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.
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 . 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 illnesses. Despite being the 12th most common cause of death in the United States , 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 . 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 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 . 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) . 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 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 . 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 , 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 . Furthermore, the longitudinal ability of MELD to predict survival beyond three months is not established .
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 . 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 . (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'.)
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 , 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. Ideal timing of specialty 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 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 . 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 . 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 clinician. (See "Overview of comprehensive patient assessment in palliative care" and "Palliative care delivery in the home" and "Palliative care: Nursing home" and "Benefits, services, and models of subspecialty palliative care" and "Grief and bereavement in adults: Management".)
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 . Most patients in this study expressed a preference for dying rather than living in a coma or on prolonged 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 , 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” . 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].
Palliative care and liver transplantation may be viewed by some as mutually exclusive . 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 [31,33,38-41]. 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 .
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 . 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 5). 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 6).
Others have developed a tool (the Supportive and Palliative Care Indicators [SPICT] tool) that uses clinical indicators to identify patients for supportive and palliative care assessment . 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
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 7).
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 .
●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 .
●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 . 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 [25,49-51]. Other non-life-threatening 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 . 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 . 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.
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 [52,53]. 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 . (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 , 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 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 8). 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: End-stage renal 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 8). 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".)
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 "General principles of the management of variceal hemorrhage" 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 "Palliative care: Assessment and management of nausea and vomiting" 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'.)
For patients with ESLD, general measures that may help pruritus include  (see "Pruritus associated with cholestasis", section on 'General approach'):
●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 rifaximin  or a dose of sertraline, paroxetine , 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 [56,57]. 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 "Palliative care: Assessment and management of anorexia and cachexia".)
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, 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 9), laboratory assessment of nutritional status, and a more formal assessment of nutritional status using the patient-generated subjective global assessment (SGA) tool  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 . 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 .
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 [40,54,61,62].
●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.)
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 . Having these discussions early in the disease trajectory will make it easier to return to these discussions at a later time, if needed [64,65].
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 [30,37,66]. 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 at least 12 and/or the MELD score was at least 21 . (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 .
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 ).
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 . 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 ) 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 [54,61,69]. 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 .
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.)
●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 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 7). (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.)
- World Heealth Organization. Guidelines for palliative care. http://www.who.int/entity/cancer/palliative/definition/en (Accessed on August 22, 2016).
- Deaths: Final data for 2013. Natl Vital Stats Rep 2016; 64(2). Publication available online at http://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_02.pdf (Accessed on August 17, 2016).
- Cox-North P, Doorenbos A, Shannon SE, et al. The transition to end-of-life care in end-stage liver disease. J Hosp Palliat Nurs 2013; 15:209.
- Sanchez W, Talwalkar JA. Palliative care for patients with end-stage liver disease ineligible for liver transplantation. Gastroenterol Clin North Am 2006; 35:201.
- Bobb BT, Coyne PJ. Compendium of Treatment of End Stage Non-Cancer Diagnoses: Hepatic. 2nd ed. Hospice and Palliative Nurses Association, Pittsburgh PA. 2012; www.AdvancingExpertCare.org/
- http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/03_liver_13.pdf (Accessed on August 22, 2016).
- National Institute on Alcohol Abuse and Alcoholism (NIAAA): Liver Cirrhosis in the United States, 1970-2005 http://pubs.niaaa.nih.gov/publications/surveillance83/Cirr05.htm (Accessed on September 22, 2015).
- United Network for Organ Sharing. Transplants by Organ Type-2005 https://www.unos.org/data/transplant-trends/#transplants_by_organ_type+year+2005 (Accessed on September 22, 2015).
- Dolan B, ARnold R. Prognosis in decompensated chronic liver failure. Fast Facts and Concepts #189. 2007. Available at: http://www.mypcnow.org/blank-t9wv6 (Accessed on August 18, 2016).
- D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44:217.
- Brown CL, Hammill BG, Qualls LG, et al. Significant Morbidity and Mortality Among Hospitalized End-Stage Liver Disease Patients in Medicare. J Pain Symptom Manage 2016; 52:412.
- Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646.
- Infante-Rivard C, Esnaola S, Villeneuve JP. Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhotics. Hepatology 1987; 7:660.
- Albers I, Hartmann H, Bircher J, Creutzfeldt W. Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroenterol 1989; 24:269.
- Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003; 124:91.
- Cholongitas E, Papatheodoridis GV, Vangeli M, et al. Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther 2005; 22:1079.
- Poca M, Puente A, Graupera I, Villanueva C. Prognostic markers in patients with cirrhosis and portal hypertension who have not bled. Dis Markers 2011; 31:147.
- Salpeter SR, Luo EJ, Malter DS, Stuart B. Systematic review of noncancer presentations with a median survival of 6 months or less. Am J Med 2012; 125:512.e1.
- Allegretti AS, Ortiz G, Wenger J, et al. Prognosis of Acute Kidney Injury and Hepatorenal Syndrome in Patients with Cirrhosis: A Prospective Cohort Study. Int J Nephrol 2015; 2015:108139.
- Boyd K, Kimbell B, Murray S, Iredale J. Living and dying well with end-stage liver disease: time for palliative care? Hepatology 2012; 55:1650.
- Chen WT, Lin CY, Sheen IS, et al. MELD score can predict early mortality in patients with rebleeding after band ligation for variceal bleeding. World J Gastroenterol 2011; 17:2120.
- Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med 2008; 359:1018.
- Meghani SH, Hinds PS. Policy brief: the Institute of Medicine report Dying in America: Improving quality and honoring individual preferences near the end of life. Nurs Outlook 2015; 63:51.
- Quill TE, Abernethy AP. Generalist plus specialist palliative care--creating a more sustainable model. N Engl J Med 2013; 368:1173.
- Younossi ZM, Boparai N, Price LL, et al. Health-related quality of life in chronic liver disease: the impact of type and severity of disease. Am J Gastroenterol 2001; 96:2199.
- Bjørk IT, Nåden D. Patients' experiences of waiting for a liver transplantation. Nurs Inq 2008; 15:289.
- Brown J, Sorrell JH, McClaren J, Creswell JW. Waiting for a liver transplant. Qual Health Res 2006; 16:119.
- Martin SC, Stone AM, Scott AM, Brashers DE. Medical, personal, and social forms of uncertainty across the transplantation trajectory. Qual Health Res 2010; 20:182.
- Roth K, Lynn J, Zhong Z, et al. Dying with end stage liver disease with cirrhosis: insights from SUPPORT. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. J Am Geriatr Soc 2000; 48:S122.
- Poonja Z, Brisebois A, van Zanten SV, et al. Patients with cirrhosis and denied liver transplants rarely receive adequate palliative care or appropriate management. Clin Gastroenterol Hepatol 2014; 12:692.
- Baumann AJ, Wheeler DS, James M, et al. Benefit of Early Palliative Care Intervention in End-Stage Liver Disease Patients Awaiting Liver Transplantation. J Pain Symptom Manage 2015; 50:882.
- Lai JC, Dodge JL, Sen S, et al. Functional decline in patients with cirrhosis awaiting liver transplantation: Results from the functional assessment in liver transplantation (FrAILT) study. Hepatology 2016; 63:574.
- Larson AM, Curtis JR. Integrating palliative care for liver transplant candidates: "too well for transplant, too sick for life". JAMA 2006; 295:2168.
- Teno JM, Clarridge BR, Casey V, et al. Family perspectives on end-of-life care at the last place of care. JAMA 2004; 291:88.
- Steinhauser KE, Christakis NA, Clipp EC, et al. Factors considered important at the end of life by patients, family, physicians, and other care providers. JAMA 2000; 284:2476.
- Singer PA, Martin DK, Kelner M. Quality end-of-life care: patients' perspectives. JAMA 1999; 281:163.
- Walling AM, Asch SM, Lorenz KA, Wenger NS. Impact of consideration of transplantation on end-of-life care for patients during a terminal hospitalization. Transplantation 2013; 95:641.
- Medici V, Rossaro L, Wegelin JA, et al. The utility of the model for end-stage liver disease score: a reliable guide for liver transplant candidacy and, for select patients, simultaneous hospice referral. Liver Transpl 2008; 14:1100.
- Lamba S, Murphy P, McVicker S, et al. Changing end-of-life care practice for liver transplant service patients: structured palliative care intervention in the surgical intensive care unit. J Pain Symptom Manage 2012; 44:508.
- Walling AM, Schreibeis-Baum H, Pimstone N, et al. Proactive case finding to improve concurrently curative and palliative care in patients with end-stage liver disease. J Palliat Med 2015; 18:378.
- Rossaro L, Troppmann C, McVicar JP, et al. A strategy for the simultaneous provision of pre-operative palliative care for patients awaiting liver transplantation. Transpl Int 2004; 17:473.
- Beck KR, Pantilat SZ, O'Riordan DL, Peters MG. Use of Palliative Care Consultation for Patients with End-Stage Liver Disease: Survey of Liver Transplant Service Providers. J Palliat Med 2016; 19:836.
- Boyd K, Murray SA. Recognising and managing key transitions in end of life care. BMJ 2010; 341:c4863.
- Kim SH, Oh EG, Lee WH, et al. Symptom experience in Korean patients with liver cirrhosis. J Pain Symptom Manage 2006; 31:326.
- Desbiens NA, Wu AW. Pain and suffering in seriously ill hospitalized patients. J Am Geriatr Soc 2000; 48:S183.
- Bianchi G, Marchesini G, Nicolino F, et al. Psychological status and depression in patients with liver cirrhosis. Dig Liver Dis 2005; 37:593.
- Santos GR, Boin IF, Pereira MI, et al. Anxiety levels observed in candidates for liver transplantation. Transplant Proc 2010; 42:513.
- Kimbell B, Murray SA. What is the patient experience in advanced liver disease? A scoping review of the literature. BMJ Support Palliat Care 2015; 5:471.
- Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001; 120:170.
- Kanwal F, Hays RD, Kilbourne AM, et al. Are physician-derived disease severity indices associated with health-related quality of life in patients with end-stage liver disease? Am J Gastroenterol 2004; 99:1726.
- Saab S, Ibrahim AB, Shpaner A, et al. MELD fails to measure quality of life in liver transplant candidates. Liver Transpl 2005; 11:218.
- Perri GA. Ascites in patients with cirrhosis. Can Fam Physician 2013; 59:1297.
- Kathpalia P, Bhatia A, Robertazzi S, et al. Indwelling peritoneal catheters in patients with cirrhosis and refractory ascites. Intern Med J 2015; 45:1026.
- Bajaj JS, Wade JB, Gibson DP, et al. The multi-dimensional burden of cirrhosis and hepatic encephalopathy on patients and caregivers. Am J Gastroenterol 2011; 106:1646.
- Xander C, Meerpohl JJ, Galandi D, et al. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database Syst Rev 2013; :CD008320.
- Berger L, Popov AG, Berger B. Case Report: Relieving the Itch of Cholestasis with Corticosteroids in Palliative Care. J Palliat Med 2015; 18:913.
- Dillon S, Tobias JD. Ondansetron to treat pruritus due to cholestatic jaundice. J Pediatr Pharmacol Ther 2013; 18:241.
- Hasse J, Strong S, Gorman MA, Liepa G. Subjective global assessment: alternative nutrition-assessment technique for liver-transplant candidates. Nutrition 1993; 9:339.
- Curtis JR. Palliative and end-of-life care for patients with severe COPD. Eur Respir J 2008; 32:796.
- Jackson VA, Jacobsen J, Greer JA, et al. The cultivation of prognostic awareness through the provision of early palliative care in the ambulatory setting: a communication guide. J Palliat Med 2013; 16:894.
- Miyazaki ET, Dos Santos R Jr, Miyazaki MC, et al. Patients on the waiting list for liver transplantation: caregiver burden and stress. Liver Transpl 2010; 16:1164.
- Rakoski MO, McCammon RJ, Piette JD, et al. Burden of cirrhosis on older Americans and their families: analysis of the health and retirement study. Hepatology 2012; 55:184.
- Bernacki RE, Block SD, American College of Physicians High Value Care Task Force. Communication about serious illness care goals: a review and synthesis of best practices. JAMA Intern Med 2014; 174:1994.
- Curtis JR, Wenrich MD, Carline JD, et al. Patients' perspectives on physician skill in end-of-life care: differences between patients with COPD, cancer, and AIDS. Chest 2002; 122:356.
- Knauft E, Nielsen EL, Engelberg RA, et al. Barriers and facilitators to end-of-life care communication for patients with COPD. Chest 2005; 127:2188.
- Fukui N, Golabi P, Otgonsuren M, et al. Demographics, Resource Utilization, and Outcomes of Elderly Patients With Chronic Liver Disease Receiving Hospice Care in the United States. Am J Gastroenterol 2017; 112:1700.
- Walling AM, Ahluwalia SC, Wenger NS, et al. Palliative Care Quality Indicators for Patients with End-Stage Liver Disease Due to Cirrhosis. Dig Dis Sci 2017; 62:84.
- Lisotti A, Fusaroli P, Caletti G. Palliative care in patients with liver cirrhosis: it is the time to deal with the burden. BMJ Support Palliat Care 2015; 5:466.
- Rodrigue JR, Dimitri N, Reed A, et al. Quality of life and psychosocial functioning of spouse/partner caregivers before and after liver transplantation. Clin Transplant 2011; 25:239.