Liver transplantations. Eight of the patients had undergone orthotopic


Liver transplantation was
first attempted in dogs by Welch in Albany in 1955 and Cannon in California in
1956.In the late 1950s and early 1960s two centers, Starzlworking in Denver1 and Moore in Boston were
interested in the technique of transplanting the liver, which was clearly going
to be a formidable undertaking. Both had realized that dogs would not tolerate
clamping of the vena cava and portal vein that is necessary to take out and transplant
the liver.2
On 1st March, 1963, Thomas E Starzl (Figure 1.1) in Denver, University
of Colorado Health Sciences Center (UCHSC), USA had performed the first human
liver transplantation in the world in a 3 years old child with biliary atresia
and received the liver from another child who died from brain tumor. But they
could not complete the surgery and patient died due to uncontrolled hemorrhage.3 The second liver transplantation
in man was performed on 5th May, 1963.Patient died on the 22nd postoperative
day due to pulmonary embolism but with a normal liver. Starzl therefore decided
to have a moratorium on clinical application of liver transplantation that
lasted until 1967when he started his main program. The first long term survival
was achieved in 1967 by Starzl in Denver,Colorado, USA. 4,5


Despite the developments in
surgical techniques, liver transplantation remained experimental till 1970 with
1 yr patient survival rate around 25%.

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Figure 1.1: Prof Thomas E Starzl (World’s 1st Liver transplantation)

Contributed and reproduced
with permission of Terry Mangan,UPMC, USA


By the end of summer 1967,
the Denver experience included 11 liver transplantations. Eight of the patients
had undergone orthotopic liver transplantation, and three had been provided
with an auxiliary liver. Early immunosuppressivetherapy consisted of
azathioprine andprednisolone, but rejection was usually rapid. None of these
patients had recovered their health; the longest survival was 34 days. In the
same year, a chamber for the preservation of the liver was developed in
Denver.The system included perfusion of the liver with diluted blood under
hypothermia and hyperbaric oxygenation.When dog livers were placed in the
chamber, it was found that the livers could be preserved for 8 hours.6 At the same time,
Denver group set out to prepare antihuman anti-lymphocyte globulin (ALG).In
July 1967, a 2½ yrs old child underwent orthotopicliver transplantation on
(23rd July, 1967). The donor liver had been maintained for 3 hours in the
preservation chamber. The early postoperative function was satisfactory.
Postoperatively, antilymphocyte globulin(ALG) was given for several months in
combination with azathioprine, and prednisolone. During the following 2 months,
two more infants, both suffering from biliary atresia, underwent orthotopic
liver transplantation. The protocol was the same as that for the first child.
These three children were the first to achieve extended survival after liver
In 1969, Starzl published a monograph on liver transplantation, and by that
time 25 patients had been treated in Denver and a number of the patients had
survived for more than 1 year.8Thomas E Starzl’s pioneering efforts in organ transplantation
for four decades have resulted in clinically proven treatments for patients
with end-staged organ failure, who were previously doomed to death. His contributions
to immunosuppression, organ procurement, organ preservation, tissue
matching,surgical transplant technology, and the team approach to organ
transplantation paved the way for the acceptance of heart, lung, pancreas,
intestinal, liver, and kidney transplantation. Starzl combined the marginally
effective drugs, azathioprine and prednisolone, in a strategy (1962-63) that
made kidney transplantation a viable option for treatment of end-stage renal
disease.Dr Starzl introduced the first major innovation in hypothermia, when
canine liver allografts were cooled by infusion of chilled fluids into the
vascular bed of hepatic allografts via the portal vein.9 In the initial stages of
liver transplantation, 1-year survival rates were below 30% due to various
limitations related to surgical technique, ineffective immunosuppression,
andinadequate postoperative care. But results later improved drastically.Till
now, 8 patients have survived for more than 30 years after liver
transplantation worldwide and 6 of them are from the Denver series.10 The longest
survivor has had her new liver for 38 years. This patient was only 3 years old
at the time of transplantation. Carl Groth reported that a total of 8 patients
transplanted with livers from non heart-beating donors have by now survived for
more than 20 years in Stockholm.11One of Starzl’s early experimental animals survived for
many years after the immunosuppressant had been stopped.12 In Cambridge,
Roy Y Calne (Figure 1.2) and team were fascinated with the immunological
studies of orthotopic liver transplantation and decided to follow Starzl with
clinical application in April 1968.13 Clane performed 1st OLT on May 2, 1968,
in Addenbrookes Hospital, Europe. In any immunosuppressed patient with an organ
graft, there is a danger of sepsis, or infection,and this was in fact the cause
of failure in many of the early cases performed in Cambridge.



 Figure 1.2: Sir Roy
Yorke Calne (Introduced cyclosporine, 1st liver

transplantation in Europe, and World’s 1st
combined heart, lung

and liver transplantation)








TABLE 1.1: Historical milestones of liver

Type of liver transplantation                                                   Surgeon
and Country

1963                            1st Liver
transplantation (biliary atresia)            
                Starzl TE,
Denver, Colorado, USA
1964                                1st Liver transplantation
in Asia from
                                non-heartbeating donor (biliary
atresia  )                                      Nakayama, Chiba Univ., Japan
1967                          1st Successful liver transplantation                                        Starzl TE Denver, Colorado, USA
1968                          1st Long-term
survival (1 yr) of child                                           
Denver, Colorado, USA
1968                       1st Liver
transplantation in Europe                                             Roy Y Calne,Cambridge,
1983                    NIH Consensus Conference
declares liver transplantation
justified in the treatment of ESLD
1984                     1st Reduced-size liver
             Bismuth H, Univ
Paris Sud, France
1987                               1st LDLT in a
Raia S, Univ. of São Paulo Brazil
1987                     Introduction of
University of Wisconsin Solution
1988                              1st Split Liver
transplantation (2nd Feb.)                                Pichlmayr R,
1989                             1st Successful
LDLT in child                                          
Strong RW, Brisbane, Australia
1989                         1st LDLT in Asia
(Biliary atresia)                                                       
Nagasue, Japan
1993                        1st Adult to adult
T Makuuchi, Tokyo Univ., Japan
1997                           1st Split Liver
transplantation in Asia                 
             Chen CL, Chang Gung
Univ, Taiwan
2000                    1st Dual graft transplantation                                                           
Lee SG, Ulsan Univ., Korea
2001                   UNOS/OPTN Board of
Directors approve MELD and PELD
                          scoring system for
organ allocation in liver transplantation
2002                        MELD and PELD Scoring
system becomes effective
1st Dual graft transplantation in Europe                              Broering DC,
H-E Univ, Germany




Silvano Raia (Figure
1.3) in San Paolo, Brazil, introduced the concept of a living donor
transplant to a child15
The first attempt was performed in December, 1988 without success (the child
died on the 6th postoperative day during hemodialysis). The second one was
performed in July, 21st, 1989 and the girl survived for 4.5 months and died
probably due to CMV infection. His efforts were not successful but were
followed up shortly afterward by cases done in Brisbane, Australia by Russell
Strong with success.16
This provided an opportunity to develop liver transplantation in Japan by
Makuuchi M and Tanaka K(16)that
previously had been impossible due to the law on organ donation and reluctance
of the public to donate organs. However, parents would frequently offer a lobe of
a liver for their child. The Japanese became the most experienced and skillful
exponents of this technique in the world, although there was also enthusiasm
for it in other centers particularly in the United States.As results improved
and FK506 (tacrolimus) became available as another calcineurin inhibitor like cyclosporine,
but with certain advantages in therapeutic index for liver transplants, the
criteria of selection for living donors widened to people who are not
necessarily parents of a child, but more distant relatives or even friends.
Then, adult-to-adult living donation was popularized in Hong Kong by ST Fan
whose excellent techniques showed that good results could be obtained either
using the right or left lobe, depending on the size of the donor and recipient.17 In Taiwan,
first successful deceased donor liver transplantation was performed in March
1984 by CL Chen and his team



Figure 1.3: Prof Silvano Raia. Professor emeritus at the Faculty subject
of interest.

Medicine of the University of San Paulo, San Paulo, Brazil (World’s

Living Donor Liver Transplantation in a child) (Contributed and

with permission of Dr. Sergio Mies, Sao Paulo Medical

School – USP, Liver Unit, Instituto
Dante Pazzanese de Cardiologia,São Paulo–SP, Brazil




Initially adult-to-adult
liver transplantation was considered as hazardous to the donor. The exact
mortality is not known but it has been calculated to be around 0.1-1% either
due to complications or inappropriate donor selection with small residual
volume or a fatty liver leading to hepatic failure after surgery. But the
techniques of LDLT are refined with gaining experience the morbidity and
mortality rates are less and risk of the donor can be balanced against the
benefits of the recipient.


First split liver
transplantation was done on 2nd Feb. 1988 by Rudolf Pichlmayr (Figure 1.4),
Germany, later many studies have been reported and is an option to increase the
donor pool in carefully selected deceased donor. In Asia, Chen CL from Taiwan
performed the first split liver transplantation in May 1997, followed by KC Tan
in July1997 in Singapore18
Initially, split liver was used for one adult and one pediatric patient, but in
the present transplantation scenario, split liver for 2 adults is the subject
of interest.


Figure 1.4: Prof Rudolf Pichlmayr
(1932-1997) (First split livertransplantation)(Contributed and reproduced with
permission of S.Karger AG, Medical and Scientific Publishers,
Allschwilerstrasse,Basel, Switzerland









long-term shortage of livers available for transplantation has spurred the
development of many strategies to bolster the donor organ supply. One
particularly innovative strategy is domino liver transplantation in which a
select group of liver transplant recipients can donate their explanted native
livers for use as liver grafts in other patients. Several hereditary metabolic
diseases (such as familial amyloid polyneuropathy, maple syrup urine disease,
and familial hypercholesterolemia) are caused by aberrant or deficient protein
production in the liver, and these conditions can be cured with an orthotopic
liver transplant. Although their native livers eventually caused severe
systemic disease in these patients, these livers are otherwise structurally and
functionally normal, and they have been used successfully in domino liver
transplants for the past 15 years.19




The first ABO-I LDLT was
performed in November 1991 in Japan to overcome the organ shortage. As per the
data of National Registry of the Japan Study Group for ABO incompatible,291
(155 children and 136 adults) ABO-ILDLTs have been performed till March 2006 in
Japan from 28 institutions. ABO-incompatible LDLT is a standard practice in
children (