower
albumin
Máthé et al. Systematic 85 NELM 54.45/– 44%/– 47%/– Age ≥55,
[17] review simultaneous
LT-pancreatic
resection
(continued)
Table 22.2 (continued)
230
Median
Number OS/DFS 5-year/10-year 5-year/10- Adverse prognostic
Authors Design of pts Inclusion criteria (months) OS year RFS factors
Le Treut Retrospective, 85 NELM from bronchial or GEP-NETs ± 56/– 47%/– 20%/– Upper abdominal
et al. [18] multicenter visceral resection exenteration∗,
duodenopancreatic
primary∗,
hepatomegaly ∗
Olausson Retrospective, 15 NELM from GEP-NETs ± multivisceral –/22.8 90%/– 20%/– Ki-67 >2%
et al. [19] single center transplant
Frilling Prospective, 16 NELM, absent or resectable extrahepatic – 67%/– 48%/– –
2006 et al. single center spread, progressive hepatic tumor load,
[20] refractory symptoms, Ki-67 <10%
Van Prospective, 19 Bilobar, unresectable, progressive – 88% (1 year OS)/– 80%(1yRFS)/– –
Vilsteren single center NELM, complete resection of primary,
et al. [21] absent extrahepatic spread with
exception of perihepatic lymph nodes
Florman Retrospective, 11 NELM from GEP-NETs (histology – 36%/– – –
et al. [22] single center confirmed), unresectable, progressive or
with uncontrolled symptoms
Cahlin Retrospective, 10 NELM from bronchial or GEP-NETs ± – 80% (2 years OS)/– – Pancreatic origin
et al. [23] single center multivisceral transplant
Rosenau Retrospective, 19 NELM from bronchial or GEP-NETs ± –/10.5 80%/50% 21%/21% Ki-67 >5%, aberrant
et al. [24] single center visceral resection, symptomatic staining for
E-cadherin, positive
regional lymph nodes
at LT
∗Significant on multivariate analysis
pts patients, OS overall survival, DFS disease-free survival, RFS recurrence-free survival, NELM neuroendocrine liver metastases, PR partial response, SD
stable disease, GEP gastroenteropancreatic, NET neuroendocrine tumor, WHO World Health Organization, PRBC packed red blood cells, LT liver
transplantation
M. Droz dit Busset et al.
transplant. The presence of extrahepatic disease should be ruled out by means of

robust staging, using conventional radiology and nuclear scan (i.e., Ga68 PET-CT
scan) prior to enlisting and while on the waitlist. Primary tumors not drained by
the portal system should reasonably be excluded, as the liver might not be the
first level of hematogenous spread of malignant cells. A negative prognostic fac-
tor is the presence of primary tumors located in the pancreas (pNET) but this is
not a contraindication to LT. Exploratory laparoscopy to detect peritoneal depos-
its might be considered.
2. Exclude high grade NETs. As the Ki-67 mitotic index significantly predicts out-
come in NET patients irrespective of treatment, well to moderately differentiated
NETs with a Ki-67 index <10% appear the most reasonable candidates for LT
consideration.
3. Exclude patients with high metastatic tumor burden. Tumor burden is the single
most important prognostic factor in NELM and that is no exception for trans-
plantation as well. The cut-off of 50% metastatic liver involvement of the liver
well defines the perceived threshold for proposing transplantation for palliation
or for cure, should any extrahepatic tumor deposits be absent. Aiming at optimi-
zation of patients’ survival and benefit and at the best use of donated organs as
well, the use of a restrictive limit for NET intrahepatic burden is recommended.
4. Observe for a period of 3–6 months to assess disease stability from the removal
of the primary tumor to listing. Time is the best surrogate of tumor biological
behavior, in order to rule out aggressive disease undergoing rapid systemic pro-
gression. Bridging locoregional therapies and systemic medical treatments are
allowed to sustain tumor and symptom control.
Current transplant protocols do not consider specific immunosuppression proto-

cols for NET patients, although the risk of tumor recurrence or de-novo tumor
occurrence remains significant [10, 11].
Considering the donor scarcity and the good performance status observed in
NET patients listed for LT under restrictive criteria, an alternative source of dona-
tion should be considered (i.e., marginal donors, non-heart-beating donors, machine-
perfused grafts) also encompassing living-related donation. Even though transplant
candidates with metastatic NET have low priority to receive an organ with respect
to patients with advanced primary liver diseases, access to LT should be pursued,
particularly in young patients with long life expectancy.
In conclusion, as summarized in Fig. 22.3, the main drivers for selecting patients
with NELM to LR and LT are the reduction of adverse prognostic factors and the
likelihood to prolong the patient’s survival. LR should avoid the futility of proce-
dures associated with prohibitively high recurrence rates in the short term, while LT
has to be offered to patient in whom a true gain in survival can be achieved com-
pared with any other non-transplant options.
LT offers the best long-term outcome among the other available treatments for
NELM. The identification of specific biomarkers to select the best candidates for
either surgical, locoregional and systemic therapy remains the major unmet need of
this intriguing and worthy indication to liver-directed surgical therapies.
Liver resection
Magnitude
Magnitude of adverse of survival
prognostic factors Avoidance of
futility
Liver transplantation
Demonstration of
Survival rates obtained through transplant benefit
non-transplant alternative
options
Magnitude
of survival
time
Fig. 22.3 Endpoints of surgical treatment for neuroendocrine liver metastases. Selection criteria
for liver resection (LR) and liver transplantation (LT) consider the reduction of tumor burden and
subtraction of adverse prognostic factors as main drivers. However, in LR the main endpoint is
avoidance of futility, whereas in LT it is the demonstration of a benefit in survival with respect to
non-transplant options
References
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of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms
(NEN) and NEN of unknown primary site. Neuroendocrinology. 2016;103:172–85.
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in functional well-differentiated neuroendocrine tumours metastatic to the liver. Eur J Surg
Oncol. 2017;43:380–7.
3. Frilling A, Li J, Malamutmann E, Schmid K-W, et al. Treatment of liver metastases from neu-
roendocrine tumours in relation to the extent of hepatic disease. Br J Surg. 2009;96:175–84.
4. Frilling A, Modlin IM, Kidd M, et al. Recommendations for management of patients with
neuroendocrine liver metastases. Lancet Oncol. 2014;15:e8–21.
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tion for staged hepatectomy offers high oncological feasibility with adequate patient safety: a
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select patients for liver transplantation? J Hepatol. 2007;47:460–6.
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hepatic metastases from neuroendocrine tumors. Am J Transplant. 2016;16:2892–902.
8. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of Lu-dotatate for midgut neuroendo-
crine tumors. N Engl J Med. 2017;376:125–35.
9. Sposito C, Droz Dit Busset M, Citterio D, et al. The place of liver transplantation in the treat-
ment of hepatic metastases from neuroendocrine tumors: pros and cons. Rev Endocr Metab
Disord. 2017;18:473–83.
10. Rossi RE, Burroughs AK, Caplin ME. Liver transplantation for unresectable neuroendocrine
tumor liver metastases. Ann Surg Oncol. 2014;21:2398–405.
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ses. Endocrinol Metab Clin N Am. 2018;47:627–43.
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tumors: outcomes and prognostic variables. J Surg Oncol. 2015;112:125–32.
13. Grat M, Remiszewski P, Smoter P, et al. Outcomes following liver transplantation for meta-
static neuroendocrine tumors. Transplant Proc. 2014;46:2766–9.
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in Europe: results and trends in patient selection: a 213-case European liver transplant registry
study. Ann Surg. 2013;257:807–15.
15. Gedaly R, Daily MF, Davenport D, et al. Liver transplantation for the treatment of liver
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16. Nguyen NT, Harring TR, Goss JA, O’Mahony CA. Neuroendocrine liver metastases and
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doi.org/10.4061/2011/742890.
17. Máthé Z, Tagkalos E, Paul A, et al. Liver transplantation for hepatic metastases of neuroendo-
crine pancreatic tumors: a survival-based analysis. Transplantation. 2011;91:575–82.
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19. Olausson M, Friman S, Herlenius G, et al. Orthotopic liver or multivisceral transplantation as
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Updates in Surgery

More information about this series at http://www.springer.com/series/8147

Liver Transplantation and

Foreword by Paolo De Paolis

ISSN 2280-9848 ISSN 2281-0854 (electronic)

© Springer Nature Switzerland AG 2020

Revision and editing: R. M. Martorelli, Scienzaperta (Novate Milanese, Italy)

Padua, Italy Umberto Cillo

1 Cross Training and Didactic Interplay in Liver

11 Extended Right Split Liver Graft ������������������������������������������������������������ 107

Salvatore Agnes Catholic University of the Sacred Heart, Rome, Italy

Stefania Camagni Department of Organ Failure and Transplantation, ASST Papa

Fabio Ferla Department of General Surgery and Transplantation, Niguarda

Ernestina Mazza Division of Anesthesia and Intensive Care 2, Niguarda Hospital,

Marco M. Pascale Fondazione Policlinico Universitario A. Gemelli IRCCS,

William Halsted’s paradigm for surgical residency training is recognized as the

Q. Lai (*) · M. Rossi

© Springer Nature Switzerland AG 2020 1

1.2 Surgical Training in Hepatopancreatobiliary Surgery

1.3 Surgical Training in Liver Transplantation

1.4  he Peculiar Importance of the Organ Procurement

patient, thus representing a great advantage in trauma surgery as well [19]. As a

1.5 Minimally Invasive Liver Surgery and Training

After the First International Consensus Conference on Laparoscopic Liver Surgery

1.6 Women in Hepatopancreatobiliary

Particular consideration should be given to the training of women in surgery. An

HPB/LT training is the cornerstone of the education of general surgeons, especially

Preoperative assessment of comorbidities has received increasing attention in order

published, innovative clinical research lines on national and risk-adjusted models

2.2  aseline Clinical Evaluation and Multidisciplinary

2.3 Risk Stratification Tools

It is known that preoperative investigations are designed to provide diagnostic and

2.4 Morphologic and Functional Diagnostic Tools

and detoxification requirements. It could lead to post-hepatectomy liver failure, and

2.5 Surgical Decision-Making

Hepatobiliary surgery and LT has achieved important technical breakthroughs, but

2.5.1 The Elderly

2.5.2 Chronic Degenerative Disease

Identification of risk factors in patients undergoing LT and hepatobiliary surgery is

2.5.3 Nutritional Status

Pathological changes in nutritional status increase the risk of surgical morbidities in

2.6 Referral Center

3.1 Introduction and Historical Background

Electronic supplementary material The online version of this chapter (https://doi.org/10.1007/

© Springer Nature Switzerland AG 2020 21

3.2 Fundamental Surgical Considerations

3.3 Surgical Procedures

3.3.1 Total Vascular Exclusion Preserving Caval Flow

Although hemodynamic tolerance to TVE can be achieved in most cases, some

TVE TVE preserving TVE with in situ

TVE preserving caval Ante situm liver

3.3.4 Ante Situm Liver Resection

3.4 Authors’ Comments

4.1 Cooling Techniques

Hypothermic preservation is a strategy to reduce ischemia-reperfusion injury in both

Electronic supplementary material The online version of this chapter (https://doi.org/10.1007/

© Springer Nature Switzerland AG 2020 29

4.2 Total Vascular Exclusion and Ex Situ Liver Surgery

personalized medicine and precision medicine have redefined surgical indication

4.2.1 Total Vascular Exclusion

4.2.2 Ex Situ Surgery

Fig. 4.1 Different liver a

Fig. 4.3 Bench surgery

Padua, Italy Umberto Cillo

1 Cross Training and Didactic Interplay in Liver

11 Extended Right Split Liver Graft �� 107

1.2 Surgical Training in Hepatopancreatobiliary Surgery

1.3 Surgical Training in Liver Transplantation

1.4 he Peculiar Importance of the Organ Procurement

1.5 Minimally Invasive Liver Surgery and Training

1.6 Women in Hepatopancreatobiliary

2.2 aseline Clinical Evaluation and Multidisciplinary

2.3 Risk Stratification Tools

2.4 Morphologic and Functional Diagnostic Tools

2.5 Surgical Decision-Making

2.5.1 The Elderly

2.5.2 Chronic Degenerative Disease

2.5.3 Nutritional Status

2.6 Referral Center

3.1 Introduction and Historical Background

3.2 Fundamental Surgical Considerations

3.3 Surgical Procedures

3.3.1 Total Vascular Exclusion Preserving Caval Flow

3.3.4 Ante Situm Liver Resection

3.4 Authors’ Comments

4.1 Cooling Techniques

4.2 Total Vascular Exclusion and Ex Situ Liver Surgery

4.2.1 Total Vascular Exclusion

4.2.2 Ex Situ Surgery

5.4 Timing and Temperature

5.5 Hypothermic Machine Perfusion

5.5.1 Physiological Mechanisms

5.5.2 Hypothermic Oxygenated Perfusion in Clinical Practice

5.5.3 Limitations and Future Perspectives

5.6 Normothermic Machine Perfusion

5.6.2 Limitations and Remaining Questions

5.7 Subnormothermic Machine Perfusion

5.8 I nterplay Between Machine Perfusion

5.8.1 Liver Splitting During Machine Perfusion

5.8.2 Machine Perfusion in Liver Resections

6.2 Inferior Vena Cava and Hepatic Veins

6.3 Portal Vein

6.4 Hepatic Artery

7.2 istorical Milestones of Biliary

7.3 Biliary Anatomy

7.3.1 Anatomy of the Intrahepatic Bile Ducts

7.3.2 Anatomy of the Extrahepatic Bile Ducts

7.4 iliary Reconstruction Techniques in Oncological

7.4.1 Hepaticojejunostomy in Oncological HPB Surgery

7.4.2 I ntrahepatic Cholangiojejunostomy

7.5 iliary Reconstruction Techniques in Liver

7.5.1 Duct-to-Duct Anastomosis in Liver Transplantation

7.5.2 Hepaticojejunostomy in Liver Transplantation

8.1 Introduction and Historical Background

8.2 echnical Interplay Between Living Donor Liver

8.2.1 The Role of Liver Volume

8.2.2 Small-for-Size Syndrome and Its Implications

8.2.3 From LDLT to ALPPS

8.2.4 Minimally Invasive Liver Surgery: A Mutual Understanding

8.3 Surgical Technique: The Niguarda Experience

8.3.1 Donor Hepatectomy (Right Lobe: Segments 5, 6, 7, and 8)

8.3.2 Recipient Hepatectomy and Implantation of Right Lobe

8.4 Italy: Recent Advances and Future Prospects

8.5 Experts’ Comments