Nutrition, frailty assessment, and interventions for the liver transplant candidate.

Abstract

WHAT IS FRAILTY? Frailty—a broad term classically used in the medical literature by geriatricians—is a clinical state of decreased reserve and the ability to endure health stressors, such as the age-related cumulative decline of multiple organ systems.1 The operational definition of frailty in the potential liver transplantation (LT) candidate refers to physical frailty, the manifestations, and the consequences of the loss of muscle function—in contrast to sarcopenia, the measurable loss of muscle mass in patients with progressive liver dysfunction.2 Many clinical factors contribute to the development of the frail phenotype. Malnutrition, a spectrum of disorders that results in an imbalance of energy, protein, and other nutrients—and notably, a spectrum that can manifest across the entire body mass index range—is one of these factors and is modifiable. WHY IS THERE A NEED FOR NUTRITION/FRAILTY ASSESSMENT? Frailty is prevalent, present in over 30% of patients listed for LT. The construct of frailty has been strongly linked to increased waitlist mortality, decreased quality of life in patients awaiting LT, and increased hospitalizations independent of liver disease severity1,3 (Figures 1, 2). Frailty also worsens longitudinally without intervention and may persist even after LT.6FIGURE 1: Incidence of waitlist mortality for 4 patients on transplant waitlist classified by MELDNa and LFI.4 Abbreviations: LFI, Liver Frailty Index; MELDNa, model for end-stage liver disease sodium.FIGURE 2: Predicted probabilities of survival for 4 patients with cirrhosis on liver transplantation waitlist by the combination of MELDNa and frailty index scores.5 Abbreviation: MELDNa, model for end-stage liver disease sodium.These outcomes underscore the need to use standardized tools to assess and intervene in frailty and malnutrition in the LT setting.1,6 After all, the “model for end-stage liver disease” score is the foundation of the current liver allocation policy in the US but does not include an objective measure of a common clinical decompensation among patients requiring LT: poor nutritional and/or functional status. In addition, the model for end-stage liver disease score is a poor predictor of post-transplant mortality, particularly in patients who are physically frail.6 In this review, we describe nutrition and frailty assessment tools, as well as currently approved—and potential future—interventions for patients with chronic liver disease, who are LT candidates. WHY IS FRAILTY PREVALENT? Several biochemical, clinical, and even social factors lead to frailty.6 These factors, commonly encountered by patients with chronic liver disease, contribute to the high prevalence of frailty in this population. Malnutrition: impaired intake and uptake of both macronutrients and micronutrients. This includes reduced oral intake related to symptoms and disease processes; malabsorption, for instance, leading to fat-soluble vitamin deficiencies in patients with cholestatic liver disease; and altered metabolic processes, including increased catabolism. Cirrhosis itself, with factors including impaired hepatic ammonia clearance, leads to mitochondrial oxidative dysfunction and myotoxic damage. Systemic inflammation and endotoxemia. Physical inactivity is related to the severity of chronic liver disease. Social determinants of health, including limitations related to caregivers and ability to supervise physical activity. HOW TO ASSESS FRAILTY AND MALNUTRITION? The American Association for the Study of Liver Diseases recommends screening for frailty and malnutrition in patients with cirrhosis, including both compensated cirrhosis (annually) and decompensated cirrhosis (every 3–4 months). Clinicians may determine which assessment(s) to use.3 FRAILTY Although several frailty assessment tools have been used for patients with cirrhosis (Table 1), the Karnofsky performance status scale and the Liver Frailty Index (LFI) are the only longitudinal assessment tools shown to be associated with outcomes in patients with cirrhosis (transplant and nontransplant candidates) in both the inpatient and outpatient settings.3 TABLE 1 - Frailty assessment tools in adults with chronic liver disease Tool Setting studied Summary Advantage Disadvantage LFI Inpatient and outpatient Objective measure: Grip strength Chair stands Balance Categories: Robust (LFI <3.2) Prefrail (LFI 3.2–4.3) Frail(LFI ≥4.4) Strong association with pre and post-LT outcomes Potentially confounded by cardiovascular and pulmonary comorbidities KPS Inpatient and outpatient Subjective measure of ADLs Performance categories: High (80–100) Moderate (50–70) Low (0–40) Fast, equipment-free Subjectivity CFS Inpatient and outpatient Subjective measure categories: Very fit Well with treated comorbid disease Apparently vulnerable Mildly frail Moderately frail Severely frail Very severely frail Terminally ill Independent of muscle mass (reflecting sarcopenia) in patients with cirrhosis Not studied exclusively in transplant patients FFI Outpatient Based on 5 domains of physical frailty: Weakness Exhaustion Weight loss Low activity Slowness Independently associated with mortality in patients with cirrhosis Not studied in transplant patients ADLs/IADLs Outpatient and inpatient Patient or caregiver assessment of 6 essential activities within one’s home (eg, basic hygiene, eating, ambulation)3 Associated with an adjusted risk of 90 d mortalityafter discharge in hospitalized patients with cirrhosis Not studied in the transplant setting. Confounded by cardiovascular and pulmonary comorbidities and encephalopathy, as well as social determinants of health (such as finances) SPPB Outpatient Performance-based model Repeated chair stands Balance testing Gait speed Predictive of LT waiting list mortality, disability, and hospitalization, in older patients7 Confounded by cardiovascular and pulmonary comorbidities, and encephalopathy. Takes over 5 min to administer Abbreviations: ADL, activities of daily living; CFS, clinical frailty scale; FFI, Fried Frailty Index; IADL, instrumental activities of daily living; KPS, Karnofsky performance status; LFI, Liver Frailty Index; LT, liver transplantation; SPPB, Short physical performance battery. The Karnofsky performance status is a quick, equipment-free, subjective measure of a patient’s ability to perform activities of daily living, categorizing the patient’s performance as high, moderate, or low. Lower functional status on the Karnofsky performance status is associated with increased waitlist mortality and predicts worse post-transplant outcomes, including graft failure.8 As this assessment includes subjectivity, it may be influenced by factors not accurately tied to physical performance, thereby skewing risk assessment for individual patients.8 The LFI (https://liverfrailtyindex.ucsf.edu/) objectively measures physical frailty, using grip strength, chair stands, and balance testing to categorize patients as robust, prefrail, or frail.3 The LFI improves risk prediction of 3-month waitlist mortality for LT compared with the model for end-stage liver disease alone and predicts post-transplant functional status.1 In addition, longitudinal assessment of a patient’s LFI informs mortality risk.6 We advocate for the use of LFI and use this measure in the assessment of LT candidates at our center. NUTRITION Assessing nutritional status in LT candidates is challenging and complicated by the lack of reliable serum markers (eg, albumin and prealbumin), due to the decreased synthetic function in liver diseases, as well as a lack of reliable patient weight measurement due to fluctuations in volume status. Two malnutrition screening tools, the royal free hospital nutritional prioritizing tool6,9 and the liver disease undernutrition screening tool,9 are validated for patients with cirrhosis, but they have not been specifically studied in the transplant setting.9 These tools are summarized in Table 2. TABLE 2 - Nutrition assessment tools for patients with cirrhosis Tool Summary Advantage Disadvantage LDUST Questions: Nutrition intake Weight loss s.c fat loss Muscle mass loss fluid accumulation Decline in functional status Studied transplant patients Subjectivity RFH-NPT Presence of acute hepatitis or need for enteral nutritional support Low BMI, unexplained weight loss, or maintenance of volitional nutritional intake Whether fluid overload interferes with the ability to eat Studied in transplant patients: high nutritional risk is associated with reduced survival, worsened liver function, and reduced quality of life This tool has not been evaluated systematically in the transplant setting SGA Questionnaire: Weight loss Unintentional reduction of dietary intake Gastrointestinal disturbances Physical function muscle and fat mass loss Fluid retention Adequate nutritional state is indicated as grade A, moderate malnutrition as grade B and severe malnutrition as grade C 9 Most broadly used nutritional assessment tools for patients irrespective of disease etiology9 Subjective, not specifically studied in patients with cirrhosis or those requiring LT AMs AC and CC used to calculate muscle mass index and BMI; TSF thickness and WC used to calculate fat mass10 Objective data: convenient and noninvasive Confounded by fluid overload. Surrogate for nutritional status but not a direct measurement Abbreviations: AC, arm circumference; AM, anthropometric measurement; BMI, body mass index; CC, calf circumference; LDUST, liver disease undernutrition screening tool; LT, liver transplantation; RFH-NPT, royal free hospital nutritional prioritizing tool; SGA, subjective global assessment; TSF, triceps skinfold; WC, waist circumference. Currently, the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend using the royal free hospital nutritional prioritizing tool to screen for nutritional status in patients with cirrhosis.9,11 Further studies are required to compare the efficacy of these 2 tools in the LT population. HOW AND WHEN TO INTERVENE? Interventions to prevent the occurrence of adverse health outcomes related to malnutrition and/or frailty can be classified into 4 groups: (1) liver-specific, (2) physical activity, (3) nutritional, and (4) other organ systems6 (Table 3). TABLE 3 - Interventions to address frailty in the liver transplant candidate Intervention category Nontransplant intervention Transplant intervention Examples Liver-specific Treat underlying etiology of liver disease and manage complications including hepatic encephalopathy and ascites Same as for nontransplant patients Eradication of Hepatitis C reduces systemic inflammation, thereby reducing muscle injury and lowering metabolic demand Cessation of alcohol use reduces alcohol-associated muscle toxicity In patients with NAFLD, healthy weight loss prevents sarcopenia Treatment of ascites improves early satiety, exercise capacity, and mobility Physical activity Physical activity plan consisting of a combination of aerobic and resistance training for 150 min a week that is tailored to the patient’s baseline frailty and functional status Same as for nontransplant patients. In addition: weighing the risk of falls that may delay transplant Based on a baseline assessment of physical functioning, create a tailored plan to include at least 150 min (per week) of moderate to vigorous intensity exercise Muscle-strengthening exercises at least 2 d per week Using modern technology such as fitness trackers or smartphone applications to provide real-time objective tracking data and to identify areas for improvement Nutrition Create a personalized nutrition prescription with more intense intervention for patients who are more frail. Reassess progress at regular intervals. Current guidelines recommend a weight-based daily caloric intake of at least 35 kcal/kg/d. Promoting protein intake of 1.2–1.5 g/kg/d in most patients (1.2–2.0 g/kg/d using ideal body weight in critically ill patients) Same as for nontransplant patients. In addition, consider more frequent reassessment in patients on the liver transplant waiting list Estimate the patient’s caloric needs, through indirect calorimetry or other weight-based equations. Balancing sodium restrictions to encourage oral intake while simultaneously preventing excess fluid retention Of particular note within the nutritional interventions is the importance of protein intake, with guideline recommendations now available to emphasize the importance of a protein intake of 1.2–1.5 g/kg/day for adults with cirrhosis. This level of protein intake safely maintains a positive protein balance and importantly does not worsen hepatic encephalopathy.6 Furthermore, prolonged fasting should be avoided to limit exacerbation of catabolism in cirrhosis, with further evidence supporting an early morning breakfast or late evening snack in these patients with chronic liver disease. Enteral supplementation—particularly in the inpatient population not meeting nutrition needs despite oral nutritional supplementation—should be considered, particularly for patients awaiting LT, who have failed oral supplementation.3 In addition to liver-specific interventions and interventions related to physical activity and nutrition, clinicians must also ensure attention to other organ systems impacting outcomes related to malnutrition and frailty (eg, endocrine system). One area warranting consideration and future research is testosterone replacement in patients with cirrhosis with low testosterone. There are data to suggest that providing testosterone replacement in male patients with low testosterone improves muscle mass and glucose metabolism.3 Current guidelines note that as exogenous testosterone increases malignancy risk (including HCC) and thrombophilia, the approach to this evolving intervention must be carefully individualized. The use of testosterone in potential transplant recipients must be further investigated with larger randomized control trials before being routinely prescribed. CONCLUSION Frailty and malnutrition are common clinical complications of liver diseases. Fortunately, standardized tools are available to assist the liver transplant team’s assessment of these complications. Importantly, these tools also provide an opportunity for intervention, which may improve not only access to transplantation but also post-transplant outcomes.