Abdominal Radiology

https://doi.org/10.1007/s00261-019-02357-w

SPECIAL SECTION: LIVER TRANSPLANTATION

Liver transplantation: current and future

Christopher B. Hughes1 · Abhinav Humar1

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose The aim of this paper is to summarize the allocation challenges facing the field of liver transplantation while pro-
viding examples of the expansion of indications for the procedure.
Methods UNOS allocation policy was reviewed as well as the recent literature describing expanded criteria for recipient
candidate selection.
Results Liver allocation policy changes for deceased-donor organs remain gridlocked in legal and bureaucratic red tape.
Meanwhile, the indications for liver transplantation are being expanded to include acute alcoholic hepatitis, intrahepatic chol-
angiocarcinoma, and colorectal metastasis, previously viewed as absolute contraindications, but under strict selection criteria.
Conclusions Attempting to meet the demand for livers, transplant centers are increasingly turning to living donor liver
transplantation, protocols such as HCV-positive to HCV-negative transplants, and machine perfusion of marginal organs.

Keywords Liver · Transplantation · Allocation

Introduction liver transplants performed last year. Another 12,000 will

Since the first liver transplant by Thomas Starzl in 1963,
little has changed in terms of the surgical procedure itself,
except that the vena cava is routinely spared with a “pig-
gyback” anastomosis instead of caval interposition. Trans-
plantation is the gold standard treatment for virtually all
causes of liver failure. Outcomes continue to improve, with
one-year graft and patient survival now around 90% [1], and
indications for liver transplantation are expanding. But the
same question remains—where do we find more organs and
how do we allocate them fairly?
The teetering status of liver allocation
Transplantation of the liver, as is true with other organs,
has been hampered by the lack of available donors in rela-
tion to the number of people waiting. Currently there are
13,000 patients on the national waiting list, with only 8200
* Christopher B. Hughes
hughescb@upmc.edu
1
Starzl Transplantation Institute, University of Pittsburgh
Medical Center, 3459 Fifth Avenue, MUH N725, Pittsburgh,
PA 15213, USA
be added in 2019 (Projected from OPTN/UNOS Data) [1].
Those not transplanted will die or be removed from the
list because they are too sick or too frail. Over the years,
changes have been made to the organ allocation system
in an attempt to decrease the number of deaths on the
waiting list. These include adoption of the Model for End-
stage Liver Disease (MELD) scoring system, introduction
of “Share 35” to broaden sharing for the sickest patients,
and the limitation of subjective criteria in influencing
patient position on the waiting list. Transplant centers are
becoming more aggressive in the use of marginal donors,
including increased use of organs from donors after car-
diac death (DCD) and the expansion of living donor liver
transplantation (LDLT). Despite best efforts, the organ
shortage problem likely will not be overcome. In 2018,
20% of waitlisted candidates died while waiting or became
too sick to be transplanted [1]. The likelihood that a wait-
listed patient will be transplanted varies from center to
center based on geography. Currently, livers are allocated
based on 11 arbitrarily drawn regions, subdivided into 58
Donor Service Areas (DSA, See Fig. 1), with boundaries
defined at the inception of the Organ Procurement and
Transplantation Network (OPTN) in the 1980s. This sys-
tem has been cited as being unfair in that certain regions
are more privileged in terms of organ access resulting in

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 Abdominal Radiology

Fig. 1  Current liver allocation scheme for the contiguous USA. Hawaii and Alaska are in Region 6. 11 UNOS Regions are further subdivided
into Donor Service Areas, each managed by an Organ Procurement Organization

more favorable outcomes for waitlisted patients, a problem
identified in the early 1990’s [2]. In 1998, Congress passed
the Final Rule (Title 42, Part 121), tasking UNOS with
making liver allocation fairer, including adopting a plan
for broader sharing; but UNOS, managed by Committees
of transplant center representatives, has never reached a
consensus for change. Representatives of regions 1, 2, 5,
and 9 have pushed for change because they were trans-
planting patients at higher average MELD scores and expe-
riencing more waitlist deaths than centers in other regions,
who opposed any changes. The stalemate lasted two dec-
ades. In 2018, six patients representing California (Region
5), Massachusetts (Region 1), and New York (Region 9)
brought forward a lawsuit claiming that the current region-
based system unfairly disadvantaged them, increasing their
likelihood of death without a transplant [3]. In response,
the Department of Health and Human Services (HHS),
tasked with OPTN oversight, mandated that UNOS should
create a system that would not rely upon set geographic
boundaries, but that would allow more broad sharing pref-
erably based on distance from the donor hospitals. UNOS
created this new allocation scheme based on the distance
of concentric circles from the donor hospital and put it
in place in May 13, 2019 (See Fig. 2). Fourteen hospitals
representing UNOS Regions 3, 6, 8, 10, and 11 filed a
countersuit to stop the new allocation process stating that
it would lead to “higher costs and fewer transplants in our
region” [4]. Just one day after the new system was imple-
mented, U.S. District Judge Amy Totenberg in Atlanta
ordered that HHS cease and desist the implementation of
the new system stating that it disadvantaged patients in
rural areas [5]. As a result of this ruling, the new system
was abandoned and Region-based allocation continues as
of the writing of this article.

Fig. 2  New proposal for liver

allocation based on concentric
circles drawn at 150, 250, and
500 miles from the donor hospi-
tal. In this figure, the concentric
circles are projected on top of
the existing UNOS Regions to
show how a donor liver in Nash-
ville, TN, for example, would
be allocated across a much
larger area than just Region
11, thereby potentially reach-
ing more patients with higher
MELD scores

13
Abdominal Radiology
Frailty and sarcopenia
With ever-increasing waiting times, transplant teams are
faced with the problem of patient frailty. We can manage
edema with diuretics, ascites with a TIPSS, variceal bleed-
ing with prophylactic banding, and hepatic encephalopathy
with lactulose and rifaximin, but frailty and sarcopenia
are worthy nemeses. Nutritional support, physical therapy,
and even activity monitoring with wearable devices are
now routine for waitlisted patients. A recent multicenter
opinion paper advocates for the use of CT-based skele-
tal muscle area measured at the third lumbar vertebra in
patients with cirrhosis as a baseline sarcopenia assess-
ment [6]. Sarcopenia is defined as skeletal muscle index
(SMI) < 50 cm 2/m 2 in men and < 39 cm 2/m 2 in women
[7]. These SMI cutoff points were associated with waitlist
mortality independent of age or MELD score [7]. A frailty
assessment is a routine part of continued waitlist surveil-
lance as patients frequently decline in physical status such
that transplant is no longer an option and the patient must
be delisted. Routine surveillance of patients and monitor-
ing of the activity has been shown not only to improve
their likelihood of transplant, but also to decrease the
number of hospital readmissions while waitlisted (inter-
nal data, University of Pittsburgh). In patients who make
it to transplant, Masuda et al. found that sarcopenia was an
independent predictor of postoperative sepsis in patients
undergoing living donor liver transplant (LDLT) and a car-
ried a twofold higher risk of postoperative death [8].
HCV treatment and transplantation
Changes in the prevalence of liver diseases in the USA
population are similarly changing the most common indi-
cations for transplant. With the onboarding of protease
inhibitors and direct-acting antiviral agents for the treat-
ment of hepatitis C, beginning in 2011 with boceprevir and
telaprevir for genotype 1 patients, the number of hepatitis
C-positive patients progressing to a need for transplanta-
tion has decreased. Since 2011, the percentage of liver
transplants for HCV in the USA dropped from 31.9 to
23.6% [9]. In fact, many transplant centers have run out
of waitlisted HCV-positive patients to transplant. In fact,
transplant centers now are implementing protocols for
transplantation of livers from donors who are hepatitis
C-positive into HCV-negative recipients with the plan to
treat HCV after the transplant [10]. In 2018, the Univer-
sity of Cincinnati reported a series of 25 HCV-negative
patients receiving liver transplants from donors who were
HCV-antibody positive but non-viremic by nucleic acid
testing (NAT-negative). At a median of 11 months fol-
low-up, only 4 of 25 patients had seroconverted to HCV-
positive. The four donors died of drug overdose and may
have been re-infected with HCV and within the window
before NAT became positive again. Of these 4 recipients,
one died of pulmonary complications unrelated to HCV,
two were treated and achieved a sustained viral response,
and one was in the process of treatment at the time of
manuscript publication [11].
The epidemic of fatty liver disease
The decline in the incidence of HCV-positive patients
requiring transplant has been offset by an exploding epi-
demic of nonalcoholic fatty liver disease (NAFLD). In 2003,
the percentage of all US liver transplants for NASH was
5.8%, but this number had skyrocketed to 16.5% by 2017
[9].These patients not only bring along the added potential
operative morbidity of obesity, but also the difficulties and
medical management associated with the metabolic syn-
drome of diabetes, volume overload, renal insufficiency, and
cardiac issues. The problem of hepatic steatosis is not only
seen in patients on the waiting list, but it is increasing in the
donor population as well. In 1995, 15.0% of donors had a
BMI > 30 kg/m2, but by 2010, this had increased to 30.3%
[12]. Higher BMI means higher likelihood of steatosis on
liver biopsy where more than 50% of donor livers will be
declined if macrosteatosis is more than 30% [12]. Certainly
fatty liver disease is a societal epidemic which extends far
beyond the transplant world.
Acute alcoholic hepatitis as a potentially
transplantable disease
With ever-increasing improvements in overall survival, indi-
cations for liver transplantation are expanding. In a 2011
New England Journal publication, Mathurin et al. reported
a series of patients successfully transplanted for acute alco-
holic hepatitis [13]. Acute alcoholic hepatitis is often a
patient’s first indication of a liver problem from drinking. In
its most severe form, alcoholic hepatitis carries a mortality
rate of 20–40% at 3 months [14]. Early studies have shown
that the prognosis and the recidivism rate in patients receiv-
ing early liver transplantation for selected cases of acute
alcoholic hepatitis is similar to the rates seen in patients
transplanted for chronic alcoholic hepatitis [13, 15, 16]. In
the Mathurin article, 6-month survival was 77% for those
transplanted early versus 23% for those without transplant.
Additionally, only 3 of 26 patients returned to drinking and
all more than 1 year after transplant [13]. To achieve these
results, the selection criteria for transplant candidacy in this
13

setting must be stringent. According to our protocol at the
University of Pittsburgh, insight into addiction, an agree-
ment to long-term counseling, and, most importantly, a
strong and an ever-present caregiver support structure are
critical to a successful outcome. Failed prior detoxification/
therapy programs, coexisting psychiatric disorders, current
use of other recreational drugs, prior treatment for other sub-
stance addictions, prior history of suicide attempts, and lack
of a caregiver or support person present during the patient’s
hospitalization are considered exclusion criteria for potential
transplant. These criteria exclude most patients who present
with acute alcoholic hepatitis. In our center, fewer than 5%
of patients admitted with acute alcoholic hepatitis would
qualify for potential early liver transplant.
Hilar and peripheral cholangiocarcinoma
At one time, the diagnosis of hilar cholangiocarcinoma, or
Klatskin tumor, was a contraindication to liver transplant.
Early studies at the University of Nebraska and Mayo Clinic
showed improved survival in patients who were selected
according to a stringent protocol [17, 18]. Many centers
around the country now have protocols for transplanting
patients with hilar cholangiocarcinoma and UNOS has cri-
teria for acquiring MELD exception points. Most commonly,
patients present with a hilar stricture and the diagnosis of
malignancy must be supported by having one of the follow-
ing: ERCP brushings or intraductal biopsy demonstrating
malignancy, carbohydrate antigen 19-9 greater than 100 U/
mL in absence of cholangitis, or aneuploidy. (UNOS/OPTN
Allocation Policy 9.6.A). In general, a hilar mass, if present,
should be less than 3 cm and not suitable for conventional
resection; there should be no transhepatic biopsy and no
evidence of extrahepatic disease by chest and abdominal/
pelvic imaging. These patients must undergo treatment with
chemotherapy and radiation and must have an exploratory
laparotomy, open or laparoscopic, to assess hilar lymph
nodes. If those nodes are positive, the patient is not a can-
didate for potential transplant. If the nodes are negative, the
patient may be listed. Following these protocols, 5-year sur-
vival is 65–70% [19].
Embryologically, the extrahepatic biliary tree arises from
the cranial part of the ventral foregut endoderm, while the
caudal part gives rise to intrahepatic bile ducts. It is unclear
as to whether this leads to different metastatic potential from
tumors arising from these different areas, but certainly the
management of tumors, perihilar versus peripheral, has been
different from a surgical standpoint.
Historically, peripheral hepatic tumors with a cholangio-
cellular component (either CCA or mixed CCA/HCC) have
been a contraindication to transplant because of the high
13
Abdominal Radiology
recurrence rates and less than 30% 3-year survival seen post
transplantion [20].
More recently, protocols for management of peripheral
cholangiocarcinomas and mixed hepatocellular/cholangio-
carcinoma have been published. The groups at M.D. Ander-
son and Methodist Hospital in Houston published a small
series of 12 patients with intrahepatic cholangiocarcinoma
evaluated for potential transplant [21]. All patient’s had
confirmation of cholangiocarcinoma by biopsy or cytology
and had disease stability or tumor regression for at least
6 months with neoadjuvant chemotherapy. At the time of
transplant, just as with hilar cholangiocarcinoma protocols,
the hilar lymph nodes are examined by frozen section his-
tologic analysis and confirmed negative prior to proceed-
ing with the hepatectomy and ultimate transplant. 6 of the
12 patients fulfilled all criteria and ultimately they were
transplanted. 1-, 3-, and 5-year overall survival was 100%,
83.3%, and 83.3%, respectively. 3 of the 6 patients trans-
planted developed recurrent disease, with 50% recurrence-
free survival at 1, 3, and 5 years. Arguably, the most impor-
tant part of this protocol leading to a successful outcome is
the mandatory 6 months of disease containment, which is
likely a method of selection for less aggressive tumor biol-
ogy. One hurdle for these patients is that UNOS Policy does
not provide a pathway for MELD exception; these patients
rely upon their own native MELD score for their position on
the waiting list. This means that many of these patients with
lower MELD scores will receive a more marginal organ, that
is, one would be turned down for patients higher on the list,
unless they have a potential living donor. Having an avail-
able living donor provides an advantage for patients with
either hilar or intrahepatic cholangiocarcinoma because it
means they may move to transplant once the neoadjuvant
therapy is completed without a long wait time. With a living
donor available, the requirement of hilar node examination
does not have to be a separate operation from the transplant.
The recipient can undergo exploratory laparotomy and the
hilar lymph nodes sent for frozen section analysis prior to
the surgery beginning on the living donor. Once there is no
gross evidence of extrahepatic disease and the nodes are
deemed negative by histology on the frozen specimen, the
team can proceed with native hepatectomy in the recipient
while the donor team begins the hemihepatectomy for dona-
tion in an adjacent room.
Neuroendocrine tumors with liver
metastasis
Neuroendocrine tumors (NET) encompass a range of heter-
ogenous neoplasms that comprise about 2% of all GI tract
malignancies. Most NET are metastatic at the time of diagno-
sis, with the liver being the most common site of metastasis.
Abdominal Radiology
Surgical resection is often not an option due to the high inci-
dence of bilobar disease. Prior to presentation to a transplant
center, most patients with hepatic metastasis have already
undergone multiple procedures, such as chemoembolization,
to attempt local regional control. With appropriate patient
selection, 5-year overall survival results with transplanta-
tion have reached 90% with 77% disease-free survival [22].
Prompted by optimistic results, UNOS has adopted guidelines
for transplantation of patients with metastatic NET (OPTN/
UNOS NET Guidelines). The patient should have already
undergone resection of the primary tumor which should be
from the portal circulation, as primaries located in the lower
rectum, esophagus, lung, adrenal gland, and thyroid have
higher likelihood of extrahepatic disease. The patient should
have at least 6 months of observation after resection of the pri-
mary, a criterion to identify pre-existing extrahepatic disease
or unfavorable tumor biology. The tumor must be by lobar
and not amenable to standard resection. Only well- and mod-
erately differentiated tumors with a mitotic rate less than 20
per 10 high power fields and less than 20% Ki-67 positive
markers should be considered for potential MELD exception
points. Tumor metastatic replacement should not exceed 50%
of the total liver volume and the metastatic workup should
include one of the following: Positron emission tomography
(PET scan), Somatostatin receptor scintigraphy, Gallium-68
(68 Ga)-labeled somatostatin analog 1,4,7,10-tetraazacyclo-
dodedcane-N, N′, N″,N′″-tetraacetic acid (DOTA)-D-Phe1-
Try3–octreotide (DOTATOC), or other scintigraphy to rule
out extrahepatic disease, especially bone metastasis(OPTN/
UNOS NET Guidelines). If the patient meets these criteria,
the center may request MELD exception points from UNOS’
National Liver Review Board (NLRB). These exception
points are generally below the Median MELD at Transplant
(MMAT); therefore, the patient is less likely to receive primary
liver offers from deceased donors as they are not “top of the
list.” More likely, these patients will be offered livers rejected
for patients higher on the list. Alternatively, if the patient has
a potential living donor, the donor can be evaluated once the
recipient is listed regardless of MELD and the transplant can
proceed at the discretion of the transplanting center. While
the patient is waiting, a metastatic survey must be completed
every 3 months showing no extrahepatic disease progression
in order to maintain MELD exception points. If the patient
develops extrahepatic disease during this time, he or she is no
longer considered a transplant candidate.
Colorectal metastasis as a transplant
indication
If left untreated, median survival for patients with hepatic
metastasis of colorectal cancer is about 6 months [23]. With
chemotherapy and/or immune therapies, such as VEGF or
EGFR antibodies, extension of median survival is still less
than 2 years [24]. Of patients with colorectal metastasis to
the liver, fewer than 10% are likely curable with surgical
resection or transplant [25]. If possible, the patient should
have resection; however, bilobar disease may be amenable
to transplant under strict criteria. In 2013, Hagness et al.
reported a series of 21 patients with colorectal hepatic
metastasis treated with liver transplantation [26]. All pri-
mary tumors had been previously resected. The median
number of metastases was 8 (range 4-40). The median time
from primary resection to liver transplant was 36 months for
metachronous metastasis and 16 months for synchronous
metastasis. Overall survival was 95%, 68%, and 60% at 1,
3, and 5 years, respectively. Metastatic or local recurrence
was diagnosed in 19 of 21 patients after a median time of
6 months. Despite the recurrent disease, overall 5-year sur-
vival was 60% with 1-year disease-free survival of 35% and
no patients with long-term disease-free survival. The overall
5-year survival of 60% was a significant survival advantage
over those not qualifying for transplant. The report was
from Oslo University Hospital which has the advantage of
Norway’s high donation rate with a surplus of donor liv-
ers such that these patients could receive deceased-donor
transplants. In the USA, there is no advantage or MELD
exception provided to patients with colorectal metastases
to the liver, so there is little option to provide these patients
with a deceased-donor transplant, unless via a marginal
organ turned down for others higher on the list. Living
donation can provide a mechanism to be able to transplant
these patients. Our criteria at the University of Pittsburgh
include prior resection of the primary, confirmed colorectal
metastasis to the liver not amenable to curative resection,
chemotherapy of at least 6–12 weeks with no evidence of
disease progression, a waiting period of at least 6 months
after resection of the primary as an assessment of tumor
biology, no evidence of extrahepatic metastases on CT or
MRI of chest/abdomen/pelvis, PET scan, or bone scan at
time of transplant evaluation, CEA less than 100 ng/dl at
time of evaluation, and the availability of a living donor.
BRAF mutant tumors are excluded secondary to aggres-
sive biologic behavior. At time of transplant, the abdomen
is explored for gross evidence of metastatic disease and the
hilar lymph nodes are resected and sent for frozen section
histologic analysis to confirm no evidence of nodal disease
prior to proceeding with the transplant.
The future for liver transplantation
With expanding indications for liver transplantation, the
near future is focused on identifying ways to find trans-
plantable organs. Xenotransplantation and organ manufac-
turing through scaffolding or 3-D printing are experimental
13

concepts but are likely far in the future in terms of clinical
feasibility. Machine perfusion of deceased-donor livers is
being increasingly used to assess function and perfusion,
particularly of marginal organs such as those from DCD
donors. With an increase in number of livers being trans-
planted from donors after cardiac death, ischemic chol-
angiopathy is a concern for transplant centers in terms
of patient outcomes as well as transplant center graft and
patient survival metrics. Ex vivo machine perfusion may
be particularly helpful in sparing these grafts. Ischemic
cholangiopathy has been described as the Achilles heel of
transplantation using livers from donors after cardiac death
[27]. It is hypothesized that the process of cardiac function
decline with hypotension and hypoxia after donor extubation
until declaration of death and perfusion of the liver leads to
micro-thrombi formation within the peribiliary plexus such
that the bile ducts are poorly reperfused in the recipient.
Days to months after transplant this may result in biliary
strictures and intrahepatic abscesses requiring endoscopic
or percutaneous stenting, drainage procedures, and the pos-
sibility of the need for retransplantation. Early data suggests
that machine perfusion of livers ex vivo may reduce the inci-
dence of clinically significant ischemic cholangiopathy [28].
There are currently two ongoing multicenter trials in the
USA studying the benefits of machine perfusion. One is with
the OrganOx device and one with Transmedics. These trials
will likely conclude within the next year.
Living donor liver transplantation
With a high percentage of waitlist deaths in an unchanging
deceased-donor pool, US transplant centers are increasingly
looking toward living donor liver transplantation (LDLT) to
bridge the gap. In 2018, there were 402 LDLT s performed
in the USA, accounting for fewer than 5% of all transplants.
The Starzl Transplantation Institute at the University of
Pittsburgh has prioritized LDLT and considers it the first and
best option for patients needing liver transplant. By adopting
a philosophy that any patient who is a candidate for liver
transplant is a candidate for LDLT, as well as a program of
education and identification of a “Donor Champion,” LDLT
has surpassed deceased-donor liver transplants at our center,
increasing more than 30% over the past 5 years. This has
significantly decreased waitlist deaths and overall waiting
time at our center [29].
Conclusion
The liver transplant field is ever changing and evolving.
As one problem is conquered, another takes its place. It is
unlikely that the need for liver transplantation will go away,
13
Abdominal Radiology
nor that the organ supply will suddenly get better, but we
must not be afraid to accept new indications if they arise or
shy from the technical difficulties of the surgery. In all, our
best efforts should be spent in educating our patients and
our potential donors as to realistic expectations from the
transplant process.
Acknowledgements This work was supported in part by Health
Resources and Services Administration Contract 234-2005-37011C.
The content is the responsibility of the authors alone and does not nec-
essarily reflect the views or policies of the Department of Health and
Human Services, nor does mention of trade names, commercial prod-
ucts, or organizations that imply endorsement by the US Government.
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