End-Stage Liver Disease

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End-stage liver disease in palliative care

Authors: Anne M Walling, MD, PhD, Neil Wenger, MD
Section Editors: R Sean Morrison, MD, Sanjiv Chopra, MD, MACP
Deputy Editors: Kristen M Robson, MD, MBA, FACG, Jane Givens, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2019. | This topic last updated: May 07, 2018.
INTRODUCTION
Palliative care is an interdisciplinary medical specialty that focuses on preventing and relieving
suffering, and on supporting the best possible quality of life for patients facing serious illness and
their families. The primary tenets of palliative care are symptom management; establishing goals
of care that are in keeping with the patient’s values and preferences; consistent and sustained
communication between the patient and all those involved in his or her care; and psychosocial,
spiritual, and practical support both to patients and their family caregivers. Palliative care is
applicable early in the course of terminal illness in conjunction with other therapies that are
intended to prolong life; it is not limited to end of life care [1]. Palliative services, including setting
patient-centered achievable goals for medical care and aggressive symptom management, should
be routinely offered alongside curative and disease-modifying treatments for patients with serious
illnesses (the simultaneous care model). (See "Benefits, services, and models of subspecialty
palliative care", section on 'Rationale for palliative care'.)
Palliative care has been best studied and implemented among patients with malignancy, yet there
is growing evidence of the many benefits of integration of palliative care for a variety of advanced
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illnesses. Despite being the 12th most common cause of death in the United States [2], end-stage
liver disease (ESLD) has only recently become a focus of palliative care research.
Palliative care issues in adult patients with ESLD will be reviewed here. An overview of the
benefits, services, and models of subspecialty palliative care is provided elsewhere. (See
"Benefits, services, and models of subspecialty palliative care".)
DEFINITIONS, CLINICAL COURSE, AND CAUSES OF DEATH
Cirrhosis versus end-stage liver disease — Cirrhosis represents the irreversible late stage of
chronic progressive liver disease; it is characterized by the distortion of hepatic architecture and
the formation of regenerative nodules. Patients with cirrhosis who have not developed major
complications are classified as having compensated cirrhosis. Patients who have developed
complications of cirrhosis, such as variceal hemorrhage, ascites, spontaneous bacterial peritonitis,
hepatocellular carcinoma (HCC), hepatorenal syndrome, or hepatopulmonary syndrome, are
considered to have decompensated cirrhosis. These complications are the primary causes of
death in ESLD. (See "Cirrhosis in adults: Overview of complications, general management, and
prognosis".)
The term “end-stage liver disease” is synonymous with advanced liver disease, liver failure, and
decompensated cirrhosis, given the general irreversibility of these conditions [3-5]. However, in
contrast to other terminal illnesses, liver transplantation can be a definitive and potentially curative
treatment for irreversible liver disease. While liver transplantation is a viable treatment option for
patients with decompensated cirrhosis (and for patients who develop HCC in the setting of
cirrhosis as long as they meet criteria for listing), many are not candidates for transplantation
because of clinical and social factors. Furthermore, the number of patients who qualify for
transplantation is much greater than the availability of donor organs. Because of wait times for
organ transplantation, approximately 14 percent of patients on a transplant waitlist die annually [6].
Many others will be delisted as they become too ill for transplantation. Thus, even with the hope of
transplant, most patients with decompensated cirrhosis will die as a result of their underlying
illness [7,8]. It may seem counterintuitive to initiate palliative care for patients considered for
transplant because of the potential for cure; however, the potential for adverse outcomes and
significant symptom burden is also high. Therefore, it is appropriate to initiate palliative care, even
while recognizing the possibility of long-term survival. (See "Cirrhosis in adults: Overview of
complications, general management, and prognosis", section on 'Liver transplantation' and "Liver
transplantation in adults: Patient selection and pretransplantation evaluation" and "Staging and
prognostic factors in hepatocellular carcinoma" and "Liver transplantation for hepatocellular
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carcinoma".)
Disease trajectory and estimating prognosis — The prognosis of cirrhosis is highly variable
since it is influenced by a number of factors, including etiology, severity, type of and severity of
complications, and comorbid disease. Patients with compensated cirrhosis have a median survival
that may extend beyond 12 years. Patients with decompensated cirrhosis have a worse prognosis
than do those with compensated cirrhosis; the average survival without transplantation is
approximately two years [9,10]. The trajectory of functional decline in patients with decompensated
cirrhosis may be erratic and unpredictable, and many patients are in a constant state of poor or
declining health interspersed by intermittent exacerbations and hospitalizations [11]. Death may be
relatively sudden and unexpected. (See "Cirrhosis in adults: Overview of complications, general
management, and prognosis".)
In general, the degree of hepatic decompensation is an important determinant of prognosis.

Multiple studies have attempted to predict the prognosis based upon clinical and laboratory
assessment of liver function. Two commonly used models are the Child-Pugh classification and the
Model for End-Stage Liver disease (MELD) score.
An important point is that, although these predictive models are useful for predicting long-term
outcomes in ESLD and guiding treatment decisions, they do not always align with the patient’s
reported functional status and sense of well-being.
Child-Pugh classification — The Child-Pugh classification (table 1) was initially developed to

assess the risk of non-shunt operations in patients with cirrhosis (calculator 1 and calculator 2)
[12]. Patients with a score of 5 or 6 have Child-Pugh class A cirrhosis (well-compensated
cirrhosis), those with a score of 7 to 9 have Child-Pugh class B cirrhosis (significant functional
compromise), and those with a score of 10 to 15 have Child-Pugh class C cirrhosis
(decompensated cirrhosis).
The Child-Pugh classification system correlates with survival in patients with cirrhosis; one-year
survival rates for patients with Child-Pugh class A, B, and C cirrhosis are approximately 100, 80,
and 45 percent, respectively [13,14]. (See "Cirrhosis in adults: Overview of complications, general
management, and prognosis", section on 'Child-Pugh classification'.)
MELD score — Another model to predict prognosis in patients with cirrhosis is the Model for
End-Stage Liver Disease (MELD) score, which was originally designed to predict 90-day mortality
in those undergoing placement of a portosystemic shunt. The MELD score is based upon bilirubin
levels, creatinine, the international normalized ratio (INR; a measure of hepatic synthetic function),
and sodium level (calculator 3 and calculator 4). The MELD score has been adopted for use in
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prioritizing patients awaiting liver transplantation and has an expanding role in predicting outcomes
in patients with liver disease in the non-transplantation setting. (See "Model for End-stage Liver
Disease (MELD)".)
The utility of the MELD score for predicting mortality among patients awaiting liver transplantation
was demonstrated in a study that included 3437 adult liver transplantation candidates who were
listed between 1999 and 2001 [15]. Of these, 412 died during the three-month follow-up period.
Waiting list mortality was directly proportional to the MELD score at the time of listing, with
mortality being 1.9 percent for patients with MELD scores less than 9, and 71 percent for patients
with MELD scores ≥40 (figure 1). A table using MELD scores to predict 3, 6, 12, and 24-month
survival is provided (table 2) [9,15].
Although the MELD score has a better ability to predict 90-day mortality than does the Child-Pugh
classification [16], an important limitation is that clinical markers, such as ascites and varices, that
represent portal hypertension are excluded from the model. Patients with portal hypertension are
often at a higher risk for short-term mortality compared with those without portal hypertension and
similar MELD scores [17]. Furthermore, the longitudinal ability of MELD to predict survival beyond
three months is not established [4].
The utility of these predictive models in estimating prognosis among patients with decompensated
cirrhosis is illustrated by a systematic review that found that the median survival was ≤6 months in
patients with decompensated cirrhosis, and a Child-Pugh score ≥12 or a MELD score ≥21 [18]. In
addition, patients with decompensated cirrhosis who had been hospitalized with an acute liver-
related illness (eg, variceal hemorrhage or spontaneous bacterial peritonitis) had a median survival
of ≤6 months if the Child-Pugh score was ≥12 or the MELD score was ≥18. Patients with ESLD
who have an estimated survival of six months or less may be eligible for hospice care, particularly
if they are not candidates for transplantation. (See 'Considerations for end of life care and hospice
referral' below.)
Other important prognostic variables — The presence of hepatorenal syndrome or renal

failure due to acute tubular necrosis in patients with cirrhosis is a particularly poor prognostic
indicator, with 90-day mortality approaching 60 percent [19]. (See "Cirrhosis in adults: Overview of
complications, general management, and prognosis", section on 'Major complications' and
"Hepatorenal syndrome".)
Among patients with ESLD, variceal bleeding has a very high mortality rate, whether or not
hemostasis is achieved [20,21]. (See "Cirrhosis in adults: Overview of complications, general
management, and prognosis", section on 'Variceal hemorrhage'.)
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Other factors associated with poor survival in patients with decompensated cirrhosis included
hepatopulmonary syndrome, intensive care unit admission for complications of liver disease with
hypotension requiring pressor support, hyponatremia [22], or jaundice. (See "Cirrhosis in adults:
Overview of complications, general management, and prognosis" and "Hyponatremia in patients
with cirrhosis".)
USE AND BENEFITS OF PALLIATIVE CARE
For patents with serious life-threatening illness, including ESLD, the primary goal of palliative care
is to improve quality of life for the patient and their family through relief of emotional distress and
physical symptoms. Ideally, palliative care should be provided throughout the trajectory of illness,
beginning with the diagnosis of ESLD. Relief of emotional distress and physical symptoms can be
provided by primary care physicians and gastrointestinal and hepatology specialists (termed
primary palliative care, to distinguish it from secondary or subspecialty palliative care). Ideal timing
of subspecialty palliative care consultation depends on local resources and patient need. (See
'What is the difference between primary and secondary (subspecialty) palliative care?' below and
'Indications for a specialty palliative care consultation' below.)
What is the difference between palliative care and hospice? — While hospice and palliative
care share the same principles of providing comfort and support for patients, palliative care differs
from hospice care. In the United States, the term hospice is used to describe a model of palliative
care that is offered to patients with a terminal disease who are at the end of life (generally with an
estimated life expectancy of six months or less) when curative or life-prolonging therapy is no
longer the focus of treatment. In contrast, palliative care should be appropriately offered to patients
at any time along the trajectory of any type of serious life-threatening illness, even concurrent with
restorative, life-prolonging therapies. While all care that is delivered by hospice programs can be
considered palliative care, not all palliative care is considered to be hospice care.
Eligibility for hospice care generally requires that a physician estimate that life expectancy is six
months or less. Estimating prognosis in ESLD is discussed above, and disease-specific criteria for
hospice referral for patients with ESLD, as well as non-disease specific criteria are outlined in the
tables (table 3 and table 4) and discussed in more detail below. (See 'Disease trajectory and
estimating prognosis' above and 'Considerations for end of life care and hospice referral' below.)
What is the difference between primary and secondary (subspecialty) palliative

care? — Hospice and Palliative Medicine is now recognized as a medical subspecialty by the
American Board of Medical Specialties, as well as in Canada, England, Ireland, Australia, New
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Zealand, and many other countries. Many other European countries are also in the process of
developing certification for palliative care. In most jurisdictions, palliative care is provided by an
interdisciplinary team of specially trained physicians, nurses, social workers, chaplains, and other
specialists with advanced training in palliative care, who work with a patient’s other clinicians to
provide an “extra layer” of support. Clinicians who are specifically trained in palliative care can
provide in-depth pain and symptom management, communication regarding goals of care, and
care coordination across settings and over time. Subspecialty palliative care services are most
available in high-income countries in the inpatient setting, as exemplified by the United States. The
availability of subspecialty palliative care services in low-income countries is generally quite
limited. Subspecialty palliative care may be delivered in a number of settings across the continuum
of health care, including in the home, nursing homes, long-term acute care facilities, acute care
hospitals, and outpatient clinics [23]. Moreover, palliative care can also include bereavement care
for family and loved ones following the death of the patient. (See "Benefits, services, and models
of subspecialty palliative care" and "Palliative care and hospice outside of the United States".)
In order for the large number of patients with serious life-threatening illness to benefit from
palliative care, it is important that supportive services not only be provided by specialists but also
be incorporated into the practices of all clinicians who are caring for persons with serious and
complex illness, such as ESLD. Some term this “primary” palliative care to distinguish it from
“secondary” or “subspecialty” palliative care [24]. Primary palliative care encompasses any type of
supportive care that is delivered by all health care professionals caring for patients with serious
life-threatening illness. Clinicians caring for these patients need to attain competence in providing
comprehensive supportive care, including initiating and carrying out advance care planning (ACP),
assessing and addressing symptoms, recognizing distress, and the appropriate referral for issues
not adequately addressed by the primary care or subspecialist non-palliative-care clinician (table
5). (See "Primary palliative care".)
Current state of palliative care in ESLD — ESLD has only recently become a focus of palliative
care research, and best practices for the role of palliative care in ESLD and for those patients who
are listed for transplant have not been defined.
Yet, it is well recognized that patients with ESLD have a profound level of discomfort and often
have substantial suffering. Complications of chronic liver disease compromise health-related
quality of life (HRQOL), which worsens as disease severity increases [25-28]. Over a decade ago,
the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments
(SUPPORT) study demonstrated that patients with ESLD have rates of moderate to severe pain
toward the end of life that are similar to those of patients with lung or colorectal cancer [29]. Most
patients in this study expressed a preference for dying rather than living in a coma or on prolonged
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life support, suggesting the importance of understanding patients’ preferences for care, especially
for end of life approaches. Other more recent studies have confirmed the high rate of pain and
other symptoms in cohorts of patients with ESLD [30,31].
Furthermore, even patients listed for liver transplantation experience significant functional decline
while awaiting a donor organ [32], and they have high rates of both physical and psychological
suffering [26-28]. Many people die while awaiting transplant. The current system for organ
allocation, which is based upon the severity of the underlying liver disease, has left many patients
in a sort of limbo, which has been described as “too well for transplant but too sick for life” [33].
Judicious application of the tenets of palliative care can help to bridge this gap. (See "Liver
transplantation in adults: Patient selection and pretransplantation evaluation", section on
'Cirrhosis'.)
The palliative care needs of patients with ESLD are common to those of other serious life-
threatening illnesses and include symptom control, discussing and establishing goals of care,
facilitating communication with the various members of the health care team and/or sites of care,
and emotional, spiritual, and psychosocial support, both for the patient and caregivers [23,34-36].
The available evidence suggests that existing health care services are insufficient to meet the
physical, psychological, and social needs in this population [37].
Palliative care and liver transplantation may be viewed by some as mutually exclusive [38].
However, patients awaiting liver transplantation for ESLD are likely to benefit from palliative care,
especially given the challenges around end of life communication in patients struggling to maintain
hope for a cure in the face a life-threatening illness and the high rate symptom burden in this
population.
In fact, a growing body of evidence suggests that palliative care can be successfully provided
alongside curative care, even for patients who are listed for orthotopic liver transplant
[31,33,39-43]. One uncontrolled study found significant symptom burden in this population and
improvement after a palliative care intervention, although in the absence of a control group, it is
impossible to know that the improvement resulted directly from the palliative care intervention [31].
The evolving understanding of the importance of palliative care in ESLD is reflected by the
development of a multicenter randomized trial introducing palliative care within the treatment of
ESLD. This trial will randomize patients with ESLD to receive palliative care from subspecialty
palliative care specialists or from palliative care trained hepatologists, but the recruitment phase is
not yet underway. This trial is funded by the Patient-Centered Outcomes Research Institute
(PCORI).
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Challenges — There are a number of potential challenges to the introduction of palliative care
for patients with ESLD and those awaiting transplant:
● Patients feel well for years after the diagnosis of cirrhosis and may develop symptoms of
ESLD abruptly, which could result in less time to acquire the coping skills needed to face
progressive illness and approach the end of life.
● The hope of a life-saving transplant can lead patients (and their providers) to avoid
discussions of significant issues, including ACP and end of life issues, even as they
experience functional decline while awaiting a donor organ. (See 'Advance care planning'
below.)
● Many patients and clinicians equate palliative care with “end of life” care [44]. This may result
in delay of palliative care until after removal from the transplant list. (See 'Considerations for
end of life care and hospice referral' below.)
Indications for a specialty palliative care consultation — In our view, palliative care
should be provided throughout the trajectory of illness, beginning with a diagnosis of ESLD, but
much of this supportive care can be provided by primary care clinicians and gastrointestinal and
hepatology specialists. Ideal timing of a specialty palliative care consultation depends on local
resources and patient need. An important point is that an increasing number of studies in patients
with advanced cancer have suggested that earlier involvement leads to better patient outcomes.
(See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for
palliative care'.)
Indications and clinical triggers for a formal palliative care consultation have not been established
for patients with ESLD. However, general criteria for a palliative care assessment at the time of
admission to the hospital are available (table 6). For outpatients with ESLD, an assessment of
disease severity using predictive tools (eg, Child-Pugh-Turcotte grade (table 1) or Model for End-
Stage Liver Disease [MELD] score (calculator 3)), in addition to the severity of symptoms and the
degree of functional impairment, helps guide clinicians on when to consult specialty palliative care.
(See 'Disease trajectory and estimating prognosis' above.)
If not undertaken by primary care or hepatology clinicians as part of primary palliative care, an
early consult to specialty palliative care may facilitate a discussion about goals of care. However,
we strongly recommend that these conversations are begun by the continuity clinicians. These and
other suggested criteria for considering a secondary (specialist) palliative care consultation are
outlined in the table (table 7).
Others have developed a tool (the Supportive and Palliative Care Indicators [SPICT] tool) that
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uses clinical indicators to identify patients for supportive and palliative care assessment [45]. For
patients with advanced liver disease, the clinical criteria include:
● Advanced cirrhosis with one or more complications: intractable ascites, hepatic

encephalopathy, hepatorenal syndrome, bacterial peritonitis, and/or recurrent variceal bleeds
● Serum albumin <2.5 g/dL (25 g/L), and prothrombin time raised or international normalized
ratio (INR) prolonged
● Hepatocellular carcinoma
What are the important components of palliative care in ESLD? — Important components of
palliative care include assessing and managing symptoms, exploring the patient’s understanding
about their illness and prognosis, soliciting and discussing goals of care and ACP, coordinating
care, and helping to plan end of life care, including determining the need for and timing of hospice
care. A summary of issues that might need to be addressed in the palliative care assessment of
patients with ESLD is provided in the table (table 8).
Symptom burden and management — Few studies have explored symptom burden from the
perspective of patients with ESLD:
● One Korean questionnaire-based study of 129 cirrhotic patients identified fatigue, abdominal
distention, peripheral edema, and muscle cramps as the symptoms that most often needed
management [46].
● In the SUPPORT study of hospitalized patients with ESLD, 60 percent experienced pain,
which was rated at least moderately severe most of the time in one-third [47].
● An Italian survey of 156 patients with cirrhosis found that more than one-half had a Beck
Depression Inventory score indicative of a depressed mood [48]. Anxiety is also prevalent
[49].
● A literature review of the patient experience in advanced liver disease emphasized the dearth
of information on the holistic everyday patient experience of living with advanced liver disease
[50]. They concluded that physical and psychosocial challenges are often of a greater severity
than those reported in other chronic diseases and that patients were particularly affected by
gastrointestinal problems and fatigue, with both problems linked to higher levels of
depression.
Multiple studies have shown that the major complications of cirrhosis (hepatic encephalopathy,
variceal bleeding, ascites, and renal failure) reduce HRQOL [25,51-53]. Other non-life-threatening
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symptoms that can have a significant impact on HRQOL in these patients are muscle wasting and
cachexia, muscle cramps, pruritus, fatigue, insomnia, pain, depression, and anxiety [51].
Compared with other end-stage organ failures, such as advanced heart or renal failure, patients
with ESLD tend to report higher levels of mental health functional impairment [25]. Contributors
include cognitive impairment from hepatic encephalopathy, illness-related family and/or social
distress, or comorbid conditions such as substance abuse or depression.
Most symptoms of ESLD are best managed by following the tenets of high-quality cirrhosis care.
The treatment approach should be guided by patient goals and values in the context of the current
prognosis and available treatment options.
Ascites management — Once a patient with cirrhosis develops clinically apparent ascites, it
is unlikely to resolve without specific treatment. Many patients with ascites will be responsive to
diuretics. Diuretic therapy may be initiated with a combination of furosemide and spironolactone,
both once daily in the morning. (See "Ascites in adults with cirrhosis: Initial therapy", section on
'Diuretic therapy'.)
For most patients, sodium restriction is advised (no more than 88 mEq [2000 mg] daily). Although
fluid restriction is frequently ordered, its role is unclear, particularly since adherence is difficult to
achieve. Thus, we generally only recommend fluid restriction in patients whose plasma sodium
concentration is <120 mEq/L. (See "Ascites in adults with cirrhosis: Initial therapy", section on
'Dietary sodium restriction' and "Ascites in adults with cirrhosis: Initial therapy", section on 'Fluid
restriction'.)
Diuretic-resistant ascites in patients with cirrhosis is considered to be present when at least one of
the following criteria is present in the absence of therapy with a nonsteroidal antiinflammatory drug
(NSAID), which can induce renal vasoconstriction and diminish diuretic responsiveness (see
"Ascites in adults with cirrhosis: Diuretic-resistant ascites", section on 'Diagnosis'):
● An inability to mobilize ascites despite confirmed adherence to the dietary sodium restriction
(88 mEq [2000 mg] per day) and the administration of maximum tolerable doses of oral
diuretics (400 mg/day of spironolactone and 160 mg/day of furosemide).
● Rapid reaccumulation of fluid after therapeutic paracentesis.
● The development of diuretic-related complications, such as progressive azotemia, hepatic

encephalopathy, or progressive electrolyte imbalances.
There are a variety of approaches to ascites that is not responsive to diuretics.
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Patients can suffer pain and discomfort from severe refractory ascites due to decompensated liver
disease. Ideal management in this situation often depends on the patient’s goals of care and the
benefits and burdens of treatments:
● Medications that decrease systemic blood pressure (and thus renal perfusion) should be
discontinued; these include beta blockers, angiotensin-converting enzyme inhibitors (ACEIs),
and angiotensin receptor II blockers (ARBs). NSAIDs should also be discontinued because
they can cause renal vasoconstriction. In patients who continue to have diuretic resistance
despite the interventions, oral midodrine, a vasopressor, may be effective. (See "Ascites in
adults with cirrhosis: Diuretic-resistant ascites", section on 'Initial treatments'.)
● Some diuretic-refractory patients can benefit from transjugular intrahepatic portosystemic

shunting (TIPS). However, as a patient approaches end of life, invasive procedures such as
TIPS may not be aligned with goals, particularly if they are comfort oriented. (See "Ascites in
adults with cirrhosis: Diuretic-resistant ascites", section on 'Transjugular intrahepatic
portosystemic stent-shunt'.)
● In some cases, serial large-volume paracentesis may adequately control symptoms. This may
be challenging for a patient who, for example, prefers to have symptoms managed in home on
hospice services. In such cases, one may consider an indwelling peritoneal catheter allowing
for drainage at home. This is often more convenient for the patient, but it carries a risk of
infection, and so should only be considered in patients with strictly comfort-oriented goals
[54,55]. There are not a lot of data on this topic; however, one study suggests a 10 percent
risk of developing bacterial peritonitis within 72 hours of catheter placement [55]. (See
"Ascites in adults with cirrhosis: Diuretic-resistant ascites", section on 'Therapeutic
paracentesis' and "Malignancy-related ascites", section on 'Paracentesis'.)
Encephalopathy — Hepatic encephalopathy is linked to an increase in caregiver burden

[56], and it affects decision-making capacity. When a patient suffers from hepatic encephalopathy,
it is especially important to carry out ACP during a period when he or she is lucid and to document
evidence of decision-making capacity at the time of completion of the advance directive or
elicitation of goals of care. Patients with encephalopathy are particularly at risk of having end of life
decisions made by others. (See "Assessment of decision-making capacity in adults" and "Hepatic
encephalopathy in adults: Treatment".)
General supportive care for patients with hepatic encephalopathy includes avoiding dehydration
and electrolyte abnormalities, providing nutritional support, and providing a safe environment.
Patients should not have their protein intake restricted, unless they are severely protein intolerant.
Patients should be instructed to eat small meals throughout the day with a late-night snack of
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complex carbohydrates. Precautions to prevent falls should be instituted for patients who are
disoriented. (See "Hepatic encephalopathy in adults: Treatment", section on 'General supportive
care' and "Hepatic encephalopathy in adults: Treatment", section on 'Protein restriction and
nutritional support'.)
The initial management of acute hepatic encephalopathy in patients with chronic liver disease is
discussed in detail separately. (See "Hepatic encephalopathy in adults: Treatment", section on
'Acute therapy'.)
There are limited treatment options to improve cognition when a patient with refractory hepatic
encephalopathy cannot take oral medications, and patient preferences are comfort-oriented and
are not in line with nasogastric tube placement. While a lactulose enema can be considered,
patients in this scenario tend to be approaching the end of life, and treatment often focuses on
management of symptoms such as agitation and distress rather than attempting to resolve the
encephalopathy. (See "Palliative care: The last hours and days of life".)
Pain — Pain is challenging to treat in patients with liver failure, given the impaired hepatic
metabolism in patients with ESLD (table 9). Concurrent chronic renal failure is also common,
further limiting treatment options as well. (See "Management of pain in patients with advanced
chronic liver disease or cirrhosis" and "Palliative care for patients with end-stage kidney disease",
section on 'Pain'.)
For patients with ESLD and pain, it is important to consider whether the cause of pain is reversible
and whether interventions exist for that specific complaint. For example, pain related to ascites
often will respond to paracentesis, and edema pain may respond to diuresis. It is also important to
integrate patients’ preferences into the pain treatment plan. For example, some patients may favor
alertness over pain control, and this preference may change as the disease progresses.
NSAIDs should generally be avoided in this population. Acetaminophen should be limited to 2 to 3

g in a 24-hour period (table 9). Opioids should be used with caution in patients with ESLD (due to
challenges with metabolism), but often they are the best option for pain management, especially at
the end of life. When initiating opioid therapy in this patient population, lower doses with extended
dosing intervals should be employed, with careful monitoring of side effects (changes in respiratory
patterns, level of consciousness and cognition, myoclonus, and nausea). Titrations should be
made with caution, and patients and their families should be made aware of the signs of opioid
toxicity. If the underlying liver disease is worsening, consider reductions in dose, especially if
symptoms are adequately controlled and side effects increase. (See "Management of pain in
patients with advanced chronic liver disease or cirrhosis".)
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Where possible, nonpharmacologic opioid-sparing treatment should be considered (eg, massage,

acupuncture, cognitive behavioral therapy, electrical neuromodulation). (See "Overview of the
treatment of chronic non-cancer pain", section on 'Nonpharmacologic therapies'.)
Variceal hemorrhage — Variceal hemorrhage is a serious complication of ESLD. General

principles of supportive care and methods to achieve hemostasis are addressed in detail
separately. (See "Overview of the management of patients with variceal bleeding" and "Methods to
achieve hemostasis in patients with acute variceal hemorrhage".)
As a patient with ESLD who has had variceal hemorrhage or who is at a high risk for variceal
hemorrhage approaches end of life, careful consideration of patient goals and preferences should
guide the treatment plan, as well as the expertise of all involved treatment teams. (See "Prediction
of variceal hemorrhage in patients with cirrhosis".)
When goals are comfort focused, and a patient is at the end of life and at a high risk of bleeding, it
is good practice to provide education regarding the future risk of bleeding to the patient and family
members and to help them to have an emergency plan in place that may include dark linens,
protective equipment for family/caregivers, availability of subcutaneous or rectal opioids and
benzodiazepines if the patient is unable to take oral medications, and a transfer option to an
inpatient hospice or palliative care setting if needs cannot be met in the home.
Other symptoms — Other symptoms that may occur in patients with ESLD include pruritus,
muscle cramps, dyspnea, nausea and vomiting, constipation, and diarrhea. (See "Assessment and
management of dyspnea in palliative care" and "Assessment and management of nausea and
vomiting in palliative care" and "Overview of managing common non-pain symptoms in palliative
care", section on 'Constipation'.)
Pruritus — Pruritus may develop in patients with cholestasis due to any cause, including
cirrhosis. Pruritus in patients with cholestasis may be generalized or localized (particularly to the
palms of the hands and soles of the feet). The intensity of the pruritus is variable, and it can wax
and wane spontaneously. The severity does not correlate with the severity of the underlying liver
disease. (See "Pruritus associated with cholestasis", section on 'Clinical manifestations'.)
A presumptive diagnosis of cholestasis-associated pruritus can be made in a patient with

cholestasis who complains of itching. An extensive evaluation is generally not required, provided
the cause of the cholestasis is known, although patients should have a skin examination to look for
evidence of dermatologic disorders or infestations that may be associated with pruritus (eg, atopic
or contact dermatitis, or pediculosis corporis). (See "Pruritus associated with cholestasis", section
on 'Diagnosis and differential diagnosis'.)
13 of 26 02/01/2020, 15:19
For patients with ESLD, general measures that may help pruritus include [5] (see "Pruritus
associated with cholestasis", section on 'General approach'):
● Topical emollients
● Avoidance of hot baths and rubbing of the skin (ie, pat dry)
● Cool humidified air
● Minimize use of harsh soaps, fragrances, and detergents
● Loose-fitting clothing and bed sheets
Pharmacological therapies can be considered for patients with moderate to severe pruritus
symptoms. Treatment with a bile acid sequestrant, such as cholestyramine or colestipol, may be
tried. For patients who do not respond or do not tolerate a bile acid sequestrant, options include
rifampin [57] or a dose of sertraline, paroxetine [57], or phenobarbital at bedtime. (See "Pruritus
associated with cholestasis", section on 'Moderate to severe pruritus'.)
Case reports suggest potential benefit for ondansetron or glucocorticoids in this setting [58,59].
Antihistamines are sometimes helpful but cause drowsiness. The opioid antagonist naltrexone may
be effective, but use of this drug is often inappropriate in a palliative population because of the risk
of reducing analgesia in patients receiving opioid-containing medications.
Muscle cramps — Patients with cirrhosis may experience muscle cramps, which can be
severe. The cause is incompletely understood. For patients with muscle cramps, other causes (eg,
electrolyte abnormalities, acute kidney injury) should be excluded. If other disorders are excluded,
treatments that may be helpful include branched-chain amino acids (4 g granules three times
daily), taurine (3 g once daily), zinc repletion (for patients with low levels), and vitamin E (200 mg
three times daily). Quinine sulfate may be another option, but it is not widely available (only
through some online retailers), is contraindicated in patients with Child-Pugh C cirrhosis, and
requires close monitoring for those with liver disease of lesser severity because of the potential for
thrombocytopenia, hemolysis, and cardiac toxicity. A suggested approach to muscle cramps in
cirrhosis is provided elsewhere. (See "Cirrhosis in adults: Overview of complications, general
management, and prognosis", section on 'Muscle cramps'.)
Anorexia/cachexia — Anorexia and cachexia are often anticipated findings in patients

near death receiving palliative care, but may need to be handled differently in the palliative care
patient hoping to receive a liver transplant. (See "Assessment and management of anorexia and
cachexia in palliative care".)
Protein-calorie malnutrition is common in individuals with ESLD. Assessment of nutritional status in

the setting of decompensated cirrhosis is challenging because of volume and sodium shifts,
14 of 26 02/01/2020, 15:19
hepatic synthetic dysfunction, and changes in energy metabolism. Nonetheless, for the
pretransplant patient, an assessment of weight history, dietary intake, gastrointestinal symptoms,
and signs and symptoms of nutritional deficiency (table 10), laboratory assessment of nutritional
status, and a more formal assessment of nutritional status using the patient-generated subjective
global assessment (SGA) tool [60] may be indicated. For patients who require nutritional
intervention, guidelines are available to estimate caloric requirements and guide nutritional
intervention. These topics are discussed in detail separately. (See "Nutritional assessment in
chronic liver disease".)
Advance care planning — ACP, defined as “planning for and about preference-sensitive
decisions often arising at the end of life,” is an ongoing process in which patients, their families,
and their health care providers reflect on the patient’s goals, values, and beliefs and discuss how
they should inform current and future medical care [61]. This information is used to guide future
health care choices in the context of care that is medically reasonable and appropriate. In an ideal
ACP discussion, the clinicians, patient, and his or her loved ones think through particular
approaches to follow if (or when) the patient’s health progressively declines and plan for managing
a potential episode of acute decompensation. This process is iterative and typically occurs
longitudinally within the context of an existing and continuing medical relationship. General issues
of ACP are discussed separately (see "Advance care planning and advance directives"). For
patients with ESLD, ACP can facilitate decisions around end of life care that reflect a patient’s
goals and values [62].
However, there are several challenges to ACP in ESLD:
● A common symptom of ESLD, encephalopathy, may limit a patient’s decision-making capacity

at times during illness, making early planning, including identification of a surrogate decision
maker and conversations with this individual, important. If this does not happen, many
surrogate decision makers have difficulty predicting what their loved would want in future
circumstances; they may incorrectly predict a patient’s treatment preferences in up to one-
third of cases. It is critical to establish goals of care and ACP at a time when cognitive function
is intact. (See "Advance care planning and advance directives", section on 'Surrogate decision
makers'.)
● Lack of social support, substance abuse, and caregiver burden are prevalent in this
population, which can lead to challenges with communication and care planning [41,56,63,64].
● Consideration of transplant should be an indicator for ACP given the high risk of death,
despite hope for cure, which may seem counterintuitive for some physicians. (See 'Disease
trajectory and estimating prognosis' above.)
15 of 26 02/01/2020, 15:19
When to begin the discussion — ACP discussions should begin early in the disease process,
when the patient is well enough to participate. Based upon data from patients with chronic
obstructive pulmonary disease (COPD), most patients and their families find these discussions to
be less stressful and prefer to have these conversations in a stable medical state when they are
able to make clear decisions [65]. Having these discussions early in the disease trajectory will
make it easier to return to these discussions at a later time, if needed [66,67].
Because of the possibility of transplantation, a subset of patients pursue curative efforts until the
end of life; palliative and/or hospice care frequently is not provided or suggested until the hope of
recovery or transplantation is extinguished, which is often in the last weeks of life. Because of this,
patients with ESLD are more likely than those without chronic liver disease to receive aggressive
care despite declining poor health, and lower quality end of life care [30,38,68]. Although it may
seem counterintuitive, consideration of transplantation should be an indicator for ACP given the
high risk of death, despite hope for a cure. In this setting, discussions should include preparing the
patent and family for a range of potential outcomes, including a drastic decline and/or the
development of complications that eliminate the patient as a transplant candidate, or the patient
undergoing a transplant and then dying of complications related to the procedure.
Discussions about ACP should be patient centered and sensitive, balancing hope with reality.
Eliciting information about the patient’s perception of the impact of the disease in their life, disease
severity, and prognosis will guide the clinician in achieving this balance. Sensitivity to the individual
patient’s response to a discussion of these issues is essential due to the broad variation in patient
responses. Discussions about prognosis and the process of dying can be especially difficult.
Issues related to communication of prognosis in patients with serious life-threatening illness and
practical guidance for discussing prognosis are addressed separately. (See "Communication of
prognosis in palliative care" and "Discussing serious news".)
Considerations for end of life care and hospice referral — Hospice care is a model and
philosophy of care that focuses on palliating a terminally ill patient’s pain and other symptoms and
attending to their and their family’s emotional and spiritual needs. At least in the United States for
the Medicare hospice benefit, hospice eligibility is restricted to patients who have an estimated
survival of six months or less. Medicare guidelines for hospice eligibility among patients with ESLD
are outlined in the table (table 3). A separate table that includes non-disease-specific guidelines for
determining appropriateness for hospice referral in the United States Medicare program is also
provided (table 4).
A systematic review of non-cancer conditions by Salpeter et al suggested that a median six-month

prognosis could be expected in ESLD or decompensated cirrhosis when the Child-Pugh score was
16 of 26 02/01/2020, 15:19
at least 12 and/or the MELD score was at least 21 [18]. (See 'Disease trajectory and estimating
prognosis' above.)
Additionally, consensus-based quality indicators by a multidisciplinary expert panel for palliative

care in ESLD due to cirrhosis suggest a referral for palliative/hospice services if a patient has
advanced ESLD and hepatocellular carcinoma with either a Barcelona Clinic Liver Cancer (BCLC)
stage D tumor (algorithm 1), or hepatorenal syndrome and is not a candidate for transplant [69].
Outside of the United States, availability of hospice care is variable, and criteria for hospice
eligibility have not been established. (See "Palliative care and hospice outside of the United
States".)
The available data suggest that only a minority of individuals with ESLD are enrolled in hospice
and that the median length of time spent in hospice care is short (median nine days in one report
of hospitalized Medicare patients with ESLD [11]).
One limitation for this population, at least in the United States, is that hospice enrollment is not
widely available for patients who are pursuing potentially curative therapy, such as a liver
transplant. Providing hospice care for patients awaiting transplant was the topic of a pilot study that
showed that concurrent hospice care with transplant candidacy was feasible with specifically
trained staff [39]. Of the 157 patents with ESLD admitted to hospice, 122 died while awaiting a
transplant; the average MELD score was 21 at admission, and almost all patients with a MELD
score above 18 died within several months. The mean length of stay was 38 days. Only six (5
percent) of the listed patients went on to a successful liver transplant.
Despite this positive experience, the hospice philosophy (in the United States and elsewhere [70])
remains generally aligned with patients whose goals are primarily focused on comfort at the end of
life. For this reason, clarification of transplant status is often an important issue to inform decision-
making. (See "Hospice: Philosophy of care and appropriate utilization in the United States".)
CAREGIVER BURDEN AND SUPPORT FOR CAREGIVERS
Caregiver burden is high among patients with ESLD, including those awaiting transplant
[56,63,71]. Studies show a significant percentage reported decreased quality of life, low life
satisfaction, high levels of depression, and a high amount of caregiver strain, particularly for
women caregivers. Hepatic encephalopathy and cognitive dysfunction are associated with worse
caregiver burden [56].
17 of 26 02/01/2020, 15:19
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Hepatocellular carcinoma".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.”
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on “patient info” and the keyword(s) of interest.)
● Basics topics (see "Patient education: Medical care during advanced illness (The Basics)" and
"Patient education: Advance directives (The Basics)")
SUMMARY
● End-stage liver disease (ESLD) is synonymous with advanced liver disease, liver failure, and
decompensated cirrhosis, given the general irreversibility of these conditions. While liver
transplantation is a viable and potentially curative treatment option, many are not candidates
because of clinical or social factors, comorbidity, or in the case of hepatocellular carcinoma,
disease extent. Even with the hope of transplant, most patients with decompensated cirrhosis
will die of this condition. (See 'Definitions, clinical course, and causes of death' above.)
● The prognosis of cirrhosis is highly variable. The trajectory of functional decline in patients
with ESLD may be erratic and unpredictable, and many patients are in a constant state of
poor or declining health interspersed by intermittent exacerbations and hospitalizations. Death
may be sudden and unexpected. (See 'Disease trajectory and estimating prognosis' above.)
In general, the degree of hepatic decompensation, as reflected by the Child-Pugh
18 of 26 02/01/2020, 15:19
classification or the Model for End-Stage Liver Disease (MELD) score, is an important
determinant of prognosis. Although predictive models such as these are useful for predicting
long-term outcomes in ESLD and guiding treatment decisions, they do not always align with
the patient’s reported functional status and sense of well-being, and they should not be used
in isolation for determining eligibility for palliative or hospice care. (See 'Child-Pugh
classification' above and 'MELD score' above.)
● In our view, palliative care should be provided throughout the trajectory of illness, beginning
with the diagnosis of ESLD, but much of this supportive care can be provided by primary care
clinicians and gastrointestinal and hepatology specialists. Ideal timing of specialty palliative
care consultation depends on local resources and patient need. An important point is that an
increasing number of studies in patients with advanced cancer have suggested that earlier
involvement leads to better patient outcomes. (See "Benefits, services, and models of
subspecialty palliative care", section on 'Rationale for palliative care'.)
Important components of palliative care include exploring the patient’s understanding about
their illness and prognosis, assessing and managing symptoms, soliciting and discussing
goals of care and advance care planning, coordinating care, and helping to plan end of life
care, including determining the need for and timing of hospice care (table 8). (See 'What are
the important components of palliative care in ESLD?' above.)
● Hospice can provide an extra layer of support for patients with ESLD and their caregivers
when prognosis is estimated to be six months or less. It is noted that some pilot work using
hospice concurrently with transplant candidacy has been done, but this is not widely available,
and generally, the hospice philosophy is aligned with patients whose goals are primarily
focused on comfort at the end of life. For this reason, clarification of transplant status is often
an important issue to inform decision-making. (See 'Considerations for end of life care and
hospice referral' above.)
● Most symptoms of ESLD are best managed by following the tenets of high-quality cirrhosis
care. The treatment approach should be guided by patient goals and values in the context of
the current prognosis and available treatment options. (See 'Symptom burden and
management' above.)
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Topic 86296 Version 12.0
Contributor Disclosures
Anne M Walling, MD, PhD Nothing to disclose Neil Wenger, MD Nothing to disclose R Sean Morrison,
MD Nothing to disclose Sanjiv Chopra, MD, MACP Nothing to disclose Kristen M Robson, MD, MBA,
FACG Nothing to disclose Jane Givens, MD Consultant/Advisory Boards (Partner): CVS Health/CVS
Omnicare [Pharmaceutical management of formulary decision-making].
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy
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End-stage liver disease in palliative care

DEFINITIONS, CLINICAL COURSE, AND CAUSES OF DEATH

In general, the degree of hepatic decompensation is an important determinant of prognosis.

Child-Pugh classification — The Child-Pugh classification (table 1) was initially developed to

Other important prognostic variables — The presence of hepatorenal syndrome or renal

USE AND BENEFITS OF PALLIATIVE CARE

What is the difference between primary and secondary (subspecialty) palliative

● Advanced cirrhosis with one or more complications: intractable ascites, hepatic

● Rapid reaccumulation of fluid after therapeutic paracentesis.

● The development of diuretic-related complications, such as progressive azotemia, hepatic

There are a variety of approaches to ascites that is not responsive to diuretics.

● Some diuretic-refractory patients can benefit from transjugular intrahepatic portosystemic

Encephalopathy — Hepatic encephalopathy is linked to an increase in caregiver burden

NSAIDs should generally be avoided in this population. Acetaminophen should be limited to 2 to 3

Where possible, nonpharmacologic opioid-sparing treatment should be considered (eg, massage,

Variceal hemorrhage — Variceal hemorrhage is a serious complication of ESLD. General

A presumptive diagnosis of cholestasis-associated pruritus can be made in a patient with

Anorexia/cachexia — Anorexia and cachexia are often anticipated findings in patients

Protein-calorie malnutrition is common in individuals with ESLD. Assessment of nutritional status in

However, there are several challenges to ACP in ESLD:

● A common symptom of ESLD, encephalopathy, may limit a patient’s decision-making capacity

A systematic review of non-cancer conditions by Salpeter et al suggested that a median six-month

Additionally, consensus-based quality indicators by a multidisciplinary expert panel for palliative

CAREGIVER BURDEN AND SUPPORT FOR CAREGIVERS

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

In general, the degree of hepatic decompensation, as reflected by the Child-Pugh

1. World Heealth Organization. Guidelines for palliative care. http://www.who.int/entity/cancer/p

6. http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/03_liver_13.pdf (Accessed on August

8. United Network for Organ Sharing. Transplants by Organ Type-2005 https://www.unos.org/da

14. Albers I, Hartmann H, Bircher J, Creutzfeldt W. Superiority of the Child-Pugh classification to

review of the literature. BMJ Support Palliat Care 2015; 5:471.

Topic 86296 Version 12.0

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