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REVIEW ARTICLE MAZZARELLI ET AL.

Palliative Care in End-Stage Liver

Disease: Time to Do Better?
Chiara Mazzarelli,1,2 Wendy M. Prentice,3 Michael A. Heneghan,1 Luca S. Belli,2
Kosh Agarwal,1 and Mary D. Cannon1
1
Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom; 2Hepatology and Gastro-
enterology Unit, ASST Ospedale Niguarda, Milan, Italy; and 3Cicely Saunders Institute, King’s College Hospital NHS Foundation
Trust, London, United Kingdom

Optimal involvement of palliative care (PC) services in the management of patients with decompensated cirrhosis and
end-stage liver disease (ESLD) is limited. This may result from both ignorance and the failure to recognize the spectrum
and unpredictability of the underlying liver condition. Palliative care is a branch of medicine that focuses on quality of life
(QoL) by optimizing symptom management and providing psychosocial, spiritual, and practical support for both patients
and their caregivers. Historically, palliative care has been underutilized for patients with decompensated liver disease. This
review provides an evidence-based analysis of the benefits of the integration of palliative care into the management of
patients with ESLD.

Liver Transplantation 24 961–968 2018 AASLD.

Received January 17, 2018; accepted April 8, 2018.

Mortality from liver cirrhosis has increased signifi-
cantly over the past 30 years and was estimated to
account for more than one million deaths worldwide in
2010.(1) In the United States, liver disease accounts for
almost 200,000 hospitalizations annually.(2) For
patients with decompensated cirrhosis, liver transplan-
tation (LT) remains the only curative treatment option.
The scarcity of donor organs has led to the use of strict
eligibility criteria to identify those patients for whom
LT will offer the greatest benefit. For patients deemed
unsuitable for transplantation, the alternative treatment
options are supportive management and palliative care
(PC).
Given the significant symptom burden and poor
prognosis associated with the development of end-stage
liver disease (ESLD), these patients and their caregivers
may be better served by proper integration of PC into
the management of ESLD. Moreover, patients listed
for LT, who by definition have advanced disease, could
benefit from early engagement with PC as part of their
overall management plan. This would ensure optimal
symptom control, as well as providing psychosocial sup-
port to both patients and their families.

Abbreviations: ACLF, acute-on-chronic liver failure; CLIF-C,

chronic liver failure consortium; CP, Child-Pugh; ESLD, end-stage
liver disease; HE, hepatic encephalopathy; HCC, hepatocellular carci-
noma; LT, liver transplantation; MELD, Model for End-Stage
Liver Disease; MELD-Na, modified Model for End-Stage Liver
Disease score that includes serum sodium; PC, palliative care; QoL,
quality of life.
Address reprint requests to Mary D. Cannon, M.B., M.R.C.P.I.,
Ph.D., Institute of Liver Studies, King’s College Hospital, London,
SE5 9RS. Telephone: 144 203 299 3252; FAX: 144 203
2993167; E-mail; mary.cannon@nhs.net
Copyright V
C 2018 by the American Association for the Study of Liver
Diseases.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/lt.25193
Potential conflict of interest: Nothing to report.
End-Stage Liver Disease
The natural history of cirrhosis is typically progression
from an early asymptomatic phase termed
“compensated cirrhosis,” to the development of portal
hypertension and complications, with or without liver
dysfunction, termed “decompensated cirrhosis” or
ESLD.(3) ESLD is characterized by acute decompen-
sating episodes, often necessitating hospitalization for
the management of ascites, hepatic encephalopathy
(HE), portal hypertensive gastrointestinal bleeding,
and jaundice. For those with compensated liver dis-
ease, the risk of mortality is low, at 1% to 3% per year,
but the risk inexorably increases for those with decom-
pensated liver disease or evidence of portal hyperten-
sion.(3,4) Moreover, the typical representation of the
REVIEW ARTICLE | 961

MAZZARELLI ET AL.
survival of patients with ESLD by Kaplan-Meier
curves does not accurately illustrate the prognosis of
patients with liver disease, as they cannot mirror the
fluctuating trajectory of ESLD or describe the likeli-
hood of sudden decompensating events or their impact
on an individual’s prognosis.(5) Managing this uncer-
tainty in the clinical context is a challenge for all those
involved in healthcare.
LT: Too Sick to Transplant
Approximately 50% of patients evaluated for LT are
deemed ineligible due to the presence of serious
comorbidities, advanced hepatocellular carcinoma
(HCC), psychosocial issues, or because they are con-
sidered too early for transplantation.(6,7) Those who
are on the waiting list remain at risk of further deterio-
ration including the development of muscle wasting
and functional decline. In fact, it has been reported
that 20% of LT candidates in the US die or are
delisted every year because they become “too sick for
transplantation,” often related to progression of HCC
or clinical deterioration.(8,9) Model for End-Stage
Liver Disease (MELD) score and age > 65 years at
listing are associated with a greater wait-list mortality,
with studies also identifying older age as having a neg-
ative impact on posttransplant survival.(10-12) This is
likely reflective of the relative frailty of elderly patients
who are at greater risk of developing liver-related com-
plications or physical or functional decline.(8) However,
the concept of frailty is not only limited to older
patients, but may also affect younger patients with
ESLD. The Fried Frailty score is associated with both
admission to hospital and the total number of days
hospitalized per year for patients with cirrhosis, inde-
pendent of the severity of liver disease, and it has been
shown to be a predictor of overall and wait-list mortal-
ity for patients with ESLD.(13-15) Sarcopenia, which is
present in half of patients with cirrhosis, is associated
with an increased risk of life-threatening complications
such as infections, and has also been identified as an
independent predictor of mortality in patients with
cirrhosis.(16)
The literature to date has demonstrated that PC
referral is often denied or delayed for patients who
are either delisted or die awaiting liver transplanta-
tion.(17,18) Walling et al. demonstrated that patients
considered for transplantation usually received lower
quality end-of-life care and had longer hospitaliza-
tions before death.(19) In fact, the transplant
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LIVER TRANSPLANTATION, July 2018
imperative, which is the perceived obligation of
health-care providers to proceed with organ trans-
plantation, can lead to a delay in advanced care plan-
ning and/or goals of care discussion, even for those
patients whose clinical status has worsened and have
a low likelihood of longterm survival.(20,21) However,
several promising models of integration of PC serv-
ices for patients awaiting LT have been reported. The
integration of PC referral as part of the routine out-
patient review for patients awaiting LT has been
shown to be associated with a significant improve-
ment in the symptom burden of patients with
ESLD.(22) Moreover, the hepatology unit and hos-
pice service at the University of California introduced
the concept of comanagement for patients with
ESLD.(23) A total of 157 patients with cirrhosis who
were admitted for a decompensating event were
enrolled to receive hospice service in combination
with standard of care. Of the total cohort enrolled,
only 10% were considered suitable for LT and listed,
demonstrating the pressing need for PC input in this
setting.
The Role of Palliative Care
The primary aims of PC are symptom management
and the provision of psychosocial, spiritual, and practi-
cal support for patients with life-limiting and life-
threatening illnesses and their caregivers. PC is appli-
cable early in the course of terminal illness, in conjunc-
tion with other active therapies that are intended to
prolong life. PC has been progressively integrated into
the management of other chronic diseases, including
heart failure, respiratory diseases, and renal failure.(24-
26)
This is in contrast to the management of patients
with ESLD, for whom PC is often neglected until late
in the disease course.
Over the past decade, however, referral of patients
with ESLD to PC services has slowly increased, with a
recent publication documenting a rise in referral rate
from 1% in 2006 to 7% in 2012.(27-29) Despite this,
several inequalities in access to PC services remain.
Patients with ESLD and low socioeconomic status,
Hispanic ethnicity, those who reside in the northeast-
ern part of the United States, and those treated in
small and nonteaching hospitals were less likely to
receive a PC review.(29) Conversely, patients with
HCC or a metastatic cancer were more likely to receive
a PC review, likely related to the greater awareness of
the benefits of PC for patients with cancer.(30)
 15276473, 2018, 7, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/lt.25193 by Cochrane Romania, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
LIVER TRANSPLANTATION, Vol. 24, No. 7, 2018 MAZZARELLI ET AL.

Who to Refer? higher predictive accuracy than the MELD, MELD-

In order to optimize the integration of PC into the
management of ESLD, the first step is to identify
potential clinical triggers for referral. ESLD natural
history models or scores should be routinely used for
the identification of patients at “high risk” who are
likely to benefit from PC input. Ascites is often the
first complication of ESLD, and when refractory, is
associated with a 1-year mortality of almost 70%.(31,32)
The development of encephalopathy also confers a
poorer prognosis.(32) Patients with cirrhosis, especially
those with decompensated liver disease, are also at
increased risk of concurrent infection. Arvaniti et al.
demonstrated that infection increases mortality 4-fold
for patients with ESLD; 30% of patients die within 1
month of infection and another 30% die by 1 year.(33)
Therefore, these patients should be referred for PC
evaluation, as should all patients with decompensated
cirrhosis who have contraindications to LT (older age,
decreasing performance status, metastatic HCC,
comorbidities) and patients removed from the waiting
list because they are “too sick to be transplanted.”
Moreover, it has been widely demonstrated that
liver-specific scoring systems are useful to predict mor-
tality in patients with advanced liver disease, rather
than survival after LT, and can be used to identify
patients who are approaching the end of life.(34) The
most common scores used in practice are the Child-
Pugh (CP) and MELD, with a higher CP or MELD
score reflecting more advanced liver disease. MELD
score has been shown to be a robust predictor of mor-
tality across a broad range of patients and superior to
Na, and CP score for 28-day and 90-day mortal-
ity.(38,39) On the other hand, ACLF is a dynamic con-
dition that may improve or worsen during
hospitalization, with ACLF grade at days 3-7 after
diagnosis noted to be a more accurate predictor of 28-
day and 90-day mortality than the initial ACLF grade
at diagnosis.(40) Patients with a persistent ACLF grade
of 2 or 3 at days 3-7 after admission should be referred
for PC consultation, given the high risk of death, with
reported 28-day mortalities of 57% and 87%, respec-
tively.(40) The estimated mortality rates based on CP
score, MELD score, and ACLF grade are illustrated
in Table 1.
Hudson et al. have recently presented and validated
a “Plan-Do-Study-Act” protocol in a small cohort to
identify patients with decompensated cirrhosis at
higher risk of death.(42) The presence of 3 or more fac-
tors on admission to the emergency department,
including CP-C, a history of 2 or more admissions in
the prior 6 months, ongoing alcohol use in the context
of known alcohol-related liver disease, unsuitability for
LT, and World Health Organization Performance sta-
tus 3 or 4 predicted 1-year mortality with a sensitivity
of 72%. The presence of 3 or more factors was a trigger
for implementation of the supportive care intervention,
including discussion about prognosis, referral to PC
services, allocation of a specialist hepatology nurse, and
notification of the primary care provider regarding
prognosis.(42)
Moreover, screening tools based on variables linked
to mortality risk have been developed to identify
patients with chronic diseases who may benefit from
C

CP for predicting 3-month mortality.(35) In addition, PC input. The NECPAL CCOMS-ICOV and Sur-
it has been also demonstrated that the rate of change prise question is a multidimensional questionnaire that
of MELD score over time is independently associated
with an increased mortality risk.(36) A rapid increase
(during the previous 30 days) of > 5 points in MELD TABLE 1. Mortality of Patients With Cirrhosis Based on
Child-Pugh, MELD Score, and ACLF Grade
has been associated with a 3-fold higher risk of death
compared with patients who have a gradual rise of 28-day 90-day 365-day
MELD score.(36) Recently, the combination of a novel Child-Pugh
frailty index with modified Model for End-Stage Liver A n/a n/a 5%
B n/a n/a 20%
Disease score that includes serum sodium (MELD- C n/a n/a 55%
Na) score has been shown to be a better predictor of MELD Score
wait-list mortality compared with MELD-Na 10-19 n/a 6% n/a
20-29 n/a 20% n/a
alone.(37) 30-39 n/a 53% n/a
The CLIF-C acute-on-chronic liver failure ACLF Grade
(ACLF) score has been validated for patients with ACLF 1 22% 41% n/a
ACLF 2 32% 52% n/a
ACLF, (an acute deterioration of liver function in
ACLF 3 77% 79% n/a
patients with or without cirrhosis potentially resulting
in multiorgan failure), and has been shown to have a NOTE: Data from references 3, 35, and 41.

REVIEW ARTICLE | 963


MAZZARELLI ET AL.

FIG. 1. Clinical triggers for referral of patients with ESLD to
the palliative care service.

is divided into 2 parts. The first part is based on the
surprise question, “Would you be surprised if this
patient dies within the next year,” with the second part
exploring different domains (functional, nutritional,
and cognitive status; frailty; emotional symptoms; and
comorbidities) and their severity and progression. This
has been validated in a large cohort of patients with
advanced chronic diseases and demonstrated to be a
valuable screening tool for the identification of patients
with a high risk of mortality over the subsequent 24
months.(43,44) A summary of clinical triggers for refer-
ral of patients with ESLD to PC are illustrated in Fig-
ure 1.
Quality of Life and
Palliative Management
The principle complications of advanced liver disease
significantly reduce the quality of life (QoL) and nega-
tively affect both the physical and mental health of
patients.(45) The literature to date has tended to focus
on single symptoms experienced by patients with
ESLD rather than providing an overall perspective.
Symptom management is the major component of PC,
with early recognition leading not only to an improve-
ment in the QoL of patients and enhanced satisfaction
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LIVER TRANSPLANTATION, July 2018
with hospital care, but also reducing the number of
ICU admissions and hospitalization costs.(46,47)
Moreover, the timing of referral to PC is extremely
important. It has been demonstrated that early involve-
ment of PC leads to a significant improvement in
QoL, physical and functional well-being, and longer
survival, despite less aggressive medical care at the end
of life.(48) On the contrary, the absence or delay in
referral to PC services may lead to ongoing intensive
interventions and futile management, and limit the
subsequent benefits of PC or hospice admission.(49,50)
Kelly et al. demonstrated that patients with ESLD
admitted to hospice care after PC review had a median
survival of 15 days, as compared with < 1 day for those
referred without PC consultation.(49) Fukui et al. have
recently shown that patients with chronic liver disease
have longer and more costly hospitalizations before
hospice enrollment compared with patients without
cirrhosis, likely reflecting a relatively late referral
bias.(50)
Although hepatologists are becoming increasingly
aware of the benefits of PC for patients with ESLD,
referral to the service is often delayed. In a retrospec-
tive single-center study, Kathpalia et al. demonstrated
that only 17% of patients who died awaiting LT
received a PC referral.(17) For the majority, evaluations
were performed in the inpatient setting, and for half,
they occurred at a late stage, within 72 hours of the
patient’s death. Poonja et al. reported that only 11% of
patients removed from the transplant waiting list
received a PC referral despite more than 50% of
patients having severe symptoms such as pain or nau-
sea.(18) This study also highlighted that the goals of
care and “do not resuscitate” status are rarely discussed
with patients with ESLD.(18) Although cirrhotic
patients with liver cancer are more likely to receive a
PC referral, palliative input can lead to improvements
in QoL for all patients with ESLD, facilitate advance
care planning, and provide emotional support for fam-
ily members.(51,52)
Finally, Low et al. confirmed in a recent publication
that PC provision is often offered late due to a lack of
clinician knowledge of liver disease trajectories, an igno-
rance of the benefits of PC for symptom control and
psychosocial support, together with a lack of skills and
confidence in initiating advance care planning discus-
sions with patients or family members.(53) In addition, a
patient’s expectation of LT to extend life, coupled with
the negative perception of PC services as “end of life
care” by patients and families, all contribute to a delay in
linkage with PC by both patients and clinicians.
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LIVER TRANSPLANTATION, Vol. 24, No. 7, 2018 MAZZARELLI ET AL.

TABLE 2. Major Complications Experienced By Patients With Cirrhosis and Suggested Palliative Management
Complication Treatment Prevention
Ascites - Diuretics and sodium restriction - Low sodium diet
- Therapeutic paracentesis
- Consider transjugular intrahepatic portosystemic shunt for
refractory ascites
Hepatic encephalopathy - Lactulose - Avoid sedatives.
- Rifaximin - Protein restriction is not beneficial.
Pain management - Paracetamol (reduced dose, maximum 2 grams/day) - Avoid NSAIDs due to the risks of mucosal bleed-
- Opioids (fentanyl, morphine, and buprenorphine). Lower ing, renal impairment, and precipitation of hepa-
starting dose and longer dosing interval. Regularly assess torenal syndrome.
for possible side effects and actively manage constipation
related to opioid use.
Malnutrition - A late evening snack before bedtime (210 Kcal) can
improve nutritional parameters and quality of life
Depression - Selective serotonin reuptake inhibitors. No alteration to - Tricyclic antidepressants are not recommended
starting dose, but the maximum dose is reduced by half due to an increased risk of anticholinergic and
sedative effects.

NOTE: Data from references 59-61.

The routine integration of PC referral into the out-
patient transplantation assessment process has been
shown to significantly improve the symptoms of
patients with ESLD, impacting positively on depres-
sion, pruritus, appetite, anxiety, and fatigue.(22) In sur-
gical and oncology settings, early incorporation of PC
has been demonstrated to increase family goals of care
consensus and advance directive planning, but this has
not yet been shown for patients with ESLD.(54,55)
This is likely related to a difference in the perceived
prognosis of the underlying condition. In contrast to
patients with metastatic cancer, patients awaiting LT
often have a more optimistic view of their prognosis
and tend to be less accepting of the possible negative
trajectories and connotations of their disease, and less
willing to engage in addressing end-of-life issues.(22)
Fatigue, weakness, pain, and lack of energy have
been identified as the symptoms most commonly expe-
rienced by patients with chronic liver disease.(56-58)
While expertise in symptom management for other
diseases has advanced, the selection of appropriate
medication and dosing for patients with ESLD is often
more difficult due to a lack of evidence-based litera-
ture. Suggested treatments and preventative strategies
for the management of the commonest complications
of ESLD are illustrated in Table 2.
Hospice
Hospice care is a distinctive and small program of PC
offered to patients with an estimated life expectancy of
6 months or less when curative therapy is no longer the
focus of treatment. Again, referral is often delayed for
patients with ESLD, with 1 study reporting that 22%
of patients admitted with liver and biliary disease died
within 7 days of admission to hospice, compared with
an overall mean early mortality of 15%.(62) Short sur-
vival after admission to a hospice may indicate that
hospice providers have not had sufficient time to iden-
tify the care needs and devise an optimal management
plan, and it also suggests that patients may have
received an unnecessary aggressive treatment course.
As previously reported, there are currently no practice
guidelines to facilitate the identification of which
patients with ESLD to refer to hospice care. In a very
limited patient cohort, MELD score  25 was dem-
onstrated to be an accurate predictor of 30-day mortal-
ity for patients with cirrhosis enrolled in hospice
care.(63)
Caregiver Support
Only a few small studies have explored the QoL of
caregivers of patients with ESLD and assessed the per-
spective of the relatives of patients awaiting LT. Rodri-
que et al. highlighted through a questionnaire-based
study that the presence of a caregiver during the illness
course led to numerous benefits (eg, identifying what is
important in life, realizing one’s inner strength, provid-
ing emotional support to the patient).(64) In addition,
they demonstrated that a high proportion of caregivers
experience depression, stress, and a reduced QoL
related to the burden of their caregiver role. Even if a
patient underwent LT, the caregiver’s burden
remained similar, or even increased, remaining persis-
tently greater than that of the general population.(65)

REVIEW ARTICLE | 965


MAZZARELLI ET AL.
Separately, it has been reported that caregiver
depression may potentially harm the patient due to a
reduction in caregiver support.(66) The early involve-
ment of PC in patients with advanced cancer has been
shown to extend beyond patient outcomes and posi-
tively influence the experience of caregivers through a
reduction in depression and anxiety.(54) An integrated
PC pathway for ESLD is likely to be extremely benefi-
cial not only for patients themselves but also for reduc-
ing the burden on their caregivers during the disease
course.
Integration of PC into the
Management of Patients
with ESLD
The evidence has demonstrated that better integration
of PC with hepatology services could enhance the
quality of care for both patients and their caregivers.
However, several barriers need to be addressed. Firstly,
the fluctuating trajectory of ESLD is associated with
under-referral of patients with advanced liver disease
to PC services, and an appropriate balance between
active and palliative interventions may be difficult to
reach. Breaking down misperceptions regarding the
role of PC services may support increased integration
and the potential for parallel planning in this situation.
Secondly, despite enormous improvements in the
management of patients with cirrhosis, in-hospital
mortality has remained stable for several decades.
Attention should be drawn to the dramatic increase in
mortality associated with the development of decom-
pensating events such as ascites or HE, or complica-
tions of portal hypertension. Therefore, a wide-
ranging awareness of the natural history of ESLD is
fundamental to allow the early identification of poten-
tial triggers for PC consultations and hospice referral.
Scores such as the CP, MELD, and CLIF-C ACLF
may serve as useful tools to identify those patients at
greatest risk of mortality who may benefit from pallia-
tive interventions. In addition, prognostic tools as the
C Muralidharan V, et al. Risk factors for liver transplantation wait-
NECPAL CCOMS-IQOV should be incorporated
into routine daily practice. The evidence base regarding
the use of appropriate drugs in the management of
symptoms also needs to increase.
At a societal level, the misperceptions regarding the
role of PC in the management of ESLD must be
addressed. International societies should urgently con-
sider the integration of PC into the management
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LIVER TRANSPLANTATION, July 2018
paradigms for patients with ESLD to ensure that com-
mon strategies and the same standard of care is deliv-
ered globally, as has been done with other chronic
diseases. Clinicians should start to systematically assess
the symptom burden of patients with ESLD and dis-
cuss the goals of care and the potential trajectories of
their disease. PC consultation should not be delayed to
the late hours of life, but instead should be embedded
within routine hepatology practice. An active presence
and continuous discussion between PC and the
extended hepatology team is essential to maintain the
comfort and dignity of patients, and to avoid futile and
unnecessary interventions for patients with ESLD.
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