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Palliative Care for Patients with End-Stage Liver Disease

  • Cyriac A. Philips
    Affiliations
    Department of Clinical and Translational Hepatology and the Monarch Liver Laboratory, Rajagiri Hospital, Aluva, Kerala, India
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  • Chandan K. Kedarisetty
    Correspondence
    Address for correspondence: Chandan K. Kedarisetty, MD DM, Department of Hepatology and Liver Transplantation Gleneagles Global Hospital, Lakdikapul, Hyderabad 500004, India. Tel.: +91 (040) 45928500.
    Affiliations
    Department of Hepatology and Liver Transplantation, Gleneagles Global Hospital, Hyderabad, India
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Published:August 13, 2022DOI:https://doi.org/10.1016/j.jceh.2022.08.003
      End-stage liver disease (ESLD) is the culmination of progression of chronic liver disease to cirrhosis, decompensation, and chronic liver failure, featuring portal hypertension or hepatocellular failure-related complications. Liver transplantation offers improved long-term survival for these patients but is negatively influenced by donor availability, financial constraints in developing countries, active substance abuse, progression of disease or malignancy on wait-list, sepsis and extrahepatic organ involvement. In this context, palliative care (PC), an interdisciplinary medical practice that aim to prevent and relieve suffering, offers best possible quality of life and is not limited to end-of-life care. It also encompasses achievable goals such as symptom control and aggressive disease-modifying treatments or interventions that beneficially alter the natural course of the disease to offer curative intend. In this narrative review, we discuss the prognostic factors that define disease course in ESLD, various indications and challenges in PC for advanced cirrhosis and management options for major symptom burden in patients with ESLD based on evidence-based best practice.

      Keywords

      Abbreviations:

      ACLF (acute-on-chronic liver failure), CPT (Child–Pugh–Turcotte), ESLD (end-stage liver disease), HE (hepatic encephalopathy), INR (international normalized ratio), LSM (liver stiffness measurement), LT (liver transplantation), MELD (model for end stage liver disease), PC (palliative care), TE (transient elastography), TIPS (transjugular intrahepatic portosystemic shunt)
      Cirrhosis is the terminal stage in the spectrum of chronic liver disease resulting from chronic inflammation and progressive fibrosis that occurs due to various reasons, most commonly alcohol use disorder, metabolic-associated fatty liver disease, or chronic viral hepatitis. The two clinically important stages of cirrhosis include compensated and decompensated stages. Within compensated cirrhosis, patients may or may not have clinically significant portal hypertension which is defined as either hepatic venous pressure gradient ≥10 mmHg or liver stiffness measurement via transient elastography > 25 kPa or by clinical manifestations of portal hypertension, both of which are associated with higher risk of adverse clinical events and mortality in patients with cirrhosis.
      • Franchis R.
      • Bosch J.
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      • Thomas R.
      • Ripoll C.
      on behalf of the Baveno VII Faculty
      Baveno VII - renewing consensus in portal hypertension.
      ,
      • Yoshiji H.
      • Nagoshi S.
      • Akahane T.
      • et al.
      Evidence-based clinical practice guidelines for liver cirrhosis 2020.
      As the liver disease progresses, portal pressure increases, liver function decreases, leading to development of ascites, variceal bleeding, hepatic encephalopathy (HE), jaundice, acute kidney injury, infections such as spontaneous bacterial peritonitis and hepatocellular carcinoma as well as other portal hypertension related sequela such as hepatopulmonary syndrome and portopulmonary hypertension. Transition from a compensated to a decompensated stage occurs at a rate of ∼5–7% per year.
      • Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Thomas R.
      • Ripoll C.
      on behalf of the Baveno VII Faculty
      Baveno VII - renewing consensus in portal hypertension.
      Even though liver transplantation (LT) offers the hope for cure and improved long term survival for these patients, various factors such as donor availability, financial constraints in developing countries, active substance abuse, progression of disease or malignancy on wait-list, sepsis and extrahepatic organ involvement hamper chances of a timely curative transplantation.
      • Jadlowiec C.C.
      • Taner T.
      Liver transplantation: current status and challenges.
      In such patients, the need for best supportive care – either to optimize liver disease related complications to maintain on LT wait-list or to improve quality of life, reduce hospitalizations and decrease treatment costs become the priority. In this regard, palliative care (PC), an interdisciplinary medical service that focus on preventing and relieving suffering, offering best possible quality of life for patients facing serious illness and their families become important in treating patients with ESLD.
      • Teoli D.
      • Kalish V.B.
      Palliative care.
      Core principles of PC include symptomatic treatment; establishing goals of care keeping with the patient's values and preferences; clear and consistent communication between treating physicians and paramedical staff, the patients and their families, as well as psychosocial and practical support to patients and their family caregivers. PC can be initiated early in the course of terminal illness along with other treatments that are intended to improve survival. Palliation is not limited to end-of-life care.
      • Tatum P.E.
      • Mills S.S.
      Hospice and palliative care: an overview.
      Palliation also includes patient-centered (not disease prioritized) achievable goals such as symptom control (for example severe muscle cramps) for improved quality of life; as well as aggressive disease-modifying treatments that are proven to modify natural course of the disease which may help achieve curative intend for patients with serious illnesses, known as “the simultaneous care model” (an example of this is downstaging advanced liver cancer via medical and interventional methods to within LT criteria). In this narrative review, we discuss the prognostic variables that help estimate disease trajectory and help initiate PC in ESLD, the various indications and challenges in PC for advanced cirrhosis and major symptom burden and their management options in patients with ESLD based on evidence-based published literature. Palliative care of hepatic malignancy and those focused on specific chronic organ failure in cirrhosis is beyond the scope of this review.

      Prognostic tools for initiating palliation ESLD

      Survival of patients with compensated cirrhosis patients is a median of >12 years while in decompensated cirrhosis it is only approximately two years.
      • Zipprich A.
      • Garcia-Tsao G.
      • Rogowski S.
      • Fleig W.E.
      • Seufferlein T.
      • Dollinger M.M.
      Prognostic indicators of survival in patients with compensated and decompensated cirrhosis.
      The first step is to identify patients who would benefit from PC services (Figure 1). Decompensated cirrhosis patients with >1 hospital admissions in preceding 12 months have a one-year cumulative mortality of 27%.
      • Warren A.
      • Soulsby C.R.
      • Puxty A.
      • et al.
      Long-term outcome of patients with liver cirrhosis admitted to a general intensive care unit.
      Presence of ascites is associated with two-year mortality of 50%, while refractory ascites reduces the median survival to just six months, whereas the median survival after onset of overt HE is 12 months. Furthermore, presence of infections in ESLD increases mortality four-fold – approximately one-third die within one month of infection while another 30% die at the end of 12-months.
      • Mazzarelli C.
      • Prentice W.M.
      • Heneghan M.A.
      • Belli L.S.
      • Agarwal K.
      • Cannon M.D.
      Palliative care in end-stage liver disease: time to do better?.
      The commonly used clinical scoring to prognosticate cirrhosis is the Child-Turcotte- Pugh (CTP) system which comprise of five clinical and laboratory criteria including serum bilirubin, serum albumin, ascites, HE, and prothrombin time (or international normalized ratio, INR) in the modified version and clinical nutrition status instead of INR in the original version. Advanced decompensation was defined as score ≥10 (CTP class C) and ESLD at score 14–15.
      • Tsoris A.
      • Marlar C.A.
      Use of child pugh score in liver disease.
      The CTP score was useful for predicting all-cause mortality risk and development of complications such as hepatocellular failure and variceal bleeding. The overall one-year survival rate in CTP class C is 45% and the approximate proportion of patients with both variceal bleeding and ascites dying at one-year is 57%.
      • D'Amico G.
      • Garcia-Tsao G.
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
      Figure 1
      Figure 1Definition, goals, and triggers for palliation in end-stage liver disease. CPT, Child–Pugh–Turcotte score; MELD, model for end-stage liver disease; NA, sodium; ACLF, acute-on-chronic liver failure; ESLD, end-stage liver disease.
      The Model for End-stage Liver Disease (MELD) initially created to predict survival in patients with complications of portal hypertension undergoing elective transjugular intrahepatic portosystemic shunts uses only objective variables and was shown to be an accurate predictor of survival among different populations of patients with ESLD. The score also predicts survival in cirrhosis patients with sepsis (higher score more likely to get infected or die of infections), variceal bleeding (poor in MELD ≥15), as well as alcohol-associated hepatitis (MELD ≥22) and acute-on-chronic liver failure (ACLF, score ≥30 predicted poor survival). In ESLD patients with MELD score 20–29, 30–39, and > 40, the estimated 3-month mortality is 19.6%, 52.6%, and 71.3%, respectively.
      • Kamath P.S.
      • Kim W.R.
      Advanced liver disease study group. The model for end-stage liver disease (MELD).
      MELD was shown to be superior to CTP score for predicting 3-month mortality in a broad range of patients with ESLD. Furthermore, the delta change in MELD score on follow-up was independently associated with increased risk of death. An increase in >5 points in MELD score, during previous 30 days was associated with 3-fold higher risk of death. Similarly, increased by ≥ 2 points after 2 weeks of diagnosis of ACLF was also predictive of short-term mortality.
      • Kim H.J.
      • Lee H.W.
      Important predictor of mortality in patients with end-stage liver disease.
      • Gotthardt D.
      • Weiss K.H.
      • Baumgärtner M.
      • et al.
      Limitations of the MELD score in predicting mortality or need for removal from waiting list in patients awaiting liver transplantation.
      • Kumar R.
      • Krishnamoorthy T.L.
      • Tan H.K.
      • Lui H.F.
      • Chow W.C.
      Change in model for end-stage liver disease score at two weeks, as an indicator of mortality or liver transplantation at 60 days in acute-on-chronic liver failure.
      The incorporation of serum sodium into the MELD score was shown to provide a more accurate survival prediction than MELD alone and was demonstrated to aid providers in identifying patients with increased 6-month mortality in time-constrained settings. A MELD sodium score ≥28 could be used to trigger a discussion for hospice care for improving value-based health care was advocated in a recent study.
      • Brown C.
      • Aksan N.
      • Muir A.J.
      MELD-Na accurately predicts 6-month mortality in patients with decompensated cirrhosis: potential trigger for hospice referral.
      Frailty, defined as a clinical state of decreased physiologic reserve and increased vulnerability to health stressors, which in turn predisposes individuals to adverse clinical outcomes is an important factor that decide short- and long-term mortality in ESLD. Physical frailty encompasses sarcopenia (generalized loss of skeletal muscle mass), reduction in physical function (progressive decrease in muscle strength) and aerobic exercise capacity (decreased capacity to sustain physical work or endure physiological stresses) and physical disability which include deficits in the ability to complete activities necessary to live independently within one's home or in one's community.
      • Williams F.R.
      • Milliken D.
      • Lai J.C.
      • Armstrong M.J.
      Assessment of the frail patient with end-stage liver disease: a practical overview of sarcopenia, physical function, and disability.
      Frailty measurement tools include Fried Frailty Index, Short Physical Performance Battery, Rockwood Frailty Index, Clinical Frailty Scale, Braden Scale, Liver Frailty Index, Gait Speed Score, Activities of Daily Living Score and the 6-minute Walk Test. These scoring systems measure physical strength, subjective fatigue and functionality and balance. Frail decompensated cirrhosis patients were most hospitalized for infection, HE and ascites suggesting that frailty did not increase likelihood of a particular complications, but reduced tolerance and reserve to withstand decompensation. Every one-point increase in the frailty score was associated with a 50% increased mortality risk in LT wait-listed patients. Even if MELD score was <18, death or delisting occurred at least twice as frequently in frail compared to patients with non-frail cirrhosis and every 100 m reduction in 6-minute walk test increased waitlist mortality by 48%.
      • Laube R.
      • Wang H.
      • Park L.
      • et al.
      Frailty in advanced liver disease.
      Frailty was associated with a 2-fold higher risk of wait-list mortality in patients with ESLD, whereas the combination of frailty indices along with MELD sodium score was shown to be a better predictor of wait-list mortality compared to MELD-Na alone.
      • Soto R.
      • Díaz L.A.
      • Rivas V.
      • et al.
      Frailty and reduced gait speed are independently related to mortality of cirrhotic patients in long-term follow-up.
      ,
      • Haugen C.E.
      • McAdams-DeMarco M.
      • Verna E.C.
      • et al.
      Association between liver transplant wait-list mortality and frailty based on body mass index.
      Hence, rapidly declining frailty scores can be a considered for initiating PC in decompensated cirrhosis irrespective of liver disease severity scores.
      In cirrhotics with acute deterioration of liver function, presenting as ACLF, different scoring systems are useful for the identification of futility in medical management and initiation of PC. The Chronic Liver Failure Consortium ACLF (CLIF-C-ACLF) score was shown to have higher predictability when compared to other standard scores for 28- and 90-days mortality. Similarly, persistence of higher grades of ACLF, i.e., grades 2 and 3 at 3–7 days after admission (and not the baseline grade) predicts high mortality (57% and 87% respectively) in the short term and can be used to activate PC early on, in this sick group of patients.
      • Moreau R.
      • Gao B.
      • Papp M.
      • Bañares R.
      • Kamath P.S.
      Acute-on-chronic liver failure: a distinct clinical syndrome.
      Using the “‘Plan–Do–Study–Act” protocol, researchers identified patients with decompensated cirrhosis at very high risk of short-term mortality. The presence of at least three factors at emergency admission (CTP class C, >1 admission in prior six months, active alcohol use, no candidacy for LT, World Health Organization Performance status 3 or 4, one-year mortality with sensitivity of 72%). Trigger for implementation of PC intervention and notification of prognosis should be started when score is more than two.
      • Hudson B.E.
      • Ameneshoa K.
      • Gopfert A.
      • et al.
      Integration of palliative and supportive care in the management of advanced liver disease: development and evaluation of a prognostic screening tool and supportive care intervention.

      Current reviews on palliative care for ESLD

      In a seminal study, patients were removed from the transplant wait list due to noncompliance or substance abuse in 26% and progressive organ dysfunction in 25%. After these patients were removed from the list, 17% received renal replacement therapy, and 48% were subsequently admitted to the intensive care unit. Only 10% of these delisted patients were referred for PC.
      • Poonja Z.
      • Brisebois A.
      • van Zanten S.V.
      • Tandon P.
      • Meeberg G.
      • Karvellas C.J.
      Patients with cirrhosis and denied liver transplants rarely receive adequate palliative care or appropriate management.
      Up to 14% of patients hospitalized for complications of cirrhosis were readmitted within one week, 30–37% within one month and over 50% in three months. On average, this population had three hospitalizations per person year. The majority of patients taken off the transplant list at a single center were referred to palliative care only in the final two weeks of life.
      • Mazzarelli C.
      • Prentice W.M.
      • Heneghan M.A.
      • Belli L.S.
      • Agarwal K.
      • Cannon M.D.
      Palliative care in end-stage liver disease: time to do better?.
      Evidence suggests referral to palliative care in the final days of life is not effective. In a randomized control trial, a brief palliative care intervention for patients intubated for greater than 7 days in the ICU failed to reduce anxiety symptoms and may have increased symptoms of post-traumatic stress disorder in the families.
      • Carson S.S.
      • Cox C.E.
      • Wallenstein S.
      • et al.
      Effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial.
      A US National in-patient survey examining more than 12,000 patients’ terminal hospitalizations reported that from 18% of patients who had PC referrals in 2009, an increase to 36% by 2013 was reported. In the same study, authors also noted that PC was associated with lower procedure burden-after adjusting for other factors; and significant cost reduction of approximately $10,062.
      • Patel A.A.
      • Walling A.M.
      • Ricks-Oddie J.
      • May F.P.
      • Saab S.
      • Wenger N.
      Palliative care and health care utilization for patients with end-stage liver disease at the end of life.
      In this context, patients with cirrhosis who undergo cardiopulmonary resuscitation following cardiac arrest have a dismal prognosis, with an in-hospital mortality ranging from 85 to 100%. Concerningly, studies have shown that 66% patient with advanced cirrhosis were listed with full code measures despite their poor prognosis. A critically ill cirrhotic is attended by multiple specialists, each of whom focus on their area of expertise with a granted decision of continuation of life sustaining treatment without addressing overall prognosis. The primary decisions on end-of-life care or palliation for prolonging quality of life in such clinical scenarios must be borne by the treating physicians or hepatologists.
      • Lisotti A.
      • Fusaroli P.
      • Caletti G.
      Palliative care in patients with liver cirrhosis: it is the time to deal with the burden.
      ,
      • Larson A.M.
      Palliative care for patients with end-stage liver disease.
      In a structured palliative care intervention study in cirrhotics and liver transplant patients admitted to the surgical intensive care unit, initial intervention was aimed at reviewing prognosis, advanced directives, decision surrogate and symptom management within 24 h of admission, while the second intervention, was a family meeting with both primary and palliative care teams to review goals of care. With this two-tier intervention, the goals of care meetings increased from 2% to 38% and do-not-resuscitate rates increased from 52% to 81% leading to increased withdrawal from life support from 35% to 68% of cases with significant reduction under intensive care management by 3 days, without a change in mortality rates. Thus, only patients undergoing futile care had life sustaining care withdrawn, which was cost effective, reduced hospital resource burden along with improved understanding and promotion of actual goals of care.
      • Lamba S.
      • Murphy P.
      • McVicker S.
      • Harris Smith J.
      • Mosenthal A.C.
      Changing end-of-life care practice for liver transplant service patients: structured palliative care intervention in the surgical intensive care unit.
      In the last five years, multiple prospective and retrospective studies were conducted assessing role of PC in ESLD. These studies showed that barriers to providing PC in ESLD was mainly because of complexities in management of ESLD complications. One of the main aspects in patient management that was neglected was treatment of depression. However, when offered PC early during the course of ESLD, patients and care givers were both motivated and driven to follow goals of care and improved quality of life, rather than treatment options and curative intend. Furthermore, age, do-not-resuscitate orders, admission to a large/academic hospital, or cancer diagnosis was associated with more PC use in some studies. Nonetheless, in most of these studies patients and providers cited uncertainty as the main factor hindering end-of-life care planning and initiation and utilization of PC services.
      • Fricker Z.P.
      • Serper M.
      Current knowledge, barriers to implementation, and future directions in palliative care for end-stage liver disease.
      The indications of PC in cirrhosis is shown in Figure 2.
      Figure 2
      Figure 2Indications for palliation in patients with advanced liver disease. The infographics also depict barrier to palliative care initiation from patient and physician point of view. PC, palliative care.

      Symptomatic management of patient with ESLD in palliation

      At the outset, one must realize that PC is more than hospice care. Goals of care in PC involve supportive care alongside specialized interventions, which can change over time in accordance with patient's needs and wishes while hospice focuses on ensuring comfort and dignity for dying patients. Depending on the complications associated with ESLD, PC can include interventions such as transjugular intrahepatic portosystemic shunt or treatment of liver cancer for increasing progression free survival. Hospice care is associated with non-curative symptomatic treatment for patients with terminal or incurable disease with an expected survival <6 months.
      • Langberg K.M.
      • Kapo J.M.
      • Taddei T.H.
      Palliative care in decompensated cirrhosis: a review.
      Decompensated cirrhosis patients have uncertainty with regard to the course of their disease, high incidence of symptoms that impair quality of life and are also subject to futile intensive interventions with minimal addressing of actual goals of care. Symptomatic management of patients with ESLD as part of palliation requires abolishing potential barriers to utilization of PC services. These include patient-related factors such as misperception of PC, focusing on liver-only interventions, uncertainty about prognosis and lack of knowledge of disease severity; physician-related factors such as focusing on liver-related interventions, overestimation of life expectancy, lack of communication regarding poor prognosis, lack of clarity regarding indications for PC referral and unpredictable episodes of decompensations. The overall burden of symptoms in ESLD is comparable to that of other diseases of progressive organ failure, and approximately 72% report an overall poor quality of life. The most frequently reported symptoms in patients with ESLD include pain (prevalence range 30–79%), breathlessness (20–88%), muscle cramps (56–68%), insomnia (26–77%), daytime sleepiness (29.5–71%), depression (4.5–64%) and anxiety (14–45%).
      • Peng J.K.
      • Hepgul N.
      • Higginson I.J.
      • Gao W.
      Symptom prevalence and quality of life of patients with end-stage liver disease: a systematic review and meta-analysis.
      One-third of patients with cirrhosis report moderate-to-severe pain and confusion, particularly in the last month of life. In patients with depression not receiving LT, the 100-day mortality is approximately double the rate of those without depression. Approximately half of the patients with ESLD listed for transplantation were unable to independently complete at least one activity of daily living with almost 70% reporting a perception of disability.
      • Saracino R.M.
      • Jutagir D.R.
      • Cunningham A.
      • et al.
      Psychiatric comorbidity, health-related quality of life, and mental health service utilization among patients awaiting liver transplant.

      Management of Pain and Neuropsychiatric Symptoms

      Patients with cirrhosis commonly complain of acute or chronic pain (lasting >12 weeks), which maybe localized or generalized/widespread and nociceptive (somatic or visceral) or neuropathic in nature. Assessment of impact of pain can be easily done via the three-question validated Pain–Enjoyment––General activity tool.
      • Krebs E.E.
      • Lorenz K.A.
      • Bair M.J.
      • et al.
      Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference.
      Apart from overt or subjective feeling of pain, cirrhotic patients also suffer from depression and anxiety that are closely related to chronic pain driven poor quality of life. The common site of pain includes abdomen (gaseous distension due to poor oral intake, ascites, spontaneous bacterial peritonitis, neuropathic/autonomic dysfunction leading to visceral hypersensitivity, and splenomegaly), lower back (osteoporosis and related fractures, massive ascites, generalized immobility, and metastatic liver cancer related), and large joints (degenerative diseases such as osteoarthritis, chronic infections such as tuberculosis and non-specific diffuse joint pains). A widespread type of pain is commonly encountered in patients with cirrhosis akin to “fibromyalgia”-like syndrome which may be due to chronic progressive systemic proinflammation.
      • Klinge M.
      • Coppler T.
      • Liebschutz J.M.
      • et al.
      The assessment and management of pain in cirrhosis.
      Certain non-pharmacologic treatments have been shown to benefit chronically debilitated patients with acute and chronic pain. Data with regards to cirrhosis population is lacking. Physical therapy improves pain due to acute injuries and can also aid in management of pain related to chronic debility. However, in those with sarcopenia and severe frailty, passive physical therapy could be undertaken and subjective improvements maybe difficult to comprehend. Cognitive behavioral therapy improves pain by directly improving neuropsychiatric conditions associated with cirrhosis. There is no conclusive evidence that mindfulness therapies are useful in patients with advanced cirrhosis. Alternative treatments like acupuncture should be avoided in decompensated cirrhosis as it can lead to bleeding complications and has no demonstrable clinical benefits in other chronic conditions.
      • Ehrlich A.C.
      • Soumekh A.
      Pain management in patients with hepatic impairment.
      Advanced liver disease is associated with altered drug pharmacokinetics and metabolism, which increases risk for hepatotoxicity and accumulation of toxic metabolites that prolong drug action and promote adverse events. Important considerations while prescribing analgesics in cirrhosis include the following:
      • Starting with low dose and using extended dosing intervals
      • Using short acting drugs as much as possible
      • Watchfulness regarding HE precipitation and careful monitoring for sedation
      • Avoidance of non-steroidal anti-inflammatory drugs (NSAIDs) and morphine in those with renal dysfunction
      • Close review for potential for abuse
      Topical anesthetics such as lidocaine patches can be safely used in advanced cirrhosis due to poor systemic absorption for control of local pain. Contrary to popular belief, acetaminophen is one of the safest analgesics for patients with cirrhosis, when taken in appropriate doses. Oral NSAIDs must be totally avoided in cirrhotics while topical NSAIDs may be offered as a short course depending on the type of pain. Calcium channel alpha-2-delta ligands class of anticonvulsants such as gabapentin and pregabalin are not metabolized in the liver and hence are considered first line non-opioid therapy but require dose adjustment in those with renal dysfunction. Tricyclic antidepressants are effective in pain resulting from various aetiologies. Desipramine and nortriptyline are recommended due to reduced sedation when compared to amitriptyline and imipramine. Serotonin-norepinephrine reuptake inhibitors such as venlafaxine (causes hyponatremia, increased half-life and clearance) and duloxetine (hepatotoxicity as a black box warning) are not ideal in advanced cirrhosis. Similarly, selective serotonin-reuptake inhibitors can also increase risk of variceal bleeding. The use of opioids in advanced cirrhosis is limited to non-acute pain and immediate release formulations. Tramadol must be used with caution in those already on antidepressant and hydrocodone (combination with acetaminophen) must be limited to six tablets per day. Hydromorphone (largely unaffected by liver disease) but not morphine should be first choice opioid in patients with renal failure. Fentanyl patches are only recommended until after total daily opioid levels have plateaued. Methadone, meperidine, and codeine must be avoided in advanced liver disease. Some studies have shown risk for hepatotoxicity and fibrosis progression due to marijuana, and hence, its use in chronic pain management in cirrhosis is currently unvalidated.
      • Rakoski M.
      • Goyal P.
      • Spencer-Safier M.
      • Weissman J.
      • Mohr G.
      • Volk M.
      Pain management in patients with cirrhosis.

      Management of Muscle Cramps, Pruritus, Sleep Disturbances, Sexual Dysfunction, and Fatigue

      Muscle cramps affect close to one third of patients with advanced cirrhosis affecting work quality, daily routine and disturbing sleep. The causes for muscle cramping are thought to include neuronal pathway dysfunction, dehydration, plasma volume, and electrolyte changes. Beneficial pharmacologic interventions based on anecdotal single center studies include use of oral taurine; night-time branch-chain amino acid granules; quinidine (albeit with rare but severe hematological adverse events such as immune-mediated hemolysis, and thrombocytopenia), muscle relaxants such as baclofen, methocarbamol, and orphenadrine and l-carnitine or oral zinc supplementation but not oral vitamin E supplementation alone and in some studies, anti-spasmodic eperisone (suppression of pain reflex) and intravenous human albumin supplementation.
      • Vidot H.
      • Carey S.
      • Allman-Farinelli M.
      • Shackel N.
      Systematic review: the treatment of muscle cramps in patients with cirrhosis.
      ,
      • Lechner K.
      • Jäger U.
      How I treat autoimmune hemolytic anemias in adults.
      Even though pruritus is commonly associated with chronic cholestatic liver disease, it is also prevalent among patients with advanced liver disease of any etiology. Pruritus worsens during night and predominantly affects distal extremities. The vaguely studied reasons include dysregulated metabolism of “pruritogens” such as bile salts, lysophosphatidic acid, and autotaxins; collateral changes in opioid and serotonin pathways; hormonal changes associated with advanced cirrhosis; nutritional deficiency, dry skin, drug induced pruritis, skin changes, and dehydration. Pharmacologic therapies, mostly studied in cholestatic liver disease, that have some benefit in reducing itching include use of ursodeoxycholic acid, cholestyramine, rifampin, naltrexone, and sertraline. Nonetheless, no recommended therapy for pruritus of advanced liver disease exists in current literature due to complexities associated with pathophysiology of this symptom.
      • Moore C.
      Evaluation and management of insomnia, muscle cramps, fatigue, and itching in cirrhotic patients.
      One of the most burdensome symptoms commonly seen in advanced cirrhosis is sleep disturbances, in the form of difficulty in initiating sleep, poor sleep maintenance, early morning awakenings, and daytime sleepiness. Scored measures of sleep quality such as the Epworth Sleepiness scale can help quantify the severity of sleep abnormalities. Treatment of sleep disorders should be targeted at causes such as lactulose for correction of minimal HE, treatment of depression and anxiety, curbing stimulants such as coffee, nicotine at night, and complete avoidance of alcohol. Pharmacologic treatments include use of antihistamines such as hydroxyzine, controlled use of benzodiazepines with safer profile such as clonazepam (HE and addictive potential risk), and zolpidem (memory loss, HE risk). Another important aspect is to avoid using diuretics at night and use of melatonin, which has been shown to improve quality of sleep in primary and secondary insomnia in well conducted metanalyses of mostly non-cirrhosis patients.
      • Tapper E.B.
      • Ufere N.N.
      • Huang D.Q.
      • Loomba R.
      Review article: current and emerging therapies for the management of cirrhosis and its complications.
      Sexual dysfunction occurs in more than 50% of patients with cirrhosis and occurring in up to 93% in those with advanced cirrhosis. Tadalafil was found useful in males with cirrhosis when used for 12 weeks without major adverse events and improvement in erectile function.
      • Jagdish R.K.
      • Kamaal A.
      • Shasthry S.M.
      • et al.
      Tadalafil improves erectile dysfunction and quality of life in men with cirrhosis: a randomized double blind placebo controlled trial.
      Both low testosterone and muscle wasting are not uncommon in end-stage liver disease. Administering testosterone significantly increases muscle mass, bone mass, hemoglobin level, and sarcopenia, thereby improving survival.
      • Sinclair M.
      • Grossmann M.
      • Hoermann R.
      • Angus P.W.
      • Gow P.J.
      Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial.
      Neither fluvoxamine nor modafinil was found useful in improving fatigue associated with primary biliary cholangitis. Generalized use in end stage liver disease is still awaited.
      • Lee J.Y.
      • Danford C.J.
      • Trivedi H.D.
      • Tapper E.B.
      • Patwardhan V.R.
      • Bonder A.
      Treatment of fatigue in primary biliary cholangitis: a systematic review and meta-analysis.
      A summary of symptomatic management in ESLD is shown in Figure 3.
      Figure 3
      Figure 3Brief summary of various treatment options for reducing symptom burden and improving quality of life in patients with advanced liver disease on palliation. BCAA, branched-chain amino acids; NSAIDs, non-steroidal anti-inflammatory drugs; CPT, Child–Pugh–Turcotte score; UDCA, ursodeoxycholic acid; HE, hepatic encephalopathy; FMT, fecal microbiota transplantation; TIPS, transjugular intrahepatic portosystemic shunt; HPS, hepatopulmonary syndrome; POPH, portopulmonary hypertension.

      Special treatment considerations in end-stage liver disease on palliation

      The World Health Organization's defined PC as the “interdisciplinary care to improve the quality of life of patients facing life-threatening illness by addressing their physical, emotional, and spiritual needs and by supporting their families.” While the effect of palliative care on patients with decompensated cirrhosis has not been studied extensively, several strategic care therapeutic strategies when bundled with PC have been found useful in improving transplant free survival and quality of life in such patients. In this context, two important clinical events as well as others require special mention – refractory ascites and recurrent or persistent hepatic HE, two most implicated events that force patients to frequently visit the day care or impose hospital admissions while in hospice or on transplant waitlist. In ESLD, hyponatremia and renal injury limit the rational and tolerable use of diuretics leading to refractory or recurrent ascites. The addition of sodium-glucose cotransporter 2 inhibitors in cirrhosis patients with diabetes and refractory ascites in a preliminary study showed improved volume status, electrolyte balance, and ascites mobilization, which requires further validation in larger trials.
      • Montalvo-Gordon I.
      • Chi-Cervera L.A.
      • García-Tsao G.
      Sodium-glucose cotransporter 2 inhibitors ameliorate ascites and peripheral Edema in patients with cirrhosis and diabetes.
      Tender gynecomastia which precludes use of spironolactone for control of ascites can be managed by switching to eplerenone or amiloride, and addition of tamoxifen was found to be effective and safe in the management of mastalgia in male patients with cirrhosis on spironolactone.
      • Li C.P.
      • Lee F.Y.
      • Hwang S.J.
      • et al.
      Treatment of mastalgia with tamoxifen in male patients with liver cirrhosis: a randomized crossover study.
      The role of transjugular intrahepatic portosystemic shunt (TIPS) placement early on during the disease course as well as in those with refractory ascites has demonstrated improved quality of life as well as survival. Nonetheless, TIPS requires a preserved liver and cardiac function. Furthermore, the risk of HE can be reduced using a smaller diameter TIPS stent (8 mm vs. 10 mm) and initiation of rifaximin prior to procedure.
      • Rajesh S.
      • George T.
      • Philips C.A.
      • et al.
      Transjugular intrahepatic portosystemic shunt in cirrhosis: an exhaustive critical update.
      In patients not eligible for TIPS procedure, the role of palliative long-term abdominal drains versus large-volume paracentesis in refractory ascites was recently published. The “REDUCe Study” demonstrated feasibility with preliminary evidence of long-term abdominal drain with respect to acceptability, effectiveness, safety, and overall reduction in health resource utilization.
      • Macken L.
      • Bremner S.
      • Gage H.
      • et al.
      Randomised clinical trial: palliative long-term abdominal drains vs large-volume paracentesis in refractory ascites due to cirrhosis.
      In patients with ESLD who have diuretic intractable or resistant ascites requiring repeated paracentesis and are specifically not ideal candidates for TIPS placement, the use of Alfapump® system could be an appropriate option where expertise is available. The Alfapump® moves abdominal fluid into the bladder from where it is then removed by urination. Compared with standard treatment, it was demonstrated to reduce the need for large volume paracentesis and improve health-related quality of life at 90 days.
      • Stepanova M.
      • Nader F.
      • Bureau C.
      • et al.
      Patients with refractory ascites treated with alfapump® system have better health-related quality of life as compared to those treated with large volume paracentesis: the results of a multicenter randomized controlled study.
      Experts developed recent consensus care recommendations for Alfapump® in cirrhotic patients with refractory or recurrent ascites in which recommendations were made in the areas of pre-implantation procedure, surgical implant procedure, immediate post-implant care, and long-term management.
      • Aagaard N.K.
      • Malago M.
      • De Gottardi A.
      • et al.
      Consensus care recommendations for alfapump® in cirrhotic patients with refractory or recurrent ascites.
      A small retrospective study showed that both TIPS and Alfapump® were effective treatments for refractory ascites in cirrhosis. Nonetheless, patients treated with former had a better 1-year transplant-free survival.
      • Will V.
      • Rodrigues S.G.
      • Stirnimann G.
      • Gottardi A.
      • Bosch J.
      • Berzigotti A.
      Transjugular intrahepatic portosystemic shunt and alfapump® system for refractory ascites in liver cirrhosis: outcomes and complications.
      Another important aspect to consider is the use of non-selective beta blockers in patients with advanced cirrhosis and refractory ascites. Beta blockers should be avoided in cirrhotic patients with compromised cardiac performance, which can be easily assessed by mean arterial pressure and left ventricular stroke work index (LVSWI), as it may lead to worsening clinical outcomes, including renal dysfunction. Furthermore, refractory ascites, infections, and acute-on-chronic liver failure are not contraindications for beta blocker treatment. Doses should be carefully tapered, with a temporary reduction or discontinuation in patients who develop signs of decreased organ perfusion or significant hypotension. In the context of current evidence, the dose of propranolol should not exceed >80 mg/d in patients with refractory ascites, whereas carvedilol can probably be used safely at low doses (6.25–12.5 mg/day), provided the patient maintains a systolic blood pressure over 90 mmHg.
      • Rodrigues S.G.
      • Mendoza Y.P.
      • Bosch J.
      Beta-blockers in cirrhosis: evidence-based indications and limitations.
      In patients with chronic persistent HE or features of hepatic Parkinsonism, the search for and embolization of large spontaneous portosystemic shunts have shown to improve quality of life and transplant free survival.
      • Rajesh S.
      • Philips C.A.
      • Ahamed R.
      • Abduljaleel J.K.
      • Nair D.C.
      • Augustine P.
      Friend or foe? Spontaneous portosystemic shunts in cirrhosis-current understanding and future prospects.
      Thus, in patients on PC within a window period, timely interventional procedures help reduce clinical complications, financial burden, and hospital visits. Physicians caring for patients with ESLD on PC must not forget to focus on the nutritional aspects that needs mandatory addressal such as late-night snacks, avoiding long fasting periods, high (1 g/kg/day) protein and calorie (∼30 kcal/kg/day) consumption, and motivating to improve and increasing physical activity.
      • Lai J.C.
      • Tandon P.
      • Bernal W.
      • et al.
      Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American association for the study of liver diseases.
      In the ATTIRE trial, investigators found that in patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g/L or more was not more beneficial than the current standard care. Nonetheless, the ANSWER trial showed that long-term human albumin administration prolonged overall survival and acted as a disease modifying treatment in patients with decompensated cirrhosis. The use of protocolized albumin infusions, even though controversial, maybe offered to patients with ESLD to improve short-term clinical outcomes.
      • China L.
      • Freemantle N.
      • Forrest E.
      • et al.
      A randomized trial of albumin infusions in hospitalized patients with cirrhosis.
      ,
      • Caraceni P.
      • Riggio O.
      • Angeli P.
      • et al.
      Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.
      Finally, therapeutic use of healthy donor fecal microbiota transplantation (FMT) for various clinical events in advanced liver disease is an exciting area of research that could prove useful for improving various difficult to management complications associated with ESLD. These include use of FMT in recurrent HE, recurrent sepsis, multidrug resistant infections, severe alcohol-associated hepatitis not amenable for conventional care or LT and alcohol use disorder.
      • Philips C.A.
      • Schnabl B.
      • Bajaj J.S.
      Gut microbiome and alcohol-associated liver disease.
      ESLD is an illness that is associated with huge burden of clinical complications leading patient suffering. LT, the only known cure for ESLD is not available in a timely manner for everyone with an ever-increasing waitlist. Palliative care is a special area of clinical care which improves the quality of life in patients with advanced cirrhosis by undertaking advanced care planning, ameliorating physical symptoms along with the use of timely interventional techniques, providing emotional support to the patient and family. Nonetheless, PC is used infrequently, and referral made late in patients with advanced liver disease. There is evidence that PC in other patient populations reduces financial burden and lowers hospital resource utilization to ultimately improve symptom control and provide patient satisfaction. This aspect requires further prospective randomized control trials in advanced liver disease who are transplant eligible and ineligible, so as to decide on futility and initiate hospice care with the proper education leveraged on emotional and evidence-based management of symptoms associated with ESLD.

      Credit authorship contribution statement

      Cyriac A. Philips: Conceptualization, Methodology, Original draft preparation. Chandan K. Kedarisetty: Conceptualization, Methodology, Reviewing and Editing.

      Conflicts of interest

      The authors have none to declare.

      Acknowledgements

      None.

      Funding

      No funding received in any form.

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