Current Approaches in the Allocation of Liver Transplantation

Abstract

In recent decades, important advances have been made in the field of liver transplantation. One of the major problems remaining in this area is the small number of donors. Thus, recent data bring multiple updates of the indications and contraindications of this therapeutic method. The main goal is to increase the number of patients who can benefit from liver transplantation, a therapeutic method that can improve life expectancy and the quality of life of patients with end-stage liver disease. Another goal in the management of these patients is represented by the optimal care of those on the waiting list during that period. A multidisciplinary team approach is necessary to obtain the best results for both the donor and the recipient.

Full text

Citation: Ionescu, V.A.;
Diaconu, C.C.; Bungau, S.; Jinga, V.;
Gheorghe, G. Current Approaches in
the Allocation of Liver Transplantation.
J. Pers. Med. 2022,12, 1661. https://
doi.org/10.3390/jpm12101661
Academic Editors: Michael L. Kueht
and Muhammad Mujtaba
Received: 19 August 2022
Accepted: 4 October 2022
Published: 6 October 2022
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Journal of
Personalized
Medicine
Review
Current Approaches in the Allocation of Liver Transplantation
Vlad Alexandru Ionescu 1,2, Camelia Cristina Diaconu 1,3,4,* , Simona Bungau 5, * , Viorel Jinga 1,4,6
and Gina Gheorghe 1,2
1“Prof. Dr. Theodor Burghele” Clinical Hospital, University of Medicine and Pharmacy Carol Davila,
050474 Bucharest, Romania
2Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
3Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
4Medical Sciences Section, Academy of Romanian Scientists, 050085 Bucharest, Romania
5
Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
6Department of Urology, “Professor Dr. Theodor Burghele” Hospital, 050653 Bucharest, Romania
*Correspondence: camelia.diaconu@umfcd.ro (C.C.D.); simonabungau@gmail.com (S.B.);
Tel.: +40-726-377-300 (C.C.D.)
Abstract:
In recent decades, important advances have been made in the field of liver transplantation.
One of the major problems remaining in this area is the small number of donors. Thus, recent data
bring multiple updates of the indications and contraindications of this therapeutic method. The main
goal is to increase the number of patients who can benefit from liver transplantation, a therapeutic
method that can improve life expectancy and the quality of life of patients with end-stage liver
disease. Another goal in the management of these patients is represented by the optimal care of those
on the waiting list during that period. A multidisciplinary team approach is necessary to obtain the
best results for both the donor and the recipient.
Keywords: liver transplantation; indications; contraindications; list management; donor base
1. Introduction
Over the past three decades, liver transplantation has become an option for saving
the lives of patients with end-stage liver disease, liver malignancies, metabolic diseases
with liver damage, or acute liver failure. The purpose of the transplant is to prolong the
life of the recipient and improve their quality of life. According to data from the Organ
Procurement and Transplantation Network, in 2012, more than 6000 liver transplants were
performed in the United States (US) from brain-dead donors, while 240 transplants were
performed from living donors [
1
]. A study published in 2018 reported a significant increase
in the number of liver transplants (8082) performed in the US during that year [
2
]. However,
the same study also highlights the large number of patients who remained on the waiting
list, namely 13,869. Of these, 1169 died on the waiting list and 1304 were removed from
the list because of worsening liver disease and failure to meet the criteria for transplant
eligibility [2].
In Europe, the 2018 Liver Transplant Registry Report provides a comprehensive
overview of the status and evolution of liver transplantation [
3
]. Thus, 146,782 transplants
performed during 1968–2016 are mentioned from 169 centers in 32 European countries. To
date, both the number of liver transplant centers and the annual number of liver transplants
performed in Europe have gradually increased since the establishment of this registry date
(7 liver transplants performed in Europe in 1968 vs. 5393 liver transplants in 2016) [
3
].
However, after an exponential increase in the 1980s, over the last few years, a plateau
appears to have been reached, with an average of approximately 7700 liver transplants
performed annually in Europe [3].
J. Pers. Med. 2022,12, 1661. https://doi.org/10.3390/jpm12101661 https://www.mdpi.com/journal/jpm

J. Pers. Med. 2022,12, 1661 2 of 14
The outcomes for liver transplant patients continue to improve due to the optimization
of both surgical techniques and immunosuppressive regimens and due to better manage-
ment of infections and post-transplant complications.
Despite these successes, the spread of transplantation from brain-dead donors is lim-
ited by the reduced availability of donor organs [
4
]. A study assessing the evolution of liver
transplantation in France, however, reports an increase in the rate of liver transplantation
from brain-dead donors, from 23.8 cases per one million inhabitants in 2009 to 28.8 cases
per one million inhabitants in 2017 [
5
]. The same study reports a family refusal rate for the
years 2016–2017 of approximately 30–33% regarding organ transplantation [5].
The lack of donors remains, however, arguably the biggest challenge facing the liver
transplant community today, with aggressive approaches to organ distribution and use
being managed by an environment of intense government oversight [2].
2. World Liver Transplant History
The history of solid organ transplantation dates back several decades, but the success
of this therapeutic option has been documented since the advent of more aggressive surgical
techniques, immunosuppressive agents, and improved methods of organ preservation.
The earliest attempts at liver transplantation were in canine models but did not initially
see therapeutic success. In 1952, Vittorio Staudacher, in Italy, published the first description
of a canine liver transplant [6]. In the US in 1955, Stewart Welch described another canine
transplant attempt, followed in 1956 by Jack Cannon of the University of California, Los
Angeles, who described the concept of orthotopic transplantation [7].
These initial transplants led to the rapid death of the recipient but formed the basis for
future studies. Shortly thereafter, in 1958, teams led by Thomas Starzl in Denver, Colorado,
and Francis Moore in Boston, Massachusetts, performed canine liver transplants. They
were technically successful but were doomed to failure due to poor organ preservation, as
well as rapid organ rejection [6].
The first human liver transplant was performed by Thomas Starzl, Colorado, in 1963,
the recipient being a pediatric patient with biliary atresia [
8
]. Unfortunately, the patient
suffered intraoperative bleeding complications that led to death [
8
]. Over the next few
years, there were other failed attempts by both Starzl’s team and other doctors. Finally,
the first successful human liver transplant was performed by Starzl in 1967 on a 19-month-
old patient with hepatoblastoma. The patient survived 13 months, later dying from a
recurrence of the malignant tumor. This case was proof of the possibility of a successful
liver transplant [8].
The acceptance of the concept of brain death in the US in 1968 was an additional mile-
stone in the development of liver transplantation. The possibility of preserving the donor
organs in physiological conditions led to a better quality and survival of the graft [9,10].
When the technical feasibility of liver transplantation was demonstrated, an impor-
tant discovery was made in the field of immunological therapy. In 1969, cyclosporine
was isolated from the Tolypocladiuminflatum fungus in Norway [
11
]. The introduction of
cyclosporine in the late 1970s as part of the immunosuppressive regimen in organ transplan-
tation improved the results through a lower toxicity and prevention of graft rejection, but
also a lower rate of severe opportunistic infections compared to azathioprine [
11
]. In 1979,
Calne first used cyclosporine in two patients who underwent liver transplantation [
11
,
12
].
Following the development and administration of cyclosporine, the medical and surgical
outcomes of liver transplant patients improved. Later, the introduction of tacrolimus led to
a further improvement in survival [13].
In June 1983, at the NIHCDC (National Institutes of Health Consensus Development
Conference), after evaluating 531 cases, it was decided to approve liver transplantation as a
valid therapy for the treatment of end-stage liver disease [12].
Since the 1990s, the field of liver transplantation has grown dramatically, with a
huge expansion of the number of centers performing this procedure, and today there are
hundreds of liver transplant centers in over 80 countries [
9
,
14
]. There has been a significant

J. Pers. Med. 2022,12, 1661 3 of 14
increase in the number of diseases associated with end-stage liver disease related to liver
transplantation, and the contraindications have changed as the solutions to technical
problems have improved. This has led to a shortage of donor organs, forcing transplant
coordinators around the world to adopt organ allocation strategies [
9
,
14
]. In recent years,
epidemiological data of patients undergoing liver transplantation, such as morbidity and
mortality, have significantly improved. For example, a study published in 2018 reported a
death rate of approximately 5.8% at one year after liver transplantation, and 11.3% at three
years [15].
3. Liver Transplant Allocation
3.1. Indications for Liver Transplant
Liver transplantation is recommended in patients with end-stage liver disease, liver
malignancies, liver metabolic disease, or acute liver failure (Table 1) [16–20].
Table 1. Indications for liver transplantation.
Indications for Liver Transplantation.
âViral hepatitis
- Hepatitis B
- Hepatitis C
âAutoimmune liver disease
âToxic liver disease
âMetabolic liver disease:
- Hereditary hemochromatosis
- A-1-antitrypsin deficiency
- Wilson’s disease
- Tirozinemia
- Non-alcoholic hepatic steatosis
- Glycogen storage disease type IV
- Amyloidosis
- Neonatal hemochromatosis
- Hyperoxaluria
- Urea cycle disorders
- Amino acid metabolism disorders
âCholestatic liver disease:
- Primitive biliary cirrhosis
- Primitive sclerosing cholangitis
- Biliary atresia
- Alagille syndrome
- Progressive familial intrahepatic cholestasis
- Cystic fibrosis
âMalignancies:
- Hepatocellular carcinoma
- Cholangiocarcinoma
- Fibrolamellar hepatocellular carcinoma
- Hepatoblastoma
- Metastases of neuroendocrine tumors
âPolycystic liver disease
âVascular disease: Budd–Chiari syndrome
Acute fulminant liver failure
3.2. Models of Prognosis and Organ Allocation
The natural history of cirrhosis is a continuum in which patients can progress from
compensated liver disease to death. It is well known that decompensation due to compli-
cations of cirrhosis limits survival. This was demonstrated in a 2006 retrospective study
comparing the results of two large studies in 1500 patients [
21
]. The authors observed that

J. Pers. Med. 2022,12, 1661 4 of 14
patients without portal hypertension had a much better evolution and prognosis compared
to those with decompensated disease (average survival 12 years vs. 2 years) [21].
In view of these data, the authors suggested that cirrhosis should be divided into four
“stages”, in which the initial stages (one and two) are considered compensated disease and
the later stages (three and four) are considered decompensated disease [21].
Given the high rates of morbidity and mortality associated with end-stage liver disease,
it is essential that physicians caring for such patients have a valid, reproducible system for
staging disease severity and prognosis. Ideally, this system would be useful in determining
those who need a transplant.
Traditionally, the two scores used in this area are the Child–Turcotte–Pugh (CTP) score
and the model for end-stage liver disease (MELD) score, both of which are tools that help
clinicians to assess the risk of mortality and the need for a transplant [
22
,
23
]. The CTP
score was originally used as a prognostic tool to assess the risk of mortality in patients with
liver disease who have undergone surgical treatment to alleviate portal hypertension [
23
].
The score includes: serum bilirubin, albumin, increased prothrombin time above control
values, and the presence of hepatic encephalopathy and ascites [
24
]. One to three points are
assigned for each degree of variation in the parameters and a composite score is obtained
based on these (Table 2) [
24
]. The patient is included in a class according to the number of
points: A (5–6 points), B (7–9 points), or C (10–15 points) [
24
]. An increase in CTP score
suggests a low survival [24].
Table 2. CTP score and 1 and 2-year survival rates.
Points 1 2 3
Hepatic encephalopathy None Minimal Advanced
Ascites None Slight Moderate
Serum bilirubin (mg/dL) <2.0 2–3 >3.0
Serum albumin (g/dL) >3.5 2.8–3.5 <2.8
Prothrombin time (seconds) 1–4 5–6 >6
CTP classes Score
A 5-6
B 7-9
C 10-15
Survival 1 year 2 years
A 100% 85%
B 80% 60%
C 45% 35%
Prior to 2002, the CTP score was used as an index of disease severity for the allocation
of livers from the brain-dead donor [
23
,
24
]. Patients were grouped (2A, 2B, or 3) based
on CTP score (B vs. C), hospitalization status (outpatient, inpatient, or intensive care
unit), and waiting time [
25
]. Thus, patients were sorted based on waiting time. Priority
for transplantation was given to those who, despite having a less decompensated liver
disease, had a longer waiting time [
25
,
26
]. In addition, the subjectivity of the variables
of encephalopathy and ascites from the Child score led to differences in reproducibility
between centers [
25
,
26
]. As a result, the transplant community sought a more objective
index of disease severity and an allocation system that was not based on waiting time
but on the severity of liver disease. The MELD score is a mathematical score based on
three biochemical markers of liver function: serum bilirubin, INR, and creatinine [
25
,
26
]. It
was originally used to predict survival after portosystemic transjugular shunt intervention
(TIPS). As the liver function deteriorates, the MELD score increases, indicating an increase
in the severity of liver disease [
25
,
26
]. Following several studies, the MELD score was
validated as a tool for estimating the 90-day survival of patients with end-stage liver disease
(including those on the transplant list) and was adopted in February 2002 by the United

J. Pers. Med. 2022,12, 1661 5 of 14
Network of Organ Sharing (UNOS) as the preferred system for organ allocation [
25
–
27
]. In
the MELD era, those with the highest score have priority for transplantation and receive the
organ first, regardless of factors such as the etiology of their liver disease or their waiting
time. The use of the MELD score as a baseline score for organ allocation has led to decreased
organ waiting times and increased transplant rates [25,26].
Despite its successes, there are disadvantages to the MELD allocation system [
27
,
28
].
There are clearly some patients who are disadvantaged by the MELD score [
27
–
30
]. These
patients have diseases with an increased risk of mortality that cannot be expressed by INR,
serum bilirubin, or serum creatinine. An example might be patients with severe portal
hypertension, low MELD, rapid decompensation, or those with high mortality but less
severe liver disease [
28
–
30
]. To address these issues, there have been suggestions to change
the MELD score by introducing serum sodium into the equation (for refractory ascites or
portal hypertension) or to take into account acute changes in the MELD score (MELD delta)
to more accurately predict mortality and increase the priority for transplantation [
29
,
30
].
Hepatocellular carcinoma (HCC) is associated with a significant risk of mortality as a result
of reduced hepatic synthesis function [
27
–
30
]. For this reason, patients with limited HCC
are given “exceptional points” to accurately estimate the risk of mortality and to prioritize
them for transplantation (Table 3) [31,32].
Table 3. Exceptional MELD score points appraisal conditions.
Exceptional MELD Score Points Appraisal Conditions
1. Hepatocellular carcinoma
2. Cholangiocarcinoma
3. Familial amyloidosis
4. Primary hyperoxaluria
5. Hepatopulmonary syndrome
6. Porto-pulmonary hypertension
7. Refractory pruritus
8. Refractory ascites
9. Budd–Chiari syndrome
10.
Symptomatic polycystic liver disease
11.
Hereditary hemorrhagic telangiectasia
12.
Polycystic liver disease
13.
Recurrent bacterial cholangitis
14.
Recurrent variceal bleed
15.
Other gastrointestinal bleeding (not due to varices)
16.
Spontaneous bacterial peritonitis
17.
Hepatic encephalopathy
Since 1996, the Milan criteria (one nodule
≤
5 cm or three nodules
≤
3 cm, without
vascular invasion) have been validated for liver transplantation in patients with HCC [
33
].
Applying these criteria, the recurrence of HCC after liver transplantation was below 10%.
Milan citations are validated international criteria. There is an impetus from several teams
to expand these criteria. In France, the Milan criteria have been replaced by the AFP
score [34]. Therefore, some new criteria have been proposed:
•
University of California in San Francisco (UCSF) criteria (1 nodule
≤
6.5 cm, or
n≤3 nodules ≤4.5 cm, or total ≤8 cm) [35];
•
Additions to the Milan criteria: number of nodules + maximum tumor size without
vascular invasion should reach a maximum of seven [33];
•
The AFP score, which takes into account the size, number of nodules, and level of AFP
(applied in France) [34].
Due to improvements in the effectiveness of antiviral treatments, the number of
patients with decompensated viral etiology (hepatitis B/C virus) is significantly decreas-
ing [
36
]. In contrast, the number of patients with decompensated toxic-nutritional liver

J. Pers. Med. 2022,12, 1661 6 of 14
cirrhosis did not change, and the number of patients with decompensated liver disease due
to non-alcoholic steatohepatitis increased, as some US studies have already shown [37].
Therefore, it is very important for organ distribution agencies to maintain a good
balance between the different indications for liver transplantation, thus avoiding an increase
in the mortality or abandonment of patients of any category on the waiting list. It is
important to ensure access to liver transplantation for patients with decompensated liver
disease, as well as for patients with HCC and those with an intermediate MELD score.
Some authors believe that patients with MELD exceptions should have priority over those
with very high MELD scores [
31
,
32
]. The perfect equation does not exist, but a real-time
assessment of the dynamics of the waiting list by organ distribution agencies is essential to
maintain fairness.
3.3. Pre-Transplant Evaluation
The purpose of liver transplant evaluation is to identify patients who will receive the
greatest benefits from the transplant and who have the best chance of long-term survival.
Additionally, the evaluation for transplantation serves to identify which complications of
the liver disease can be modified, the conditions that can affect the result of the transplant,
and the possible contraindications of the procedure.
The diagnostic approach is multidisciplinary and involves evaluation at several levels:
medical, psychiatric, social, and financial (Figure 1) [
38
–
46
]. Recent data support the impor-
tant role of the evaluation of donor-specific antibodies (DSAs) for a proper allocation of the
organs, to identify the patients at a high risk of graft loss and to establish individualized
immunosuppressive regimens [
47
,
48
]. Legaz et al. highlighted a significantly lower sur-
vival rate among patients with a positive complement-dependent cytotoxicity crossmatch
(CDC-CM) compared to patients with a negative CDC-CM (23.1% vs. 59.1%) [
47
]. The
poor prognosis of patients with a positive CDC-CM was mainly due to the development of
allograft rejection in the first 3 months [47].
J. Pers. Med. 2022, 12, x FOR PEER REVIEW 8 of 16
Figure 1. Multidisciplinary team needed for pre-transplant evaluation.
3.4. Absolute Contraindications for Liver Transplantation
In the process of choosing the right candidates, it is necessary to exclude those with
extrahepatic diseases that confer a significant independent mortality risk (Table 4)
[46,49,50]. For example, patients with severe heart disease, including pulmonary hyper-
tension, or other severe comorbidities may be at an increased risk of intra-or postoperative
death [46,49,50]. Transplantation is contraindicated in patients with uncontrolled or ad-
vanced hepatocellular carcinoma because recurrence rates are high [49].
Most US centers require patients with a previous non-hepatic malignancy to have a
recurrence-free survival period before transplantation or a very low recurrence rate (i.e.,
high expectations of cancer cure) based on tumor type and stage [51,52]. Active and un-
controlled infections, particularly with fungi or resistant bacteria, at the time of transplan-
tation are associated with a low survival [53]. Psychosocial contraindications are not al-
ways as well defined as medical ones, but they are just as important.
The transplant process is extremely complicated from evaluation to postoperative
care; thus, patients who need a transplant must have an adequate social support system.
Uncontrolled psychiatric disorders are contraindications to transplantation [54]. Due to
the fact that many patients with liver disease have a history of substance abuse, strict ab-
stinence from illicit drugs and alcohol is required before and after transplantation [55].
Some centers also call for an end to the use of narcotics and tobacco, but these are variable.
A lack of compliance with medical advice and indications are also contraindications
to transplantation, as they predict an increased risk of non-compliance with post-trans-
plant medical regimens [56].
Figure 1. Multidisciplinary team needed for pre-transplant evaluation.

J. Pers. Med. 2022,12, 1661 7 of 14
Once the consultations and testing have been completed, a committee of regular
gastroenterologists, transplant surgeons, coordinators, and psychiatrists is convened to
select patients who meet the criteria for transplantation. When it is decided that a patient is
a good candidate for transplantation, they are placed on the waiting list of the National
Organ Distribution Network.
3.4. Absolute Contraindications for Liver Transplantation
In the process of choosing the right candidates, it is necessary to exclude those with ex-
trahepatic diseases that confer a significant independent mortality risk
(Table 4) [46,49,50]
.
For example, patients with severe heart disease, including pulmonary hypertension, or other
severe comorbidities may be at an increased risk of intra-or postoperative
death [46,49,50]
.
Transplantation is contraindicated in patients with uncontrolled or advanced hepatocellular
carcinoma because recurrence rates are high [49].
Table 4. Absolute contraindications for liver transplantation.
Absolute Contraindications
•
Severe and irreversible comorbidities with a negative impact on long-term life expectancy short
•Severe pulmonary hypertension (mean pulmonary arterial pressure ≥50 mmHg)
•Extrahepatic malignancies (except for certain forms of skin cancer)
•Extensive hepatocellular carcinoma or macrovascular or lymph node invasion
•Cholangiocarcinoma
•Uncontrolled sepsis
•Inadequate social support
•Alcohol and/or drug abuse
•Unacceptable risk of recurrence
•Severe uncontrolled psychiatric illness
Most US centers require patients with a previous non-hepatic malignancy to have
a recurrence-free survival period before transplantation or a very low recurrence rate
(i.e., high expectations of cancer cure) based on tumor type and stage [
51
,
52
]. Active
and uncontrolled infections, particularly with fungi or resistant bacteria, at the time of
transplantation are associated with a low survival [
53
]. Psychosocial contraindications are
not always as well defined as medical ones, but they are just as important.
The transplant process is extremely complicated from evaluation to postoperative
care; thus, patients who need a transplant must have an adequate social support system.
Uncontrolled psychiatric disorders are contraindications to transplantation [
54
]. Due to
the fact that many patients with liver disease have a history of substance abuse, strict
abstinence from illicit drugs and alcohol is required before and after transplantation [
55
].
Some centers also call for an end to the use of narcotics and tobacco, but these are variable.
A lack of compliance with medical advice and indications are also contraindications to
transplantation, as they predict an increased risk of non-compliance with post-transplant
medical regimens [56].
3.5. Relative Contraindications for Liver Transplantation
The relative contraindications to transplantation are usually specific to each center
and can sometimes be modified (Table 5) [
46
,
49
,
50
]. These contraindications increase the
risk and complexity of surgery.
As life expectancy increases, the consideration of transplanting elderly patients is
relevant in most US centers. There is no official age limit; however, the age of 70 years is
considered the limit for transplantation due to comorbidities, perioperative mortality, and
an increased risk of malignancy [57].
Many patients evaluated for transplantation are overweight or obese according to their
body mass index (BMI). Studies on this subgroup have shown that mortality at
5 years
was
significantly higher in those with severe obesity and morbidity as a result of cardiovascular

J. Pers. Med. 2022,12, 1661 8 of 14
events [
58
]. Following these results, many centers have set a BMI value requirement for
transplant listing [58].
Table 5. Relative contraindications for liver transplantation.
Relative Contraindications
•Advanced age (>70 years)
•Moderate pulmonary hypertension (mean pulmonary blood pressure between 35 and
50 mmHg)
•Severe hepatopulmonary syndrome with PaO2≤50 mmHg
•Morbid obesity (body mass index ≥40 kg/m2)
•Extensive portal thrombosis and mesenteric thrombosis
•MELD score < 15
•HIV infection
•Reduced compliance
•Psychiatric comorbidities
Porto-pulmonary hypertension should be managed by an experienced team who
can control high pulmonary pressures before, during, and after surgery [
59
,
60
]. Similarly,
advanced hepatopulmonary syndrome with significant shunts and hypoxemia may be
a relative contraindication to transplantation as it may require prolonged posttransplant
mechanical ventilation [61].
Uncontrolled mental illness is an absolute contraindication to transplantation, and
those with pre-existing mental illness should be under the care of a psychiatrist and have
the disease well controlled before they can be accepted for transplant [62].
HIV infection was initially considered an absolute contraindication; however, im-
proved treatment of HIV infection has made liver transplantation effective under certain
conditions [
63
]. HIV patients should be referred to a transplant center with experience in
managing specific issues related to HIV infection, both before and after transplantation [
63
].
3.6. Waiting List Management and Exclusion from the List
The success of liver transplantation has been considerable. Thus, in 2020, a total of
169,819 liver transplants (for the period 1968–2020) were reported in 32 countries and
171 centers [
64
]. This success can be explained by a very good survival rate after liver
transplantation, 90% at 1 year and 80% at 5 years, respectively [65].
In Europe, most donors are brain-dead patients or patients who have suffered a cardio-
respiratory arrest [
66
]. In these situations, the date of the transplant cannot be estimated,
unlike the transplant from live donors, where the date is scheduled. Thus, waiting for a
transplant may vary from a few days, in patients with acute hepatic impairment, to periods
exceeding 1 year, for patients with cirrhosis of the liver or hepatocellular carcinoma [65].
Liver transplant waiting lists are mainly made up of three categories of patients:
•
Patients with acute hepatic impairment, included in most countries on a “super-
emergency” waiting list, giving them absolute priority over all other potential recipi-
ents. In this category of patients, the transplant should be performed within hours
or days.
•
Patients with decompensated liver cirrhosis. The priority of liver transplantation is
dictated in this situation by the value of the MELD score. Thus, patients with a very
high MELD score will be able to receive a liver transplant within days or weeks, while
patients with an intermediate or low MELD score will wait for months or years.
•
Patients with hepatocellular carcinoma or compensated liver cirrhosis. Organ trans-
plant agencies give these patients an additional score depending on the size of the
tumor. Generally, the transplant is performed within 18 months [67,68].
For patients with end-stage liver disease, the liver transplant procedure and the post-
transplant period remain difficult. Therefore, these patients require prior training, both

J. Pers. Med. 2022,12, 1661 9 of 14
physical and mental. Managing patients on the waiting list is essential to avoid death or
abandonment caused by the worsening of their health, but also to ensure the best possible
physical condition prior to the surgical procedure. This is essential for postoperative
success [65].
Once on the waiting list, patients should continue to be monitored for complications of
end-stage liver disease. The transplant team should regularly evaluate patients for changes
in their medical and mental condition, including:
•the usual evaluation of the MELD score;
•
standard screening by upper gastrointestinal endoscopy for the presence of esophageal
or gastric varices and their prophylaxis;
•
in patients with hepatitis C-grafted hepatic cirrhosis, the opportunity for treatment
with direct antiviral agents without interferon should be discussed [68,69];
•
evaluation by abdominal ultrasound with vascular Doppler examination, every
6 months
,
to identify any tumors (hepatocellular carcinoma) or vascular complications;
•
adequate prophylaxis of spontaneous bacterial peritonitis. Patients with refractory
ascites may benefit from TIPS or repeated evacuation paracentesis.
In addition, physical activity during the waiting period has been shown to be beneficial
for the patient and may improve VO2[70,71].
When the patient’s condition has changed so that he or she can no longer survive a
transplant or benefit from a transplant, the team may decide to remove a patient temporarily
or permanently from the transplant list. Examples that could justify removal from the
list are resistant bacterial or fungal infections, sepsis requiring vasopressors, the need
for mechanical ventilation (especially with a high requirement for FiO
2
), or the need for
hemodialysis [72].
In rare cases, removal from the transplant list may occur when the patient’s condition
has improved such that the transplant is no longer justified [72].
Finally, given the organ deficit, liver transplantation should be performed in those
patients who would benefit the most. It is also necessary to optimize the management
of patients on the waiting list, to reduce the dropout rate and improve the results after
liver transplant.
3.7. Allocation of Organs
When a potential organ donor is identified, the local organ procurement organization
(OPO) is informed and begins to participate in the care of the donor organs. The OPO
staff obtain a detailed medical history and perform tests for potentially communicable
diseases. The recipient of that region or area with a compatible blood type and the largest
medical emergency or the largest MELD is the first to be offered the organ of the donor.
The transplant team has a limited amount of time to consider the information obtained
about the donor and the likelihood of an appropriate match between the organ and the
recipient [73–76].
If the transplant team accepts the organ, a sampling team is required to harvest the
organ in a timely manner. If the transplant team refuses the organ, it is offered to the next
candidate on the waiting list until it is accepted [73–76].
3.8. Extension of the Donor Base
While liver transplantation results continue to improve, this intervention is limited
by the low availability of donor organs. Every year, thousands of potential recipients die
while on the waiting list due to the inadequate organ supply. Out of a desire to improve
this, many centers encourage patients to follow up on living donors or to extend the criteria
for organ donation (Figure 2) [77].

J. Pers. Med. 2022,12, 1661 10 of 14
J. Pers. Med. 2022, 12, x FOR PEER REVIEW 11 of 16
In rare cases, removal from the transplant list may occur when the patient’s condition
has improved such that the transplant is no longer justified [72].
Finally, given the organ deficit, liver transplantation should be performed in those
patients who would benefit the most. It is also necessary to optimize the management of
patients on the waiting list, to reduce the dropout rate and improve the results after liver
transplant.
3.7. Allocation of Organs
When a potential organ donor is identified, the local organ procurement organization
(OPO) is informed and begins to participate in the care of the donor organs. The OPO staff
obtain a detailed medical history and perform tests for potentially communicable diseases.
The recipient of that region or area with a compatible blood type and the largest medical
emergency or the largest MELD is the first to be offered the organ of the donor. The trans-
plant team has a limited amount of time to consider the information obtained about the
donor and the likelihood of an appropriate match between the organ and the recipient
[73–76].
If the transplant team accepts the organ, a sampling team is required to harvest the
organ in a timely manner. If the transplant team refuses the organ, it is offered to the next
candidate on the waiting list until it is accepted [73–76].
3.8. Extension of the Donor Base
While liver transplantation results continue to improve, this intervention is limited
by the low availability of donor organs. Every year, thousands of potential recipients die
while on the waiting list due to the inadequate organ supply. Out of a desire to improve
this, many centers encourage patients to follow up on living donors or to extend the cri-
teria for organ donation (Figure 2) [77].
Figure 2. Criteria for expanding the donor base.
Extensive criteria for organ donors are those that pose a certain additional risk to the
recipient, such as the risk of disease transmission or the risk of low initial or long-term
function [77].
These organs usually come from older donors, donors with a history of exposure to
viral hepatitis or other infection, previously cured malignancies, a history of high-risk so-
cial behavior which is considered to be a risk factor for communicable diseases, partial
grafts, or organs donated after cardiac death [77–79].
Figure 2. Criteria for expanding the donor base.
Extensive criteria for organ donors are those that pose a certain additional risk to the
recipient, such as the risk of disease transmission or the risk of low initial or long-term
function [77].
These organs usually come from older donors, donors with a history of exposure to
viral hepatitis or other infection, previously cured malignancies, a history of high-risk social
behavior which is considered to be a risk factor for communicable diseases, partial grafts,
or organs donated after cardiac death [77–79].
Most organs are from brain-dead donors. These are donors who have suffered irre-
versible neurological damage with a loss of cortex and brainstem function. Those who
have suffered serious neurological damage or other critical illnesses without a reasonable
chance of a significant recovery but who do not meet the criteria for brain death may still
be considered donors after a sudden cardiac death, with the consent of the family. This
type of donor is called a cardiac death donation (DCD) [
80
]. Some centers report acceptable
transplant results with DCD grafts when the ischemia time is kept to a minimum. These
reports have led to a slight increase in the use of DCD organs, despite concerns about the
high rate of primary graft dysfunction, biliary ischemia, and the need for re-transplantation
due to prolonged graft ischemia [80].
The regenerative capacity of the liver allows the donor base to be expanded by two
mechanisms—division of the transplanted liver and liver transplantation from a living
donor [
81
]. Partial or dissociated liver cells allografts allow the division of a single organ
from the deceased donor to two recipients [
82
]. Divided allografts are usually divided
between a pediatric patient (left hepatic lobe or left lateral lobe) and an adult patient
(right lobe) [
82
]. Reports suggest that graft insufficiency after split liver transplantation
is only increased when these grafts are used in patients with fulminant liver failure and
malignancy, suggesting that—with the exception of these two diagnoses—this method
can be used [
83
,
84
]. The success of split liver transplantation has led to the emergence
of liver transplantation from living donors, becoming an important avenue for recipients
to benefit from liver transplants. Particular attention is being paid to the assessment of
potential living donors to ensure adequate social support but also in assessing health and
anatomy [83,84].
Although there are many benefits of transplanting from living donors, the most
important are providing much earlier access to a recipient organ and preventing the
progression to a complication of liver disease or even death [
85
]. In addition, a transplant
from a living donor removes the recipient from the waiting list, allows for a transplant
with a short ischemic time, and provides an even healthier organ if the donor is well
evaluated [85].

J. Pers. Med. 2022,12, 1661 11 of 14
The results of those who have received a liver from a living donor are similar or even
slightly improved compared to those who have received a liver from a deceased donor. One
study showed that adults who received a liver from a living donor had a lower mortality
rate than those who remained on the waiting list for liver transplant [
86
]. The outcomes
of patients who received transplants from living donors depend to a large extent on the
experience of the center; the centers that performed more than 20 transplants obtained
better results and lower post-transplant complication rates [86,87].
Although transplantation from a living donor is associated with excellent results, the
use of this technique is somewhat limited, as it requires the presence of a distinct donor
team. As with potential recipients, potential donors must go through an intensive medical,
surgical, and psychological assessment, an assessment of anatomical compatibility, and
must demonstrate a clear understanding of the risks associated with the procedure. The
procedure requires two qualified surgical teams working together to achieve excellent
results for both the donor and the recipient. The risks for donors, although small, include
infection, strictures of the bile ducts, the need for transplantation, and death—the latter
two being rare (<1%) [85–87].
4. Conclusions
Liver transplantation is a therapeutic option for patients with end-stage liver disease.
To obtain the best results for both the donor and the recipient, a key element is the optimal
management of organ allocation. The whole process—from being placed on the waiting
list to receiving a liver for transplant—is complex, involving a multidisciplinary team. In
recent decades, considerable progress has been made in the field of liver transplantation,
where the minimum goal is represented by an increase in the number of patients who can
benefit from this therapeutic method.
Author Contributions:
Conceptualization, V.A.I. and G.G.; methodology, G.G.; software, S.B.; valida-
tion, C.C.D., S.B. and V.J.; formal analysis, S.B.; investigation, V.A.I.; resources, S.B.; data curation,
G.G.; writing—original draft preparation, V.A.I. and G.G.; writing—review and editing, C.C.D.; visu-
alization, C.C.D. and V.J.; supervision, C.C.D.; project administration, C.C.D.; funding acquisition,
G.G. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: We thank the University of Oradea for covering the open access fee.
Conflicts of Interest: The authors declare no conflict of interest.
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