Gastroenterol Clin N Am 35 (2006) 201–219

GASTROENTEROLOGY CLINICS
OF NORTH AMERICA
Palliative Care for Patients with
End-Stage Liver Disease Ineligible
for Liver Transplantation
William Sanchez, MDa, Jayant A. Talwalkar, MD, MPHb,*
a
Department of Medicine, Division of Gastroenterology & Hepatology, Mayo Clinic College
of Medicine, 200 First Street, SW, Rochester, MN 55901, USA
b
Department of Medicine, Advanced Liver Diseases Study Group, Division of Gastroenterology &
Hepatology, Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN 55901, USA

A
s the final common end point in patients with chronic liver disease of
a variety of causes, end-stage liver disease (ESLD) poses an important
clinical challenge. Epidemiologic factors including the increasing num-
bers of patients with chronic hepatitis C developing cirrhosis, the increasing
age of the population, and the obesity epidemic translate into a growing num-
ber of patients with ESLD. The number of patients with ESLD is increasing,
while the number of donor organs available for transplantation remains rela-
tively stable. These patients with ESLD need to be managed in the community
without liver transplantation. These patients face a variety of symptoms and
disease-related complications, which affect their survival and health-related
quality of life. Understanding the principles of palliative medicine and the
management of complications of cirrhosis is important for improving the health
status of patients with ESLD.

SCOPE OF THE PROBLEM: CLINICAL EPIDEMIOLOGY

OF END-STAGE LIVER DISEASE
Patients with cirrhosis who develop complications, such as ascites, portal hy-
pertension, gastrointestinal hemorrhage, or hepatic encephalopathy, are con-
sidered to have ESLD. No recent population-based epidemiologic study
describing the secular trends of disease burden for cirrhosis is available; how-
ever, data support the notion that ESLD is a significant cause of morbidity, re-
source use, and death in the United States. An estimated 5.5 million people (2%
of the US population) are affected by cirrhosis, its consequences from portal
hypertension, and the attendant risk for carcinogenesis [1–12]. Approximately
26,000 patients die of chronic liver disease and cirrhosis in the United States
each year, making this condition the seventh leading cause of death among

*Corresponding author. E-mail address: [email protected] (J.A. Talwalkar).

0889-8553/06/$ – see front matter ª 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.gtc.2005.12.007 gastro.theclinics.com
202 SANCHEZ & TALWALKAR

people between the ages of 25 and 64 [13]. An additional 18,000 patients die of
hepatobiliary cancer related most often to cirrhosis. The major causes of death
in the absence of liver transplantation are liver failure, hepatocellular carci-
noma (HCC), gastrointestinal bleeding, sepsis, and renal failure[1–12,14–19].
With the development of ascites or hepatic encephalopathy, the estimated
2-year survival of patients with ESLD is less than 50% [14–19].
Despite the success of liver transplantation, only 6000 patients undergo this
curative procedure annually [20,21]. The shortage of suitable donor organs is
expected to continue to worsen as the number of potential transplant recipients
increases. Based on current data from the Organ Procurement and Transplan-
tation Network, there are more than 17,000 patients with ESLD awaiting liver
transplantation in the United States. With increasing waiting times secondary
to the lack of organs, an estimated 1500 patients die awaiting liver transplan-
tation [21]. In addition, an increasing proportion of patients with ESLD ulti-
mately are found to be unsuitable candidates for liver transplantation based
on advanced age, obesity, and comorbid illness, such as diabetes mellitus
and coronary artery disease.

DETERMINING THE PROGNOSIS OF PATIENTS

WITH END-STAGE LIVER DISEASE
Available data regarding the natural history and prognosis of cirrhosis come
largely from studies performed at referral-based centers [12,14–19] and popu-
lation-based studies from the 1970s [22]. Patients with compensated cirrhosis
can expect an estimated median survival of nearly 10 years. With the develop-
ment of esophageal varices, the median survival of patients with compensated
cirrhosis is shortened to 7 to 10 years. With a transition rate to develop ascites
at 5% to 10% annually, it is anticipated that only 50% of patients with ESLD
survive 2 years [1–12]. Regardless of liver disease severity, patients who expe-
rience acute variceal hemorrhage have a risk of bleed-related death of 10% to
20% per episode requiring hospitalization [23]. Patients who develop medically
refractory ascites have an even worse prognosis with an estimated 6-month sur-
vival rate of 50% [12,24].
To predict long-term outcome more accurately in this patient population,
many classification schemes and prognostic models have been developed for
clinical use. The two most commonly used indices are the Child-Turcotte-
Pugh (CTP) classification and the Model for End-Stage Liver Disease
(MELD) (Table 1). The CTP classification, originally introduced in 1964
and subsequently modified in 1973, has been used widely for many years by
health care providers [25,26]. Developed as a prognostic tool for patients
with cirrhosis undergoing shunt surgery for portal hypertension, the CTP clas-
sification incorporates objective parameters (prothrombin time, serum biliru-
bin, and albumin) and subjective assessments regarding the degree of
involvement with ascites and hepatic encephalopathy. Over time, the CTP clas-
sification was used in other clinical situations and found to have prognostic util-
ity in patients with cirrhosis. Based on some degree of external validity, the
PALLIATIVE CARE FOR ESLD 203

Table 1
Prognostic models in end-stage liver disease
Child-Turcotte-Pugh classification (class A, 5–6 points; class B, 7–9 points; class C, 10–15
points)
1 point 2 points 3 points
Bilirubin (mg/dL)
Noncholestatic disease <4 4–10 >10
Cholestatic disease <2 2–3 >3
Albumin (g/dL) >3.5 2.8–3.5 <2.8
Prothrombin time INR <1.7 1.7–2.3 >2.3
Hepatic encephalopathy None Stage 1–2 Stage 3–4
Ascites None Mild–moderate Severe
MELD—Model
ÿ for End-Stage Liver Disease (UNOS modification)
MELD ¼ 0:957
Loge ðcreatinine mg=dL Þ þ 0:378
Loge ðbilirubin mg=dLÞ
þ 1:120
Loge ðprothrombin time INRÞ þ 0:643Þ
10
Abbreviation: INR, international normalized ratio.
*Patients undergoing hemodialysis are considered to have a creatinine of 4 mg/dL.

CTP classification subsequently was used as a disease severity index for organ
allocation [27,28]. Numerous shortcomings limit the utility of the CTP classifi-
cation, including the subjectivity of scores regarding manifestations of portal
hypertension. Additionally, the CTP score does not take into account renal
dysfunction, which has been shown to have major prognostic importance in pa-
tients with advanced liver disease [28–30].
The MELD score initially was developed to assess mortality risk in patients
undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedures.
The MELD score is calculated using widely available, objective clinical labora-
tory values, including total bilirubin, creatinine, and international normalized
ratio for prothrombin time (see Table 1). Since its conception, the MELD score
has been validated in a variety of patient cohorts (ambulatory and hospitalized)
to predict accurately 3-month liver-related mortality risk compared with the
CTP classification [28,31]. The United Network for Organ Sharing adopted
the MELD score as the basis for organ allocation in liver transplantation in Feb-
ruary 2002. As with any prognostic model, there are some limitations with the
MELD score. Variables that represent complications of portal hypertension,
including hyponatremia, ascites and spontaneous bacterial peritonitis, are ex-
cluded from the model. Among these patients, there may be individuals with
a higher risk of short-term death compared with patients with a similar
MELD score without these complications. In addition, the longitudinal ability
to predict survival accurately beyond 3 months is uncertain in the absence of
liver transplantation.

PALLIATIVE AND END-OF-LIFE CARE

Patients with ESLD who are ineligible for or do not wish to pursue liver trans-
plantation require increasingly complex medical support. In this context,
204 SANCHEZ & TALWALKAR

a focused discussion on the palliative care aspects of medical management

should be initiated. Physician-patient communication addressing palliative
care and end-of-life issues is essential and should be initiated early rather
than at the time of acute deterioration requiring hospitalization.
Definition of Palliative Care
The National Consensus Project for Quality Palliative Care defines the goal of
palliative care as to ‘‘prevent and relieve suffering and to support the best pos-
sible quality of life for patients and their families, regardless of the stage of
the disease or the need for other therapies’’ [32]. Palliative care involves a multi-
disciplinary approach to optimize symptom management and health status
without excluding medical therapies to achieve these goals. The concept of
palliative care is integrated easily into standard medical management of
ESLD. In contrast, hospice care represents the phase at which point life-
prolonging therapies are not pursued by affected individuals [33]. Members
of the palliative care team should include physicians, expert nursing staff, and
social workers [32,33]. An important component of palliative care is the un-
derstanding that death is a normal process with support provided for the
bereavement process of the patient and his or her loved ones [34].
Controversy exists as to the role of life-extending therapies in palliative care.
The World Health Organization states that palliative care ‘‘intends neither to
hasten or postpone death.’’ The World Health Organization goes on to state
that palliative care also is ‘‘applicable early in the course of illness, in conjunc-
tion with other therapies that are intended to prolong life, such as chemother-
apy or radiation therapy’’ [34]. The National Consensus Project for Quality
Palliative Care emphasizes that although palliative care is focused on improv-
ing the patient’s quality of life, it does not exclude medical therapy aimed at
prolonging life [32].
Although frequently thought of in the context of a patient with incurable
malignancy, palliative care also is appropriate for patients ‘‘with a persistent or
recurring condition that adversely affects their daily functioning or will
predictably reduce life expectancy’’ [32]. Patients with advanced chronic dis-
ease states including ESLD are candidates for palliative care. As mentioned
previously, a palliative focus should be incorporated into the standard care
of patients with ESLD. A similar approach has been advocated for patients
with congestive heart failure, a common condition that shares several features
(chronicity, frequent hospitalizations, volume overload) with ESLD [33].
Hospice
Hospice care is directed toward providing medical care and support services at
the end of life, frequently in the patient’s home [32]. Medicare provides benefits
covering hospice services, as do most private insurance plans and state Medic-
aid programs. The National Hospice and Palliative Care Organization has pub-
lished guidelines for the use of hospice care in nonmalignant disease such as
ESLD. Hospice criteria for patients with nonmalignant diseases include docu-
mented clinical progression of a life-limiting condition, multiple emergency
PALLIATIVE CARE FOR ESLD 205

department visits or inpatient hospitalizations over the past 6 months, and im-
paired nutritional status related to the disease process [35]. These guidelines,
based on expert opinion, have been adopted by the Health Care Finance Ad-
ministration to determine eligibility for hospice benefits under Medicare. Al-
though the number of patients enrolled in hospice has increased substantially
since the 1990s, only 1.6% of 2003 hospice admissions were for ESLD [35,36].
Patients identify dying at home as an important feature of quality health care
at the end of life [37]. Most deaths occur in a hospital, however, and only 20%
of US patients receive hospice care [36]. Data from the Study to Understand
Prognoses and Preferences for Outcomes and Risk of Treatments (SUPPORT)
revealed that only 2% (54 of 2607) of eligible patients with advanced organ fail-
ure were discharged from the hospital to hospice care. One of the contributing
factors to this observation is the gross inaccuracy of clinical assessments used to
estimate an individual patient’s life expectancy. The predictive model used in
the SUPPORT study was designed to approximate the National Hospice
and Palliative Care Organization guidelines used by the Health Care Finance
Administration. General (recurrent hospitalizations, home care after discharge,
dependency for activities of daily living, weight loss, and hypoalbuminemia)
and ESLD-specific (cachexia and renal insufficiency) variables did not effec-
tively identify which patients with ESLD died within 6 months of hospitaliza-
tion [36].
ESLD also disproportionally affects younger patients relative to other pa-
tients with end-stage organ disease. In the absence of liver transplantation, pa-
tients with ESLD also typically die at a younger age. Data from the SUPPORT
trial showed that patients with cirrhosis died at a mean age of 57 years, signif-
icantly younger than patients with other severe chronic medical conditions,
such as chronic obstructive lung disease or congestive heart failure [38].
In contrast, the experience from Asia (where seropositivity for viral hepatitis
is endemic) shows that a larger proportion of patients are enrolled in hospice
care because of HCC compared with patients in the United States. Most of
these patients also have coexisting ESLD. Patients admitted to hospice for
HCC were typically younger and had a shorter survival time than non-
HCC hospice patients. Advanced liver dysfunction predicted shorter survival
time, with almost 98% of patients with CTP class C hepatic disease severity
dying while in the inpatient hospice ward [39].

Advance Directives
An important component of medical care for patients with ESLD is addressing
the use of advance directives before the end of life. In patients who are not can-
didates for organ transplantation, progressive liver disease is most likely to be
the cause of death in most cases. Data regarding how frequently health care
providers discuss the issue of advance directives with patients affected by
ESLD are scarce, however. Available information supports the notion that ad-
vance directives are addressed less frequently in these patients compared with
patients with malignancy. Among hospitalized patients in the SUPPORT
206 SANCHEZ & TALWALKAR

study, only 20% (618 of 3058) of patients had advance directives [38]. From
a study of three United States teaching hospitals, only 16% of patients with
ESLD had ‘‘do not resuscitate’’ orders written in the medical record compared
with 47% of patients with nonresectable lung cancer. Resident physicians were
more likely to discuss ‘‘do not resuscitate’’ orders with patients affected by can-
cer rather than cirrhosis or congestive heart failure, despite a good understand-
ing of their prognosis [40].
A discussion of patient preferences for end-of-life care also should include
wishes for cardiopulmonary resuscitation, intubation with mechanical ventila-
tion, invasive medical procedures (eg, emergency endoscopy), and whether
subsequent hospitalization for unstable illness is desired. The physician should
validate a patient’s wishes regarding ‘‘do not resuscitate’’ and ‘‘do not hospital-
ize’’ through written orders and reassure the patient that not proceeding with
invasive medical therapy does not equate to discontinuing care or the termina-
tion of the physician-patient relationship [33,41].

PALLIATIVE CARE TO MANAGE THE COMPLICATIONS

OF END-STAGE LIVER DISEASE
Ascites
Ascites is the most common complication of ESLD and is typically symptom-
atic [4,42]. Patients with alcoholic liver disease and ascites may benefit from the
cessation of alcohol consumption because reduction in portal pressure and im-
provement of ascites is a known outcome [42,43]. Most patients with ascites
gain control of symptoms with dietary sodium restriction (maximum 2 g/d)
and oral diuretic therapy. Initial oral diuretic therapy should consist of the com-
bination of spironolactone with a loop-acting diuretic, such as furosemide. In
most cases, the combination of 100 mg of spironolactone with 40 mg of furo-
semide (administered once daily, usually in the morning to avoid nocturia) is
more effective than single-agent diuretic therapy. In addition, the combination
of medications can ameliorate potassium derangements that can be seen with
monotherapy [42,44,45]. Dose escalation of these medications should occur
in the same ratio to control ascites with a suggested maximum of spironolac-
tone 400 mg with furosemide 160 mg daily. The development of azotemia
or hyponatremia suggests diuretic-refractory ascites, and dosages of one or
both medications should be reduced.
As the severity of liver disease progresses, an increasing percentage of pa-
tients develop symptomatic ascites refractory to medical therapy. An assess-
ment should be made for the presence of factors that could aggravate
sodium retention. Patients with a history of alcoholic liver disease should be
questioned regarding abstinence from alcohol. Adherence to sodium restriction
should be assessed by measuring urinary sodium excretion. Measured urinary
sodium excretion greater than 78 mEq/d suggests nonadherence to sodium re-
striction. Spot urinary sodium measurements may be as accurate as 24-hour
collections and are less cumbersome to collect in the outpatient setting. The
use of nonsteroidal anti-inflammatory analgesics also should be discontinued
PALLIATIVE CARE FOR ESLD 207

given their propensity to aggravate ascitic fluid accumulation via prostaglandin

inhibition [42].
Large-volume paracentesis (LVP) is a safe and effective therapy in the man-
agement of symptomatic ascites for patients with ESLD. Currently, there is no
limit to the frequency with which LVP can be performed. LVP should be per-
formed as frequently as necessary to provide symptomatic relief from tense as-
cites. The use of plasma volume expansion with intravenous albumin has been
shown to reduce significantly paracentesis-induced activation of the renin-
angiotensin system. Activation of the renin-angiotensin system is associated
with vasoconstriction, sodium retention, and a more rapid reaccumulation
of ascites (ie, postparacentesis circulatory dysfunction) [4,46]. There is some
controversy, however, regarding the use of albumin infusion given its high
cost, and it has not been uniformly recommended after LVP [42].
The medical management of refractory ascites also may be accomplished by
the use of portosystemic shunting. More commonly, TIPS placement is em-
ployed. In a prospective, randomized, multicenter study, the North American
Study for the Treatment of Refractory Ascites group compared TIPS plus med-
ical therapy with LVP plus medical therapy. Although TIPS was found to be
superior to LVP for the control of ascites, it did not reduce the need for
hospitalization or improve survival. Although the LVP group and the TIPS
group had improvement in health-related quality-of-life scores compared with
baseline, the end-of-treatment scores were not different between the two groups.
Additionally, TIPS did not eliminate the need for a sodium-restricted diet [24].
New-onset or worsening hepatic encephalopathy is the most common complica-
tion of TIPS and is due to increased portosystemic shunting. The incidence of
hepatic encephalopathy after TIPS is reported to be as high as 40% in prospec-
tive series. In most patients, hepatic encephalopathy after TIPS can be managed
using lactulose or nonabsorbable antibiotic preparations. Rarely, occlusion of
the shunt to control refractory symptoms is necessary [47–51]. The major disad-
vantage of TIPS shunts is the development of in-stent stenosis requiring revi-
sion. The shunt dysfunction rate is 75% at 1 year and approaches 100% at
2 years, although not all patients with radiographic evidence of shunt dysfunc-
tion develop clinically significant portal hypertension [50,52–54]. Relative con-
traindications for TIPS placement include severe ESLD (CTP class C liver
disease), portal vein thrombosis, pulmonary hypertension or right heart failure,
intrinsic renal disease, and prior history of hepatic artery chemoembolization.
Peritoneovenous shunts (eg, Denver shunt, LeVeen shunt) are surgically
placed shunts that have been used for the management of refractory ascites.
A high incidence of complications, including shunt malfunction, disseminated
intravascular coagulation, and sepsis from bacterial infection, is associated
with the use of this technique. Their widespread use has not occurred in recent
times [55–57]. The authors do not recommend the use of peritoneovenous
shunts for the management of intractable ascites based on the absence of
evidence-based data for efficacy and an unfavorable risk/benefit profile. Instead,
the use of serial LVP is safer and more effective.
208 SANCHEZ & TALWALKAR

In terminally ill patients with ESLD, the use of an indwelling peritoneal

drainage catheter for the management of symptomatic refractory ascites has
been described. Indwelling catheters have been used safely for the management
of malignant ascites, although it is unknown whether the complication rate
would be higher in patients with ESLD, who are typically coagulopathic and
prone to spontaneous bacterial peritonitis. The technique of bedside insertion
of an indwelling catheter has been described, and an experienced physician
can place a catheter without the need for patient hospitalization. An indwelling
catheter allows the patient (or care provider) to drain small volumes of ascitic
fluid as needed for symptom relief. Given the concerns for infectious compli-
cations, indwelling peritoneal drainage catheters seem most appropriate for
patients with terminal disease enrolled in hospice care [58–60].

Hepatic Hydrothorax
Hepatic hydrothorax is defined by the development of a transudative pleural
effusion in patients with cirrhosis and portal hypertension. The pathogenesis
is believed to be the preferential movement of ascitic fluid from the positive-
pressure abdominal cavity into the negative-pressure thoracic cavity in patients
with diaphragmatic defects. Although the abdominal cavity can expand, and
patients frequently tolerate large volumes of ascitic fluid, relatively small pleu-
ral fluid collections are often highly symptomatic.
The management of hepatic hydrothorax is important for the relief of dys-
pnea in patients with ESLD. As with the initial medical approach for manage-
ment of ascites, the mainstay of therapy is sodium restriction and combination
diuretic therapy. Large-volume thoracentesis is frequently necessary for the
rapid relief of dyspnea. Repeated thoracentesis can be performed, but if fre-
quently necessary, patients may benefit from more invasive, alternative man-
agement strategies.
Tube thoracostomy is commonly used to manage recurrent symptomatic
pleural effusions. This therapeutic modality is associated with a high rate of
complications in patients with ESLD, however, including spontaneous bacterial
empyema and hemothorax. Among 56 patients with CTP class B or C cirrhosis
who underwent tube thoracostomy for the treatment of hepatic hydrothorax,
most patients developed electrolyte disturbances or renal insufficiency. A total
of 15 patients died with the chest tube in place. Pleurodesis (most commonly
talc) has a low rate of success in ablating the pleural space, likely owing to
the rapid reaccumulation of pleural fluid driven by portal hypertension. Incom-
plete pleurodesis leads to the formation of loculated pleural effusions, which
make subsequent management by thoracentesis difficult [61–63].
By decreasing portal venous pressure, the use of TIPS is noted for reductions
in the accumulation of pleural fluid among patients with refractory hepatic hy-
drothorax. TIPS also has been shown to decrease the need for serial therapeu-
tic thoracentesis in these patients. Similarly to patients with ascites, however,
TIPS does not obviate the need for sodium restriction. Although TIPS may de-
crease the need for thoracentesis, there has been no proven survival benefit in
PALLIATIVE CARE FOR ESLD 209

the absence of liver transplantation. To date, there has been no systematic as-
sessment of the impact of TIPS on health-related quality of life in patients with
refractory hepatic hydrothorax. Despite the absence of evidence-based data
and health status information, it is reasonable to use TIPS for the palliation
of recurrent, symptomatic hepatic hydrothorax that is refractory to medical
therapy [50,63,64].

Hepatic Encephalopathy
Hepatic encephalopathy may be the most disabling complication of portal hyper-
tension experienced by patients with cirrhosis. Hepatic encephalopathy is char-
acterized by several neuropsychiatric disturbances that result in significantly
impaired health-related quality of life [65]. Although hepatic encephalopathy
occurs commonly, its manifestations range from subclinical encephalopathy to
hepatic coma. Neuropsychometric testing can identify subtle disturbances
from hepatic encephalopathy in 60% to 70% of patients with ESLD [66–68]. Fre-
quently, patients with overt hepatic encephalopathy present with confusion,
ataxia, and somnolence, which can progress rapidly to stupor and coma. Medi-
cations, particularly psychoactive agents including narcotic analgesics and seda-
tive-hypnotics, frequently are identified as precipitating factors for the acute
exacerbation of hepatic encephalopathy. In terminally ill patients with ESLD,
the presence of somnolence from hepatic encephalopathy may not be a dis-
tressing symptom for the patient; the pursuit of aggressive therapy to reverse
hepatic encephalopathy should be considered carefully on a case-by-case basis.
The most widely used first-line medical therapy for hepatic encephalopathy
is a cathartic, typically a nonabsorbable disaccharide, such as lactulose or lacti-
tol. The mechanism of action for lactulose is to acidify luminal contents that
promote the formation of ammonium chloride from ammonia, which is ex-
creted in stool. Lactulose can be administered orally or, in an obtunded patient,
per rectum. The goal of lactulose therapy is to achieve three to four soft, non-
diarrheal stools per day. Excessive administration of lactulose results in diar-
rhea, which may precipitate hepatic encephalopathy further via dehydration
and electrolyte disturbance, and negatively affects patient quality of life
[67,69]. Of concern is the more recent observation that data supporting the
efficacy of lactulose are based on methodologically weak clinical trials, which
raises the suspicion that lactulose is no better than placebo. The correction
of precipitating factors (eg, dehydration or constipation) may be the most im-
portant therapy, but remains obscured by the widespread use of lactulose in
patients with moderate-to-severe hepatic encephalopathy.
In patients who are refractory or intolerant to lactulose, the use of nonabsorb-
able antibiotic therapy can be effective for managing relapsing or treatment-
dependent hepatic encephalopathy. Oral neomycin (1 to 2 g per day) is poorly
absorbed, but long-term administration can lead to nephrotoxicity. Oral metro-
nidazole (250 mg two to three times daily) is effective, but may negatively
affect the patient’s sense of taste and can lead to significant peripheral neuropathy
[69]. Several other compounds have been evaluated, typically in small trials,
210 SANCHEZ & TALWALKAR

including ornithine aspartate (which is not available in the United States), flu-
mazenil, and sodium benzoate. The use of rifaximin, a nonabsorbable rifam-
pin analogue, has been shown to be equally effective as lactitol in the
management of acute exacerbations of hepatic encephalopathy [70]. In the
United States, rifaximin has not been approved yet by the Food and Drug
Administration for the treatment of hepatic encephalopathy, and its use re-
mains an off-label indication.

Pruritus
Pruritus is a complication of chronic liver disease and cirrhosis that can cause
patient distress. Although most commonly associated with cholestatic liver dis-
eases, the development of pruritus may complicate liver disease of any origin.
The mainstay of therapy is treatment of the underlying liver disease whenever
possible. In patients with biliary obstruction causing pruritus, obtaining ade-
quate biliary drainage is paramount for symptom relief. If endoscopic biliary
drainage is inadequate or not technically feasible, external biliary drainage
via percutaneous transhepatic cholangiography is a viable option. If necessary
(eg, a difficult central obstructing lesion), the left and right biliary ductal sys-
tems can be percutaneously accessed and drained separately by endoscopic
or percutaneous methods.
A wide range of putative agents or mediators has been proposed as the cause
of pruritus in liver disease, although medical therapies used in practice often do
not have their basis in well-defined pathophysiology. The most common first-
line therapy of choice is an oral antihistamine. Because the pruritus of liver dis-
ease is multifactorial, however, antihistamines probably work mainly through
their nonspecific sedating effect. They may be of particular benefit adminis-
tered at bedtime to allow patients to get an adequate night’s sleep [71]. Chole-
styramine, a nonabsorbable bile acid exchange resin, is administered orally and
prevents uptake of bile acids in the terminal ileum. The drug is most effective in
patients with an intact gallbladder. A total of 2 to 16 g daily is administered
orally in divided doses. Care must be taken to separate the administration of
cholestyramine from other medications because it can interfere with their ab-
sorption. Other common side effects of cholestyramine include unpalatability
and constipation [71–73].
Endogenous opioids have been implicated in the cause of liver disease–
associated pruritus. The beneficial effect of rifampin and its analogues, which
upregulate the cytochrome P-450 metabolic pathway, has been postulated to be
due to the enhanced metabolism of endogenous opioids. Rifampin is adminis-
tered orally starting at 150 to 300 mg/d [71,74–76]. The drug may have significant
hepatotoxic effects in patients with ESLD, however, and its widespread use in
patients with CTP class B and C cirrhosis is not recommended. In patients
with compensated cirrhosis, a dose escalation of rifampin to 600 to 900 mg daily
is possible. Serum liver tests should be obtained at 2 and 6 weeks after therapy to
exclude toxicity. Thereafter, serum liver tests may be obtained every 3 months
to monitor for toxicity. Numerous small clinical trials using narcotic receptor
PALLIATIVE CARE FOR ESLD 211

antagonists have shown benefit in patients with pruritus [77–81]. The oral nar-
cotic antagonist naltrexone (starting 12.5 mg twice daily titrated upwards to
50 mg daily) has been reported to provide rapid relief of pruritus in selected
patients. Patients receiving opioid antagonists can experience a narcotic with-
drawal–like phenomenon, and narcotic antagonist therapy is inappropriate for
patients receiving opioid analgesics for the management of pain [71]. Anecdotal
experience with the selective serotonin reuptake inhibitor sertraline (25–50 mg
daily) indicates improvement of pruritus in patients with noncirrhotic primary
biliary cirrhosis [82]. The safety and efficacy of sertraline in patients with
ESLD is unknown. In patients with pruritus refractory to these medical therapies,
referral to a tertiary center for investigational therapies, such as extracorporeal
hemoperfusion, may be appropriate.

Hepatocellular Carcinoma
HCC is a frequent complication of cirrhosis, occurring at an estimated rate of
1% to 6% per year. The incidence of HCC has been increasing steadily in
United Sates patients since the 1980s. In contrast, HCC is the second leading
causes of cancer-related mortality in Asia. The prognosis of unresectable HCC
is poor with a 5-year survival rate of less than 5% [39,83,84]. Additionally,
many patients are not candidates for surgical resection based on ESLD result-
ing in hyperbilirubinemia and portal hypertension. In patients with CTP class
B or C cirrhosis, hepatic resection is fraught with an increased risk of death
from progressive liver failure.
Although liver transplantation remains the treatment of choice for patients
with cirrhosis and HCC, many patients do not meet the eligibility criteria
for liver transplantation. Patients with small tumors have an excellent progno-
sis after liver transplantation. Given concerns for disease recurrence in patients
with more extensive tumors, the United Network for Organ Sharing limits al-
location of donor organs to patients with HCC according to the previously
published Milan criteria (Box 1). Although protocols for extended criteria
are being investigated, patients with large tumor burdens or vascular invasion
are not typically considered candidates for transplantation [14,85,86].
Aside from surgical interventions, many nonoperative treatment modalities
are available for palliative care in HCC. Ablative therapies include percutane-
ous ethanol injection (PEI), radiofrequency ablation (RFA), and selective he-
patic arterial chemoembolization (HACE). PEI is effective in ablating small

Box 1: Milan criteria for liver transplantation for hepatocellular

carcinoma
Single lesion <5 cm in diameter or Three lesions all <3 cm in diameter
and No extrahepatic metastasis
and No vascular invasion
212 SANCHEZ & TALWALKAR

tumors and has the advantage of being inexpensive and widely available. Suc-
cessful therapy with PEI frequently requires multiple injections, and tumors
larger than 3 cm have been shown to have a higher local recurrence rate
than smaller lesions [87,88].
Data suggest that RFA may provide more effective local tumor ablation with
fewer treatment sessions being necessary. The safety of RFA in a large series of
664 patients was found to be similar to PEI [88]. A randomized trial comparing
157 patients with HCC found that RFA was more effective than PEI in control-
ling HCC smaller than 4 cm [89]. RFA and PEI are limited by the size of tumor
amenable for treatment. Tumors close to the liver capsule are not ideal for ab-
lation because of the possible injury to adjacent organs. Percutaneous tumor
ablation should be considered carefully in patients with portal vein thrombosis
owing to the concern for causing hepatic abscess in the necrosed tissue.
Selective HACE has been shown in a meta-analysis of 545 patients to im-
prove survival among patients with unresectable HCC. The greatest and per-
haps only real benefit is in patients with compensated or CTP class A cirrhosis.
Embolization alone, without instillation of chemotherapeutic agents, has not
been shown to be equally effective [90]. HACE is generally well tolerated;
the most common side effects are fever, abdominal pain, nausea, and anorexia.
Contraindications to HACE include main portal vein thrombosis, CTP class C
liver disease, and a history of TIPS shunt placement based on the fact that por-
tal venous inflow is already reduced. Systemic chemotherapy and radiation
therapy are limited by increased side effects, dose-limiting hepatotoxicity,
and poor efficacy [91]. Several investigations have recognized the palliative
effects of thalidomide in patients with advanced HCC. Treatment often is
complicated, however, by fatigue, constipation, and peripheral neuropathy even
at low doses [92,93]. Ongoing clinical trials are evaluating new treatment modal-
ities for patients with HCC.

Symptoms That Reduce Quality of Life

Patients with ESLD have significant impairments in health-related quality of life
partly as a result of physical symptoms associated with liver disease (ascites,
pruritus) and cognitive dysfunction and psychological symptoms. Depression
is common in patients with ESLD; prevalence rates are 30% to 40% [94]. A
more precise estimate is difficult to assess based on the inability to exclude he-
patic encephalopathy as a cause of mood disturbance in terminally ill patients
[39]. Depression in patients with ESLD has been shown to be associated with
a poor outcome compared with nondepressed patients with ESLD. In a study
of 81 patients awaiting liver transplantation, 64% were found to have depres-
sion based on the Beck Depression Inventory. Among patients with depression,
the presence of diminished health-related quality-of-life scores, lower perfor-
mance status, and decreased survival among nontransplanted patients was ob-
served [94]. Although an approach similar to managing depression in patients
with advanced cancer seems applicable, there is a need for more data regarding
the management of depression in patients with ESLD.
PALLIATIVE CARE FOR ESLD 213

Insomnia with sleep disturbance is common and negatively affects health-

related quality of life in patients with ESLD. Sleep disturbances (hypersomnia
and insomnia) are early features of hepatic encephalopathy [69]. Sleep distur-
bances without hepatic encephalopathy also have been recognized as a signifi-
cant problem in patients with cirrhosis. From a questionnaire-based study,
investigators found nearly 50% of patients with cirrhosis complained of sleep
disturbances. Unsatisfactory sleep patterns were associated with higher scores
for depression and anxiety [95].
Fatigue is commonly associated with ESLD, particularly primary biliary cir-
rhosis and hepatitis C virus. Pharmacotherapy with b-adrenergic antagonists
and oral diuretics may contribute to fatigue [96,97]. Other contributing factors
include muscle wasting, hyperammonemia, depression, and sleep disruption
from poorly controlled pruritus and muscle cramps [71,98]. Lower extremity
muscle cramps can be a particularly problematic symptom. They frequently
occur at night and often disrupt sleep. A large study of factors associated with
health-related quality of life in patients with ESLD identified CTP score and
muscle cramps as the factors most associated with diminished health-related
quality-of-life scores [98]. The cause of muscle cramps in ESLD is unknown;
it is unrelated to age, severity of liver disease, electrolyte disturbance, or use
of oral diuretics. Currently, there is no identified therapy for leg cramps based
on a controlled clinical trial. Frequently, quinine sulfate 260 to 324 mg daily at
bedtime is used. Despite widespread use, patients with chronic liver disease
have been systematically excluded from randomized controlled trials of quinine
for muscle cramps. Adequately controlled studies are needed to define the
safety and efficacy of quinine therapy in patients with ESLD.

Cachexia and Muscle Wasting

Cachexia is a common finding in patients with ESLD. The cause of cachexia in
cirrhosis is multifactorial, owing in part to increased metabolic needs and dimin-
ished caloric intake. Patients with ESLD often have inadequate caloric intake to
meet their metabolic needs based on several factors, including elevated intra-
abdominal pressure from ascites resulting in early satiety, protein-calorie defi-
ciency from protein loss secondary to frequent paracentesis, or autonomic
neuropathy associated with cirrhosis resulting in gastroparesis [99]. It is crucial
to avoid protein restriction in these patients, which is frequently done in an
effort to avoid hepatic encephalopathy without proof of efficacy [69,100].
Most data regarding cachexia in terminally ill patients are from the cancer
literature [101]. The choices of therapeutic options to counteract cachexia
and muscle wasting in ESLD are limited. More recent data have shown a poten-
tial benefit for branched-chain amino acid supplementation in terms of delaying
liver disease progression and improving anorexia and health-related quality of
life [102,103]. Improvement in drug delivery (capsule form versus unpalatable
powder) and subsequent compliance with therapy is likely responsible for the
attainment of beneficial effects. Further studies are needed to verify these
findings.
214 SANCHEZ & TALWALKAR

LIMITATIONS AND FUTURE DIRECTIONS

The effectiveness of palliative care has been measured in terms of symptom
improvement, improved health status, and patient satisfaction with care. The
evidence to support these observations is not supported, however, by rigorous
investigations based on interventions in a randomized setting. Additionally, the
studies to date mainly focus on patients with advanced malignancy rather than
advanced organ failure, such as ESLD. Further study in patients with ESLD is
needed to define the important aspects of palliative care that are grounded in
evidence-based medicine.

SUMMARY
The proportion of patients with ESLD who will be managed without liver
transplantation will increase in the near future, largely as a result of the increas-
ing age of the population. Patients with ESLD are subject to many physical and
psychosocial symptoms that negatively affect health-related quality of life. Sleep
quality should be maximized by controlling pruritus and leg cramps. Many fre-
quently used therapies are not supported by a strong evidence base. Advance
directives should be addressed with all patients with ESLD, preferably in the
outpatient setting before an acute deterioration. Medicare provides a hospice
benefit for patients with ESLD, and referral to a hospice is appropriate for
patients with an expected survival of 6 months or less.
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