Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases.

Abstract

Supported by the American Association for the Study of Liver Diseases. Dr. Lai is partially supported by R01 AG059183 and R21 AG067554. Srinivasan Dasarathy is partially supported by NIH RO1 GM119174; RO1 DK113196; P50 AA024333; RO1 AA021890; 3U01AA026976 ‐ 03S1; UO1 AA 026976; R56HL141744;UO1 DK061732; 5U01 DK062470‐17S2. Potential conflict of interest: Dr. Lai received grants from Axcella and Lipocine. Dr. Bernal advises Versantis. Purpose and Scope of This Practice Guidance This is the first American Association for the Study of Liver Diseases (AASLD) practice guidance on the management of malnutrition, frailty, and sarcopenia in patients with cirrhosis. This guidance represents the consensus of a panel of experts after a thorough review and vigorous debate of the literature published to date, incorporating clinical experience and common sense to fill in the gaps when appropriate. Our goal was to offer clinicians pragmatic recommendations that could be implemented immediately in clinical practice to target malnutrition, frailty, and sarcopenia in this population. This AASLD guidance document differs from AASLD guidelines, which are supported by systematic reviews of the literature, formal rating of the quality of the evidence and strength of the recommendations, and, if appropriate, meta‐analysis of results using the Grading of Recommendations Assessment Development and Evaluation system. In contrast, this guidance was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics, with oversight provided by the AASLD Practice Guidelines Committee at all stages of guidance development. The AASLD Practice Guidelines Committee chose to perform a guidance on this topic because a sufficient number of randomized controlled trials (RCTs) were not available to support the development of a guideline. Definitions of Malnutrition, Frailty, and Sarcopenia and Their Relationship in Patients With Cirrhosis Cirrhosis is a major predisposing condition for the development of malnutrition, frailty, and sarcopenia. Multiple, yet complementary, definitions of these conditions exist in the published domain outside of the field of hepatology; but consensus definitions have not yet been established by the AASLD for patients with cirrhosis. Furthermore, there has been ambiguity related to operationalization of these constructs in clinical practice. To address this, we offer definitions of the theoretical constructs of malnutrition, frailty, and sarcopenia as commonly represented in all populations, partnered with operational definitions, developed by consensus, to facilitate pragmatic implementation of these constructs in clinical practice as applied to patients with cirrhosis (Table 1). Malnutrition is a clinical syndrome that results from “an imbalance (deficiency or excess) of nutrients that causes measurable adverse effects on tissue/body form (body shape, size, composition) or function, and/or clinical outcome.”(1) Key to this definition is the recognition that malnutrition represents a spectrum of nutritional disorders across the entire range of body mass index (BMI)—from underweight to obese. By this definition, malnutrition leads to adverse physical effects, which, in patients with cirrhosis, are commonly manifested phenotypically as frailty or sarcopenia. Frailty has most commonly been defined as a clinical state of decreased physiologic reserve and increased vulnerability to health stressors, a definition that has its roots in the field of geriatrics.(2) However, the weight of evidence available to date in patients with cirrhosis has focused predominantly on one component of frailty: physical frailty. Although this representation deviates somewhat from the classic “geriatric” definition of frailty as a global construct, physical frailty represents clinical manifestations of impaired muscle contractile function that are commonly reported by patients with cirrhosis such as decreased physical function, decreased functional performance, and disability. Sarcopenia has been defined by the European Working Group on Sarcopenia as “a progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes including falls, fractures, disability, and mortality,” combining both muscle mass and muscle strength or muscle performance in its definition.(3) However, the majority of studies in patients with cirrhosis have investigated sarcopenia using measures of muscle mass alone. Therefore, based on the evidence available to date on patients with cirrhosis, we have developed a consensus definition for operationalization of sarcopenia in patients with cirrhosis as the phenotypic manifestation of loss of muscle mass. Table 1 - Definitions for the Theoretical Constructs of Malnutrition, Frailty, and Sarcopenia and Consensus‐Derived Operational Definitions Applied to Patients with Cirrhosis Construct Theoretical Definitions Operational Definitions Malnutrition A clinical syndrome that results from deficiencies or excesses of nutrient intake, imbalance of essential nutrients, or impaired nutrient use( 4 ) An imbalance (deficiency or excess) of nutrients that causes measurable adverse effects on tissue/body form (body shape, size, composition) or function and/or clinical outcome( 1 ) Frailty A clinical state of decreased physiologic reserve and increased vulnerability to health stressors( 2 ) The phenotypic representation of impaired muscle contractile function Sarcopenia A progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes including falls, fractures, disability, and mortality( 3 ) The phenotypic representation of loss of muscle mass Although we have, for the purposes of this guidance, developed separate operational definitions for malnutrition, frailty, and sarcopenia, we acknowledge that these three constructs are interrelated and in practice are often recognized simultaneously in an individual patient. For example, a patient with cirrhosis who presents to clinic with severe muscle wasting might be described as “malnourished,” “frail,” and “sarcopenic,” each descriptor conveying similar information about the patient’s poor clinical condition and prognosis. Despite the overlap of these three constructs in clinical practice, there is value in understanding each as a separate entity as well as the relationship between the three in order to develop tailored behavioral interventions and targeted pharmacotherapies for these conditions. Herein, we propose a conceptual framework for this relationship (Fig. 1). There are a number of factors that lead to malnutrition in patients with cirrhosis, which is challenging to identify at the bedside unless it manifests phenotypically as frailty and/or sarcopenia. Malnutrition is not the only factor that contributes to frailty and sarcopenia; other factors such as cirrhosis complications, other systems‐related factors (e.g., systemic inflammation, metabolic dysregulation), physical inactivity, and environmental/organizational factors can contribute to frailty and/or sarcopenia within or independent of the malnutrition pathway. In addition, frailty and sarcopenia can contribute to each other—impaired muscle contractile function can accelerate loss of muscle mass and vice versa. It is these clinical phenotypes—frailty and sarcopenia—that ultimately lead to adverse health outcomes including hepatic decompensation, increased health care use, worse health‐related quality of life, adverse posttransplant outcomes, and increased overall risk of death.FIG. 1: Factors contributing to malnutrition, frailty, and sarcopenia and the relationship between these three constructs. Cirrhosis‐related and other systems‐related factors, along with physical inactivity and environmental/organizational factors, contribute to malnutrition—which then leads to frailty and sarcopenia. These factors can also contribute directly to frailty and sarcopenia independently of malnutrition.Factors That Contribute to Frailty and Sarcopenia in Patients With Cirrhosis Here, we describe the factors that have been shown to contribute to frailty and sarcopenia in patients with cirrhosis. We acknowledge that these factors are, in some cases, interrelated; but for the purposes of ease of clinical implementation, we have categorized these factors broadly as (1) malnutrition, (2) cirrhosis‐related, (3) other systems–related, (4) physical inactivity, and (5) environmental/organizational factors. Malnutrition Impaired Intake of Macronutrients Reduced oral intake results from many factors including early satiety, anorexia, nausea and vomiting, dysgeusia, diet unpalatability (e.g., low sodium or low potassium), impaired level of consciousness, free water restriction, and frequent fasting due to procedures and hospitalizations.(5)Excess oral intake is a root cause of obesity and is influenced by a variety of biological, sociocultural, and psychological factors.(6) Many patients with cirrhosis have limited knowledge about disease self‐management, including nutrition therapy.(7,8) Inadequate food knowledge/preparation skills and food insecurity can impact dietary intake—through either reduced or excess intake—across the spectrum of nutritional disorders from undernutrition to obesity.(7‐9) Impaired Intake of Micronutrients Malabsorption leads to high rates of micronutrient deficiency in patients with cirrhosis. Factors leading to impaired macronutrient intake and absorption also contribute to deficiency of many micronutrients. In particular, folate, thiamine, zinc, selenium, vitamin D, and vitamin E deficiencies have been reported in patients with alcohol‐associated liver disease; and fat‐soluble vitamin deficiencies have been well documented in patients with cholestatic liver disease.(10‐14) Several of these micronutrients have a strong link with frailty or sarcopenia. Vitamin D deficiency is associated with impaired muscle contractile function in the general population.(15) Although studies evaluating the role of vitamin D deficiency on frailty and sarcopenia in patients with cirrhosis are lacking, vitamin D deficiency is prevalent in patients with cirrhosis(16‐18) and may contribute to the development and progression of frailty in this population. Deficiency of zinc, a cofactor in the urea cycle that metabolizes ammonium, is associated with HE, frailty, and sarcopenia in patients with cirrhosis.(19‐21) Magnesium deficiency occurs because of malabsorption of magnesium in the small intestine and is exacerbated by diuretic use. Magnesium deficiency is associated with reduced cognitive performance as well as reduced muscle strength in adults with cirrhosis(22‐24) and with increased bone resorption in children with cholestatic liver disease.(25) Impaired Nutrient Uptake Impaired nutrient uptake is multifactorial, resulting from malabsorption, maldigestion, and altered macronutrient metabolism. Cholestasis leads to alterations in the enterohepatic circulation of bile salts and maladaptation of bile salt regulation. This may result in elevated serum and tissue levels of potentially toxic bile salts as well as impaired metabolism and malabsorption of long‐chain fatty acids and fat‐soluble vitamin deficiency in both adults and children.(26‐28) Other contributors to malabsorption and maldigestion in patients with cirrhosis include portosystemic shunting, pancreatic enzyme deficiency, bacterial overgrowth, altered intestinal flora, and enteropathy.(5) Altered macronutrient metabolism or “accelerated starvation” occurs as a result of reduced hepatic glycogen synthesis and storage during the postprandial state, an early shift from glycogenolysis to gluconeogenesis, fatty acid oxidation, and increased rates of whole‐body protein breakdown.(29,30) Hypermetabolism has been variably defined in the literature (e.g., resting energy expenditure [REE] + 1 SD or REE:REE predicted + 2SD).(31,32) With its associated catabolic state, hypermetabolism also contributes to the imbalance between intake and requirements, occurring in at least 15% of patients with cirrhosis without a clear correlation of hypermetabolism with disease severity or other predictors.(32,33) Cirrhosis‐Related Cirrhosis itself leads to frailty and sarcopenia through a number of pathways. At the pathophysiological level, the altered catabolic state in cirrhosis leads to an imbalance between energy needs and intake. Altered protein metabolism, particularly of branched‐chain amino acids (BCAAs) that are essential for supporting glutamine synthesis and extrahepatic ammonia detoxification, results in reduced levels of circulating BCAAs, which leads to accelerated muscle breakdown.(34‐36) Impaired hepatic ammonia clearance from loss of metabolic capacity, in combination with increased portosystemic shunting, increases systemic ammonia concentration with pathologic effects on the muscle.(37‐39) Ammonia is myotoxic through mechanisms that include decreased protein synthesis, increased autophagy, proteolysis, and mitochondrial oxidative dysfunction in the skeletal muscle. Posttranslational modifications of contractile proteins with bioenergetic dysfunction result in muscle contractile dysfunction and loss of muscle mass.(40‐42) The etiology of liver disease has been associated with differences in the prevalence of sarcopenia.(43,44) For example, alcohol‐associated liver disease has been associated with a particularly high prevalence of sarcopenia, affecting 80% of patients with decompensated cirrhosis—although sarcopenia was reported in approximately 60% of patients with cirrhosis from NASH, chronic HCV, and autoimmune hepatitis.(45) Patients with alcohol‐associated cirrhosis display the most rapid rate of reduction in muscle areas compared with other etiologies.(43) Alcohol exposure increases muscle autophagy, inhibits proteasome activity, and decreases the anabolic hormone insulin‐like growth factor 1.(46‐48) Patients with cirrhosis secondary to NASH may be at increased risk of sarcopenia due to the additive effects of insulin resistance and chronic systemic inflammation.(49) Finally, cholestasis‐predominant liver diseases, such as primary sclerosing cholangitis, lead to elevated serum bile acid levels that may induce skeletal muscle atrophy through the bile acid receptor G protein–coupled bile acid receptor 1 (or TGR5) that is expressed in healthy muscles.(50) Complications of portal hypertension also contribute to malnutrition and muscle dysfunction. HE is associated with anorexia, reduced physical activity, and frequent hospitalizations.(37,51) Ascites contributes to anorexia, early satiety, increased REE, and limited physical activity.(52,53) Both HE and ascites are strongly associated with frailty.(54) Other Systems Systemic Inflammation, Endocrine Factors, Metabolic Dysregulation, and Other Aging‐Related Conditions Circulating levels of inflammatory markers such as IL‐1, IL‐6, IL‐10, C‐reactive protein, and TNF‐α are elevated in patients with cirrhosis.(55,56) Low‐grade endotoxemia may result from increased gut permeability, from impaired hepatic clearance of lipopolysaccharide and portosystemic shunting, and potentially from cirrhosis‐related changes in the gut microbiome.(57) This chronic systemic inflammation may promote the development of frailty, sarcopenia, and their subsequent complications through reduced muscle protein synthesis and increased protein degradation.(58‐61) Even in the absence of cirrhosis, chronic liver disease may lead to systemic inflammation and vulnerability to developing frailty and sarcopenia. Inflammatory cytokines are elevated in chronic HCV; eradication of HCV with antiviral agents results in a decrease of these markers.(62,63) Both alcohol‐associated liver diseases and NAFLDs are also characterized by elevated systemic inflammatory markers.(64) Further disruption of mediators of the “liver–muscle axis” may result from cirrhosis‐related reduction in circulating levels of testosterone and changes in growth hormone secretion and sensitivity.(65) Low testosterone levels have been observed in male patients with cirrhosis and sarcopenia compared with patients who are nonsarcopenic.(66) Testosterone replacement resulted in improvements in total lean body mass,(67) further supporting the role of low testosterone in the development and progression of sarcopenia. Obesity has been associated with frailty and sarcopenia in patients with cirrhosis and is of increasing relevance given the rapidly rising prevalence of obesity‐related liver diseases.(6,68‐71) Obesity is associated with metabolic dysregulation, visceral fat accumulation, insulin resistance, and anabolic resistance. A strong link has been demonstrated between obesity and muscle loss in patients with cirrhosis, with nearly one third of patients with obesity and cirrhosis meeting criteria for sarcopenia by skeletal muscle index (SMI).(70) With regard to muscle function, obesity has not been associated with an increased rate of frailty, although one multicenter study of patients with cirrhosis awaiting liver transplantation did demonstrate a significant interaction between obesity and frailty on clinical outcomes: patients with a BMI ≥ 35 kg/m2 who were frail experienced a 3‐fold increased risk of waitlist mortality compared with similar‐weight patients who were nonfrail.(68) Consistent with the general population, there has been a rapid rise in the prevalence of cirrhosis in older adults.(72) In older adults with cirrhosis, a combination of primary (aging‐related) and secondary (chronic disease–related) sarcopenia occurs simultaneously and has been referred to as “compound sarcopenia.”(73) In hospitalized patients, compound sarcopenia was associated with higher odds of death (OR, 1.06; 95% CI, 1.04‐1.08) and greater resource use (OR, 1.10; 95% CI, 1.04‐1.08) than patients with cirrhosis but without compound sarcopenia.(73) Physical Inactivity Physical inactivity and sedentary behavior are common in patients with cirrhosis and are associated with frailty and sarcopenia as well as mortality.(74‐76) In one small study of 53 liver transplant candidates, participants spent 76% of their waking hours in sedentary time and completed a mean of only 3,000 steps per day.(76) Physical inactivity was significantly higher among liver transplant candidates who experienced waitlist mortality than in those who experienced other outcomes on the waitlist (e.g., transplant, removed for social reasons, or still waiting).(75) In a survey of liver transplant candidates and their caregivers, only 60% of patients and caregivers reported feeling that their clinicians “encouraged exercise,”(77) suggesting that one possible barrier to engaging in physical activity is the patient–provider communication around the benefits of physical activity. There are no prospective longitudinal studies evaluating the direct role of physical inactivity on progressive frailty and/or sarcopenia. However, a number of trials have demonstrated a benefit of interventions to increase physical activity (in combination with nutritional counseling) on muscle function, muscle mass, and functional capacity.(78‐82) These studies suggest that physical inactivity may, in part, contribute to decline in muscle function and/or muscle mass. Social Determinants of Health Social determinants of health—that is, where we live, learn, work, and play(83)—also play a role in the development of malnutrition, frailty, and sarcopenia. Health literacy is primarily governed by socioeconomic factors and is associated with physical frailty among liver transplant candidates.(84) Food insecurity owing to social factors such as poverty, isolation, or limited access to nutritious food is associated with advanced liver disease in patients with NAFLD.(85) Financial strain may limit caregiver presence in the home, resulting in limited monitoring, limited supervision for physical activity, and less attentive management of cirrhosis complications (e.g., timely lactulose therapy for HE). Conversely, increased patient needs impact caregiver productivity and earning potential. Some caregivers of patients with cirrhosis lose employment,(86) potentially worsening financial strain and thus the ability to provide adequate nutrition and management of cirrhosis complications that contribute to malnutrition. Organizational Factors Factors at the local, community, and national levels can exacerbate the development of malnutrition, frailty, and sarcopenia in this population. Community‐level barriers to access to nutritious food may accelerate the development of all of these factors, including obesity, in some populations and drive adverse outcomes. In pediatric liver transplant recipients, neighborhood deprivation, an administrative metric of socioeconomic status, has been shown to be independently associated with mortality.(87) Given the complexity of managing patients with cirrhosis, there may be insufficient time during clinical visits to devote to identifying factors and developing strategies to target the contributing causes. Although a referral to, or comanagement with, a registered dietician with expertise in managing patients with advanced liver disease is ideal, some health care systems may not offer this resource or allow for longitudinal follow‐up to assess for response to treatment recommendations. Furthermore, there may be confusion about which provider is responsible for management (e.g., primary care physician, hepatologist, registered dietician), despite the importance of a multimodal, multidisciplinary approach. Clinical Manifestations of Muscle Dysfunction: Frailty and Sarcopenia Frailty Assessment of Frailty in Adults and Children Tools to assess frailty as a multidimensional construct (e.g., global frailty) or its individual components (e.g., physical frailty, disability, functional status) that have been studied in adults or children with cirrhosis are listed in Table 2.115‐128 The tools are organized in the table from subjective, survey‐based tools assessed by the patient, caregiver, or clinician to objective, performance‐based assessments. The majority of these tools have been studied in the ambulatory setting only, underscoring the original “geriatric” construct of frailty as a chronic state of decreased physiologic reserve. However, the strong prognostic value of the two tools that have been studied in the acute care setting—activities of daily living (ADLs) and Karnofsky Performance Status (KPS)—highlights the pragmatic need for tools to measure the effects of frailty and sarcopenia in patients with acute cirrhosis complications. Table 2 - Tools to Assess Frailty or Individual Frailty Components that have been Studied in Patients with Cirrhosis Tool Setting Studied Administration Time Equipment Needed Component(s) of Frailty Measured Details Regarding Administration Clinical Frailty Scale( 96,115 ) Ambulatory inpatient <1 minute None Global frailty Rapid survey‐based instrument using clinician assessment on a scale of 1‐9 where 1 = very fit, 5 = mildly frail, and 9 = terminally ill ADLs( 97,100,113 ) Ambulatory inpatient 2‐3 minutes None Ability to conduct basic tasks to function within one’s home Patient or caregiver assesses difficulty or dependence with six activities that are essential to function within one’s home (e.g., basic hygiene, eating, ambulation) KPS( 88,89,116,117 ) Ambulatory inpatient <1 minute None Ability to carry out normal ADLs Patient, caregiver, or clinician assesses functional limitations ranging from 100 (normal, no complaints, no evidence of disease) to 50 (requires considerable assistance and frequent medical care) to 10 (moribund, fatal processes progressing rapidly). Lansky Play‐Performance Scale( 94 ) Ambulatory inpatient <1 minute None Usual play activity in children Studied in children aged 1‐17 years listed for liver transplant. Similar to KPS scale ranging from 100 (fully active, normal) to 50 (lying around much of the day, no active playing but participates in all quiet play and activities) to 10 (does not play) Eastern Cooperative Oncology Group( 103,104,118‐121 ) Ambulatory <1 minute None Ability to carry out normal ADLs Patient, caregiver, or clinician assesses functional limitations ranging 0‐5, where 0 = asymptomatic, 2 = < 50% in bed during the day, and 4 = bedbound. Fried Frailty Instrument( 75,106 ) Ambulatory 5‐10 minutes Hand dynamometer,stopwatch,tape measure Physical frailty Consists of five domains: (1) weight loss (question), (2) exhaustion (question), (3) slowness (short gait speed), (4) weakness (hand grip strength), and (5) low physical activity level (questionnaire) Modified Fried Frailty Instrument( 93 ) Ambulatory 60 minutes Hand dynamometer,stopwatch,tape measure Physical frailty Developed for children with chronic liver disease aged 5‐17 years. Consists of five domains: (1) weight loss (triceps skinfold thickness), (2) exhaustion (questionnaire), (3) slowness (gait speed), (4) weakness (grip strength), and (5) low physical activity (questionnaire) Hand grip strength( 122,123 ) Ambulatory 2‐3 minutes Hand dynamometer Physical frailty The patient is asked to grip a dynamometer using the dominant hand with their best effort. The test is repeated 3 times, and the values are averaged. Short gait speed( 105 ) Ambulatory ~1 minute stopwatch, tape measure Functional mobility One of the components of the Short Physical Performance Battery 6‐minute walk test( 107 ) Ambulatory 6 minutes Stopwatch, tape measure Submaximal aerobic capacity and endurance Distance walked on a flat surface at usual walking speed within 6 minutes Short Physical Performance Battery( 75 ) Ambulatory ~3 minutes Stopwatch,tape measure, chair Lower extremity physical function Consists of three components: (1) 8‐foot gait speed, (2) timed chair stands (5 times), and (3) balance testing three positions (feet together, semitandem, tandem) for 10 seconds each Liver Frailty Index( 54,90‐92,124‐127 ) Ambulatory inpatient ~3 minutes Stopwatch, hand dynamometer, chair Physical frailty Cirrhosis‐specific tool consisting of grip strength, chair stands, and balance testing. Changes in Liver Frailty Index are associated with outcomes. Cardiopulmonary exercise test( 102,108,128 ) Ambulatory 60 minutes Cardiopulmonary stress diagnostic system Maximal aerobic capacity Noninvasive test of functional capacity through measurement of gas exchange at rest and during exercise to evaluate both submaximal and peak exercise responses Some scales have validated thresholds to grade the severity of frailty. Specifically, patients can be categorized as having high, moderate, or low performance status using KPS thresholds of 80‐100, 50‐70, or 10‐40, respectively.(88,89) The Liver Frailty Index also has established cut‐points to define robust (Liver Frailty Index < 3.2), prefrail (Liver Frailty Index 3.2‐4.3), and frail (Liver Frailty Index ≥ 4.4).(90,91) Poor performance according to some scales (e.g., ADLs), however, suggests a greater burden of functional deficits than others (e.g., walk speed). The only tools that have also evaluated the associations between longitudinal assessments and outcomes in patients with cirrhosis are the KPS scale and the Liver Frailty Index.(88,92) When it comes to assessing frailty in children, the well‐established tools for assessment of frailty in adults are challenging to administer given the need for participation in the tests (either by survey or by performance) and consideration of age‐related and sex‐related norms. However, a few studies have demonstrated that the concept of frailty has clear applicability to children with chronic liver disease. The traditional Fried frailty phenotype, developed in older adults and validated in patients with cirrhosis of all ages, has been modified for children.(93) Although assessment of frailty was feasible in this cohort of children 5‐17 years of age, the majority of children undergoing liver transplantation are too young to use the Modified Fried Frailty Instrument (median age 18 years), highlighting the need to derive an objective pediatric frailty assessment tool for children < 2 years of age. One promising metric is the Lansky Play‐Performance Scale, a measure of global functional status developed for children with cancer aged 1‐16 years, which can be assessed by the patient, caregiver, or clinical provider.(94) Gaps remain in the measurement of muscle contractile function among those < 1 year of age. Prevalence and Natural History Frailty is common among patients with cirrhosis; its prevalence increases with liver disease severity. Estimates of frailty prevalence in this population have varied because of the use of a number of different tools to capture impaired muscle contractile function. Among patients with cirrhosis in the ambulatory setting, the reported prevalence of frailty has ranged from 17% to 43%.(54,75,95,96) Among hospitalized patients with cirrhosis, the prevalence of frailty is as high as 38% for inpatients with HE (and 18% for those without HE) when measured as disability using the ADL tool.(97,98) Rates of frailty have been reported to be as high as 68% when measured as impaired performance status using the KPS scale.(89) Using the Modified Fried Frailty Instrument, 24% of children with chronic liver disease met the criteria for frailty, with rates as high as 46% among children with more advanced/end‐stage liver disease.(93) Frailty worsens in the majority of patients with cirrhosis over time.(88,92) Among patients awaiting liver transplantation in the United States, < 20% displayed improved or stable KPS scores.(88) After liver transplantation, at least 90% experience some improvement in the