Sarcopenia in Chronic Liver Disease: Impact on Outcomes

REVIEW ARTICLE OOi et Al. Sarcopenia in Chronic Liver Disease: Impact on Outcomes Poh Hwa Ooi,1 Amber Hager,1 Vera C. Mazurak,1 Khaled Dajani,4 Ravi Bhargava,2 Susan M. Gilmour,3,5 and Diana R. Mager1,3 Departments of 1 Agricultural, Food and Nutritional Sciences, 2 Radiology and Diagnostic Imaging, Walter C. Mackenzie Health Sciences Centre, and 3 Pediatrics and 4 Department of General Surgery, University of Alberta, Edmonton, Alberta, Canada; and 5 Division of Pediatric Gastroenterology and Nutrition/Transplant Services, The Stollery Children’s Hospital, Alberta Health Services, Edmonton, Alberta, Canada Malnutrition is a common complication in patients with end-stage liver disease (ESLD) awaiting liver transplantation (LT). Malnutrition and sarcopenia overlap in etiology and outcomes, with sarcopenia being defined as reduced skeletal muscle mass and muscle function. The purpose of this review was to identify the prevalence of sarcopenia with and without obesity in adults and children with ESLD and to assess the methodological considerations in sarcopenia diagnosis and the association of sarcopenia with pre- and post-LT outcomes. A total of 38 articles (35 adult and 3 pediatric articles) retrieved from PubMed or Web of Science databases were included. In adults, the prevalence rates of pre-LT sarcopenia, pre-LT sarcopenic obesity (SO), post-LT sarcopenia, and post-LT SO were 14%-78%, 2%-42%, 30%-100%, and 88%, respectively. Only 2 adult studies assessed muscle function in patients diagnosed with sarcopenia. The presence of pre-LT sarcopenia is associated with higher wait-list mortality, greater postoperative mortality, higher infection risk and postoperative complications, longer intensive care unit (ICU) stay, and ventilator dependency. The emerging pediatric data suggest that sarcopenia is prevalent in pre- and postLT periods. In 1 pediatric study, sarcopenia was associated with poor growth, longer perioperative length of stay (total/ICU) and ventilator dependency, and increased rehospitalization in children after LT. In conclusion, there is a high prevalence of sarcopenia in adults and children with ESLD. Sarcopenia is associated with adverse clinical outcomes. The present review is limited by heterogeneity in the definition of sarcopenia and in the methodological approaches in assessing sarcopenia. Future studies are needed to standardize the sarcopenia diagnosis and muscle function assessment, particularly in the pediatric population, to enable early identification and treatment of sarcopenia in adults and children with ESLD. Liver Transplantation 25 1422‒1438 2019 AASLD. Received February 25, 2019; accepted June 24, 2019. Malnutrition is highly prevalent in patients with end-stage liver disease (ESLD).(1) The presence of malnutrition is multifactorial and is related to alterations in dietary intake, hypermetabolism, and nutrient absorption and utilization.(1) Sarcopenia represents Abbreviations: A1AD, alpha-1-antitrypsin deficiency; AIH, autoimmune hepatitis; ALF, acute liver failure; ALL, acute lymphoblastic leukemia; AS, Alagille syndrome; AWMA, abdominal wall muscle area; AWMI, abdominal wall muscle index; BA, biliary atresia; BCAA, branched-chain amino acid; BCS, Budd-Chiari syndrome; BIA, bioelectrical impedance analysis; BMI, body mass index; CMD, cardiometabolic dysregulation; CNI, calcineurin inhibitor; CT, computed tomography; DEXA, dual energy X-ray absorptiometry; ESLD, end-stage liver disease; EWGSOP, European Working Group on Sarcopenia in Older People; FHF, fulminant hepatic failure; FOXO, forkhead box transcription factor; GGT, gamma-glutamyltransferase; HAV, hepatitis A virus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; 1422 | Review ARticle 1 component within the spectrum of malnutrition: reduced skeletal muscle mass (SMM) and reduced muscle functionality.(2) Sarcopenia may occur across a spectrum of body habitus whereby relative body fat mass can be disproportionately larger relative to reduced SMM. When this occurs in overweight and obese individuals, the condition is called sarcopenic obesity (SO). In adults with ESLD, sarcopenia with and without obesity has been associated with adverse clinical outcomes.(3-6) However, the evolution of sarcopenia and the factors influencing the risk of sarcopenia have not been well defined in adults with ESLD. Even less is known regarding sarcopenia prevalence and longitudinal evolution and its associations with clinical outcomes in children. Recent evidence in children has shown that sarcopenia is highly prevalent in a variety of clinical populations (eg, appendicitis, inflammatory bowel disease [IBD], or intestinal failure) and liveR tRAnsplAntAtiOn, vol. 25, no. 9, 2019 that sarcopenia adversely influences postoperative outcomes.(7-10) Given the high prevalence of sarcopenia in adults awaiting liver transplantation (LT) and the emerging evidence in children with ESLD that sarcopenia is also highly prevalent, the inclusion of sarcopenia into the definition for organ allocations (Pediatric End-Stage Liver Disease [PELD]/Model for End-Stage Liver Disease [MELD] scores) for LT has been proposed.(11) Recent advancements and testing of imaging techniques (computed tomography [CT] and magnetic resonance imaging [MRI]) have enabled the application of these methods for body composition assessment for patients with ESLD. These measures offer an objective measure of nutritional status and body HRQoL, health-related quality of life; IBD, inflammatory bowel disease; ICU, intensive care unit; IGF1, insulin-like growth factor 1; IL, interleukin; IR, insulin resistance; LOS, length of stay; LPA, lean psoas area; LT, liver transplantation; MELD, Model for EndStage Liver Disease; MRI, magnetic resonance imaging; mTOR, mammalian target of rapamycin; NA, not available; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ND, no difference; NOS, Newcastle-Ottawa scale; OS, overall survival; PA, physical activity; PBC, primary biliary cholangitis; PELD, Pediatric End-Stage Liver Disease; PHC, perihilar cholangiocarcinoma; PKB, protein kinase B; PMA, psoas muscle area; PMI, psoas muscle index; PMT, psoas muscle thickness; POD, postoperative day; PSC, primary sclerosing cholangitis; PSMA, paraspinal muscle mass area; PSMI, paraspinal muscle mass index; SBP, spontaneous bacterial peritonitis; SD, standard deviation; SMA, skeletal muscle area; SMI, skeletal muscle mass index; SMM, skeletal muscle mass; SN, sarcopenic nonobesity; SO, sarcopenic obesity; TNF-α, tumor necrosis factor α; UL, umbilical level; UPP, ubiquitin-proteasome pathway; VFA, visceral fat area. Address reprint requests to Diana R. Mager, Ph.D., M.Sc., R.D., Department of Agricultural, Food and Nutritional Sciences, University of Alberta, 2-021D Li Ka Shing, Edmonton, AB, Canada T6G 0K2. Telephone: 780-492-7687; FAX: 780-4922011; E-mail: [email protected] Ooi Poh Hwa and Amber Hager reviewed the literature and prepared the tables. Ooi Poh Hwa, Amber Hager, and Diana R. Mager drafted the manuscript. Vera C. Mazurak, Khaled Dajani, Ravi Bhargava, and Susan M. Gilmour critically reviewed the article. All authors approved the final version of manuscript prior to submission. Additional supporting information may be found in the online version of this article. Copyright © 2019 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/lt.25591 Potential conflict of interest: Nothing to report. OOi et Al. composition without the inherent limitations in other methods (bioelectrical impedance analysis [BIA] and dual energy X-ray absorptiometry [DEXA]) related to the presence of fluid overload.(12) Despite the growing research on sarcopenia, progress is hampered by the lack of uniform definitions and methodological approaches. This is important to establish, particularly in growing children, where the need for standardized assessments of muscle strength and muscle functionality are warranted. This review evaluates the literature related to the prevalence of sarcopenia with and without obesity in adults and children with ESLD, the methodological considerations required to assess for sarcopenia, and the associated clinical outcomes that may arise from sarcopenia in the pre- and post-LT periods. Patients and Methods seARcH stRAteGY A literature search was completed via PubMed and Web of Science databases up to December 2018 using a systematic approach. The terms “sarcopenia,” “sarcopenic obesity,” “muscle depletion,” “muscle loss,” “reduced skeletal muscle mass,” “low muscle mass,” “reduced muscle strength” or “muscle function,” “anthropometry,” “obesity,” “clinical outcome,” “outcomes,” “liver transplant,” “liver transplantation” and also 1 of “childhood,” “children,” “pediatric” or “adults” were used to identify potential articles. The search was done without limiting the years of publication. inclUsiOn AnD eXclUsiOn cRiteRiA The inclusion criteria were primary studies that assessed sarcopenia and/or SO among adults and pediatric LT candidates or liver recipients. Studies that tracked changes in sarcopenic status before and after LT and the influence on wait-list or postoperative outcomes associated with sarcopenia or SO were included. All types of study designs and ESLD diagnoses were included. Articles were excluded if they were review articles, editorial pieces, case reports, studies conducted on animal models or cell culture, non-English articles, and articles without a full text. Studies that were performed in populations with other types of transplantations and articles that did not address the concept of sarcopenia or SO were excluded at screening. Review ARticle | 1423 OOi et Al. Study quality was assessed using the NewcastleOttawa scale (NOS).(13) The scale evaluates 3 subscales (selection of cohorts, comparability of groups, and outcome assessment) with a maximum score of 9. A score of ≥7 is considered to be a high-quality study. Effect sizes were determined with Cohen’s d for studies that expressed results in mean (standard deviation [SD]) and Cohen’s h for studies that reported data in proportion.(14) Effect sizes of ≤0.1, 0.2-0.4, 0.5-0.7, and ≥0.8 are reflective of no effect, small, medium, and large effects, respectively. Results The selection process and number of articles excluded are presented in Fig. 1. A total of 38 articles (years 2010-2018) were included,(1,3-6,9-12,15-43) in which 92% (n = 35) were conducted in adults(1,3-6,11,12,15-33,35-43) and 8% (n = 3) were conducted in pediatric populations.(9,10,34) liveR tRAnsplAntAtiOn, september 2019 ADUlts The majority of studies (n = 29/35) focused on pre-LT sarcopenia, which included studies that characterized patients with sarcopenia (n = 26),(1,3,6,11,12,15,17,19,21-26,28,30,32,33,35-37,39-43) SO (n = 1)(4) as well as both sarcopenia and SO (n = 2).(5,27) Five studies longitudinally tracked changes in pre-LT sarcopenia into the post-LT period (up to 19.3 months).(16,18,29,31,38) Only 1 article evaluated post-LT SO.(20) Most of the studies were performed retrospectively (n = 30/35).(1,4-6,11,12,15-30,32,33,35-37,39,40,43) The sample size ranged from 40 to 795 patients who were aged between 50 and 61 years. The MELD score ranged from 14 to 22, with hepatocellular carcinoma (HCC), hepatitis C virus (HCV), and alcoholic liver disease being the top 3 indications for LT. For the majority of the studies (n = 10/13), acute and cryptogenic liver disease accounted for ≤7% of the underlying liver disease type (Table 1).(12,19,21,26-28,32,33,36,40) The time FiG. 1. Flowchart of articles screened and reviewed based on the inclusion and exclusion of study methods. 1424 | Review ARticle liveR tRAnsplAntAtiOn, vol. 25, no. 9, 2019 between body composition measurement and LT varied from 7 to 200 days. CT was the most commonly used body composition method (n = 30/35),(1,3-6,11,12,16-19,21-29,32,33,36,38-44) followed by BIA (n = 3/35)(20,30,31) and concurrent use of CT and MRI (n = 2/35).(37) In studies that used an imaging modality (n = 32/35), there were inconsistencies in lumbar vertebrate measurement level (62% at L3,(1,3-6,11,15-18,26,28,32,35-37,40-43) 16% at L4,(22,29,33,38,39) 16% at L3/L4,(19,21,23-25) and 6% at umbilical level [UL](12,27)). A total of 16/32 studies used total skeletal muscle area (SMA) to define sarwhereas 44% copenia,(3-5,11,16-18,21,26,35,37,38,40-43) (n = 14/32) based their assessment on a single psoas muscle area (PMA).(1,6,12,15,19,22,24,25,27-29,33,36,39) One study used 3 muscle parameters (paraspinal muscle mass area [PSMA], abdominal wall muscle area [AWMA], and SMA) in defining sarcopenia,(23) whereas another study measured psoas muscle thickness (PMT) instead of the muscle area.(32) Most of the studies (n = 25/32) normalized muscle area to height.(1,4,5,11,12,16-19,21-23,26-29,32,35-38,40-43) The height correction is suggested because muscle mass is highly correlated with height.(21) Very limited studies (n = 2/35)(3,31) adhered to the European Working Group on Sarcopenia in Older People (EWGSOP) sarcopenia definition (reduced SMM and muscle function).(2) The prevalence rates of pre-LT sarcopenia, pre-LT SO, post-LT sarcopenia, and post-LT SO were 14%78%, 2%-42%, 30%-100%, and 88%, respectively (Table 2). There was a wide heterogeneity in the cutoff values used to define sarcopenia. These included the following: 1. Cutoffs defined from cancer populations (n = 8).(11,16,18,21,35,37,42,43) 2. Published healthy adult data (n = 6).(3,5,6,26,27,36) 3. Sex-specific lowest quartile/tertile (n = 10).(1,4,12,19,22,29,32,33,39,41) 4. Cutoffs specific to patients with ESLD awaiting LT (n = 3).(15,17,25) 5. Cutoffs from both cancer and LT populations (n = 1).(40) In studies that used BIA (n = 3), the cutoffs were determined by predictive equations.(20,30,31) There were 4 studies that included a control group from trauma patients (n = 2),(23,24) liver donors (n = 1),(28) and healthy adults with CT done due to unspecified abdomen pain (n = 1)(38) in defining sarcopenia. OOi et Al. More than half of the adult studies (n = 19/35; 54%) received NOS scoring of <7, indicative of poor study quality (Table 1).(5,11,12,15-18,20,21,23,28,30,31,33,35-37,39,41) Low study quality is primary due to lack of adjustment of confounding variables, such as age, sex, race, or MELD score, that may cause bias in results. In addition, lack of data related to nutrition, muscle function, immunosuppression, and inconsistencies related to the nonliver control groups (eg, cancer, trauma, or healthy) or cutoff values also contribute to reduced NOS scores. pRe-lt sARcOpeniA AnD wAit-list OUtcOMes Of the 7 studies that evaluated the relationship between pre-LT sarcopenia and mortality risk,(11,17,23,37,40,42,43) 71% (n = 5) showed an increased mortality while on the waiting list (Table 3).(11,17,23,37,40) The effect of sarcopenia on 1-year mortality was small to medium (Supporting Table 1).(14) The presence of sarcopenia was associated with increased infection rates(23) and declines in functional status(22) and pulmonary function,(36) but not with health-related quality of life (HRQoL).(43) pRe-lt sARcOpeniA AnD pOstOpeRAtive OUtcOMes Of the 20 studies that assessed pre-LT sarcopenia on postoperative mortality, 75% (n = 15/20) reported an association of sarcopenia with higher post-LT mortality risk (Table 3).(1,3-6,12,19,21,24-28,30,31) In those studies that reported greater mortality rates, 2 of 15 were conducted in patient with SO.(4,5) Mortality rates were similar in patients with sarcopenia and SO at 1, 3, and 5 years (Supporting Table 1). Out of 9 studies, 8 examined infection and showed a greater risk in sarcopenic liver recipients(1,3,6,25,27,33,35,39) compared with nonsarcopenic patients. However, 1 study showed a reduced risk of postoperative bacteremia in patients with SO when compared with sarcopenia alone.(27) Variable results were found related to sarcopenia and hospitalization, with half of the studies (n = 4/8) associating the presence of sarcopenia with longer length of stay (LOS),(1,3,21,35) and the other half (n = 4/8) demonstrating no association.(15,19,25,41) In studies that reported the effects of sarcopenia on intensive care unit (ICU) stay (n = 5)(1,19,21,25,35) and ventilator dependency (n = 3),(19,21,25) all Review ARticle | 1425 Sex, Male/ Female (%) Age, years Lurz et al.(9) (2018) Case control 23 39/61 1 (0.5, 4) Mangus et al.(10) (2017) Case control 35 37/63 8±1 Retrospective 41 41/59 2 (0.5-8) Montano-Loza et al.(11) (2015) Retrospective 669 68/32 Carey et al.(17) (2017) Retrospective 396 Tandon et al.(37) (2012) Retrospective Yadav et al.(43) (2015) Review ARticle n | Study Design Reference Pediatric studies that assessed pre-LT sarcopenia Liver Etiology (%) PELD/MELD Study Quality* BA, 65%; AS, 17%; low GGT cholestasis, 10%; AIH, 4%; B cell ALL, 4% 12 (2, 24) 5 BA, 54%; hepatoblastoma, 14%; others, 32% 14 (10-47) 5 BA, 73%; AS, 5%; PSC, 7%; others, 15% 15 ± 11 8 57 ± 1 HCV, 40%; Alcohol, 23%; NASH, 23%; Autoimmune, 8%; HBV, 6% 14 ± 0.3 6 70/30 58 (51, 62) HCV, 48%; Alcohol, 17%; NASH, 12%; PSC/PBC/AIH, 10%; HBV 6%; others, 7% 15 (11, 21) 6 142 60/40 53 (47, 57) HCV ± alcohol, 38%; AIH, 25%; alcohol, 20%; cryptogenic/ NAFLD, 11%; others, 6% 15 (12, 22) 5 Retrospective 213 61/39 55 ± 9 16 ± 6 7 van Vugt et al.(40) (2018) Prospective 585 69/31 56 (48, 62) Alcohol, 16%; HBV, 3%; HCV, 6%; PSC/PBC, 22%; HCC/PHC, 33%; NASH, 5%; cryptogenic, 5%; AIH, 3%; others, 7% 14 (9, 19) 7 Shirai et al.(36) (2018) Retrospective 207 52/48 55 (18-69) HCC, 36%; HBV/HCV, 19%; PBC and PSC, 17%; BA, 9%; ALF (unknown), 3%; alcohol, 4%; metabolic, 3%; BCS, 1%; others, 8% 17 (5-41) 5 Dolgin et al.(22) (2018) Retrospective 136 66/34 ≥55: 58% HCV, 47%; alcohol, 24%; others, 29% 21 (11, 29) 7 HCV, 60%; alcohol, 10%; NAFLD, 8%; cholestatic, 10%; others, 12% 15 (12, 18) 7 20 ± 9 6 <20: 83% 8 OOi et Al. 1426 tABle 1. study characteristics of pediatric and Adult lt Articles Pediatric study that assessed post-LT sarcopenia on post-LT outcomes Mager et al.(34) (2019) Adult studies that assessed pre-LT sarcopenia on wait-list outcomes HCV, 44%; Alcohol, 16%; PBC/PSC, 8%; NASH, 14%; cryptogenic, 6%; other, 12% Wang et al.(42) (2016) Prospective 292 66/34 61 (55, 65) DiMartini et al.(21) (2013) Retrospective 338 66/34 55 ± 10 HCV/HBV, 27%; alcohol, 23%; alcohol + HCV/HBV, 9%; NASH, 14%; autoimmune/PSC, 12%; FHF, 4%; other, 11% Masuda et al.(6) (2014) Retrospective 204 50/50 54 ± 10 HBV, 13%; HCV, 51%; PBC, 13%; alcohol, 5%; others, 18% Aby et al.(15) (2018) Retrospective 146 42/58 58 ± 10 NASH, 73%; cryptogenic, 27% 35 ± 7 6 Englesbe et al.(24) (2010) Retrospective 163 63/37 53 ± 9 Alcohol, 12%; HCC, 13%; HCV, 35%; PBC, 6%; PSC, 10%; others, 24% 19 ± 8 7 Montano-Loza et al.(35) (2014) Retrospective 248 68/32 55 ± 1 HCV, 51%; alcohol, 19%; autoimmune, 15%; HBV, 8%; other, 7% 18 ± 1 4 Adult studies that assessed pre-LT sarcopenia on post-LT outcomes ≥20: 17% liveR tRAnsplAntAtiOn, september 2019 <55: 42% Reference Study Design n Sex, Male/ Female (%) Age, years Liver Etiology (%) PELD/MELD Study Quality* Review ARticle Harimoto et al.(3) (2017) Prospective 102 44/56 56 (54, 58) HCV, 24%; HCC, 42%; others, 34% 16 (15, 18) 8 Hamaguchi et al.(26) (2017) Retrospective 250 49/51 54 (43, 62) HCC, 33%; HBC/HCV, 20%; PBC and PSC, 17%; BA, 8%; ALF (unknown), 4%; alcohol, 5%; metabolic, 2%; BCS, 2%; others, 9% 17 (14, 22) 8 Chae et al.(19) (2018) Retrospective 408 70/30 52 ± 9 HBV, 58%; alcohol, 20%; HCV, 8%; toxins and drugs, 6%; AIH, 3%; HAV, 1%; cryptogenic hepatitis, 4% 16 ± 1 7 Golse et al.(25) (2017) Retrospective 256 77/23 53 ± 11 Alcohol, 45%; HCV, 35%; HBV, 7%; NASH, 2%; autoimmune, 2%; biliary, 6%; other, 3% 19 ± 10 7 Kalafateli et al.(1) (2017) Retrospective 232 70/30 54 (22-70) AIH, 20%; viral, 35%; alcohol, 24%; others, 21% 14 (6-42) 7 Hamaguchi et al.(12) (2014) Retrospective 200 48/52 54 (18-69) HCC, 34%; HBV/HCV, 19%; PBC and PSC, 17%; BA, 10%; ALF (unknown), 4%; alcohol, 3%; metabolic, 3%; BCS, 2%; others, 8% 18 (5-55) 6 Izumi et al.(28) (2016) Retrospective 47 51/49 54 (26-66) PBC, 20%; FHF, 7%; HCC, 19%; HCV, 29%; HBV, 10%; NASH, 3%; alcohol, 5%; unknown, 2%; AIH, 2%; others, 3% 19 (5-48) 6 Kaido et al.(30) (2013) Retrospective 124 48/52 54 (19-69) HCC, 32%; HBV/HBC, 23%; PBC/PSC, 17%; alcohol, 5%; metabolic, 5%; BA, 4%; others, 14% 19 (7-41) 5 Krell et al.(33) (2013) Retrospective 207 62/38 52 ± 10 20 ± 7 6 Kim et al.(32) (2018) Retrospective 92 100/0 53 (50, 57) ≥20: 11% 7 Underwood et al.(39) (2015) Retrospective 348 62/38 52 ± 10 Itoh et al.(4) (2016) Retrospective 153 56/44 58 (34-70) Hammad et al.(27) (2017) Retrospective 200 48/52 Kamo et al.(5) (2018) Retrospective 277 48/52 HCV, 24%; HBV, 4%; HCC, 23%; alcohol, 13%; PSC, 9%; PBC, 7%; AIH, 5%; NASH, 3%; FHF, 2%; A1AD, 1%; Wilson’s disease, 1%; others, 8% HBV, 85%; HCV, 9%; alcohol, 3%; unknown, 3% 19 ± 8 5 HCC, 100% ≥15: 31% 7 54 (18-69) HCC, 34%, HCV/HBV, 19%; PBC/PSC, 17%; ALF, 4%; BA, 10%; metabolic, 3%; alcohol, 3%; BCS, 2%; others, 8% 18 (5-55) 7 54 (18-69) HCC, 27%; HBV/HCV, 22%; cholestatic, 20%; others, 31% 17 (4-55) 5 HCV, 36%; alcohol, 39%; HCC, 25% liveR tRAnsplAntAtiOn, vol. 25, no. 9, 2019 tABle 1. Continued Adult studies that assessed pre-LT sarcopenia on wait-list and post-LT outcomes 1427 Retrospective 795 71/29 54 ± 9 van Vugt et al.(41) (2018) Retrospective 224 67/33 56 (48, 62) Jeon et al.(29) (2015) Retrospective 145 80/20 50 ± 8 Tsien et al.(38) (2014) Prospective 53 77/23 57 ± 8 Prospective 72 53/47 55 (21-68) 16 ± 7 6 16 (11, 20) 6 HBV, 84% and/or HCC, 66% 14 ± 8 8 HCC, 64%; cirrhosis without HCC, 28%; cholestasis, 8% 13 ± 5 7 18 (6-41) 6 Alcohol, 62%; HBV and HCV, 10%; NASH, 6%; others, 22% Alcohol, 13%; HBV, 3%; HCV, 7%; PSC/PBC, 29%; HCC, 33%; cholangiocarcinoma, 1%; NASH, 3%; cryptogenic, 4%; AIH, 2%; other, 5% Adult studies that assessed longitudinal evolution of sarcopenia before and after LT Kaido et al.(31) (2017) HCV/HBV, 22%; HCC, 22%; PBC and PSC, 22%; alcohol, 10%; BA, 8%; NASH, 4%; others, 12% OOi et Al. | Engelmann et al.(23) (2018) 5 15 ± 6 21 ± 8 NA Alcohol, 23%; NASH, 53%; PSC, 24% Alcohol, 31%; HCV, 31%; NASH, 18%; HCC, 20% Alcohol, 30%; HCV, 22%; HBV, 17%; cryptogenic, 24%; others, 7% 54 ± 8 51 ± 11 Carias et al.(18) (2016) Choudhary et al.(20) (2015) NOTE: Data are expressed as mean ± SD or median (quartile 1, quartile 3) or median (range) or percentage (%). *Study quality was assessed by NOS based on 3 subscales (selection, comparability, and outcome) with a maximum score of 9. 57 ± 11 Retrospective Retrospective Retrospective Bergerson et al.(16) (2015) 40 69/31 84/16 | 182 82 65/35 1428 studies consistently illustrated an association of longer ICU stay and ventilator needs with sarcopenia. Postoperative complications, such as respiratory, renal, graft failure, and cardiac events, were investigated in 5 studies.(3,19,27,28,39) Of these, 4 studies showed a higher rate of these comorbid conditions in sarcopenic patients than nonsarcopenic patients,(3,27,28,39) whereas the other study reported that SO patients had a lower incidence of neurological, surgical, respiratory, and cardiovascular complications compared with those with sarcopenia alone.(27) The presence of sarcopenia has a small effect on increased total hospital cost (n = 1). 5 6 Study Quality* Liver Etiology (%) Age, years Reference Study Design n Sex, Male/ Female (%) tABle 1. Continued liveR tRAnsplAntAtiOn, september 2019 PELD/MELD OOi et Al. Review ARticle lOnGitUDinAl evOlUtiOn OF sARcOpeniA BeFORe AnD AFteR lt Of the 5 studies that assessed longitudinal evaluation of sarcopenia, 4 studies revealed an average 24% increment of post-LT sarcopenia prevalence as compared with pre-LT sarcopenia,(18,29,31,38) whereas 1 study showed a 25% reduction in sarcopenia prevalence after LT (Table 2).(16) Of these studies, 2 examined the association of post-LT sarcopenia on survival,(29,38) with 1 study illustrating increased mortality risk with newly developed post-LT sarcopenia (Table 3).(29) Only 1 study investigated post-LT SO and found higher incidence of cardiometabolic dysregulation (CMD) in those with SO.(20) peDiAtRics Three pediatric studies were available for review.(9,10,34) These studies included 23-41 infants and children, aged between 0.5 and 8 years old with biliary atresia (BA) as the most common indicator for LT (Table 1). There were 2 studies that examined children before LT(9,10) and 1 after LT.(34) Only 1 study was considered a high-quality study based on NOS.(34) Also, 2 studies investigated sarcopenia pre-LT using PMA obtained from L3/L4, L4/L5, and L2/L3 CT images.(9,10) These case-control studies demonstrated that children with ESLD have a lower SMM than healthy children, but no data were available regarding measures of muscle function/strength or perioperative and postoperative clinical outcomes.(9,10) One retrospective cohort study explored sarcopenia prevalence after LT (for up to 10 years) and examined associations with LT clinical outcomes.(34) Body composition was measured Body Composition Method Reference Muscle Measured Sarcopenia or SO Definition/Cutoff Time Frame of Body Composition Measurement Prevalence of Sarcopenia (%) Prevalence of SO (%) Pediatric studies that assessed preLT sarcopenia Lurz et al.(9) (2018) CT; L3/L4 and L4/L5 PMA Compared with controls (trauma patient with CT) NA NA NA Mangus et al.(10) (2017) CT; L2/L3 PMA Compared with controls (trauma patient with CT) 6 months before LT NA NA DEXA SMM SMM z score <–2 SD 1-13 years after LT 41 NA CT, L3 SMA Female <41 cm2/m2, male <53 cm2/m2 NA 45 NA CT, L3 SMA Female <39 cm2/m2, male <50 cm2/m2 3 months of listing 45 NA Tandon et al.(37) (2012) CT/MRI, L3 SMA Female <38.5 cm2/m2, male <52.4 cm2/m2 1.5 months of listing 41 NA Yadav et al.(43) (2015) CT, L3 SMA Female ≤38.5 cm2/m2, male ≤52.4 cm2/m2 6 months before LT 22 NA van Vugt et al.(40) (2018) CT, L3 SMA BMI ≥25 kg/m2: Female ≤41 cm2/m2 and male ≤53 cm2/m2 3 months of listing 43 NA Pediatric study that assessed post-LT sarcopenia on post-LT outcomes Mager et al.(34) (2019) Adult studies that assessed pre-LT sarcopenia on wait-list outcomes Montano-Loza et al.(11) (2015) Carey et al.(17) (2017) liveR tRAnsplAntAtiOn, vol. 25, no. 9, 2019 tABle 2. Definition and prevalence of sarcopenia in pediatric and Adult lt Articles BMI <25 kg/m2: ≤43 cm2/m2 Shirai et al.(36) (2018) Dolgin et al.(22) (2018) Wang et al.(42) (2016) CT, L3 PMA mean <–2 SD: Female 3.9 cm2/m2, male 6.4 cm2/m2 1-2 weeks before LT NA NA CT, L4 PMA >1 SD below average LPA* ≤3 months and ≥7 days before LT 50 NA Male 1488.4 mm2, female 974.8 mm2 BMI <25 kg/m2: Female <41 cm2/m2, male <43 cm2/m2 3 months before LT 38 NA CT, L3 SMA BMI ≥25 kg/m2: Male <53 cm2/m2 Review ARticle Adult studies that assessed pre-LT sarcopenia on post-LT outcomes DiMartini et al.(21) (2013) Masuda et al.(6) (2014) CT, L3/L4 SMA Female <38.5 cm2/m2, male <52.4 cm2/m2 80 days before LT 68 NA CT, L3 PMA <5th percentile 1 month before LT 47 NA Female ≤380 cm2, male ≤800 cm2 Aby et al.(15) (2018) CT/MRI, L3 PMA Female <1464 mm2, male <1561 mm2 6 months before LT 62 NA Englesbe et al.(24) (2010) CT, L4 PMA By quartile 3 months before LT NA NA Montano-Loza et al.(35) (2014) CT, L3 SMA 6 months before LT 45 NA Reference area 1.9 cm2 BMI ≥25 kg/m2: Female ≤41 cm2/m2, male ≤53 cm2/m2 BMI <25 kg/m2: ≤43 cm2/m2 SMA <75% SMA of healthy Japanese adults (sex-specific formula) and weak muscle strength (handgrip or gait speed) Before LT 24 NA Hamaguchi et al.(26) (2017) CT, L3 SMA <2 SD of mean Before LT 21 NA 1429 Female 30.9 cm2/m2, male 40.3 cm2/m2 OOi et Al. CT, L3 | Harimoto et al.(3) (2017) | Body Composition Method Reference Review ARticle Chae et al.(19) (2018) CT, L3/L4 Muscle Measured PMA Sarcopenia or SO Definition/Cutoff PMI change before LT to POD 7 Time Frame of Body Composition Measurement Prevalence of Sarcopenia (%) Prevalence of SO (%) 1 month before LT 25 NA OOi et Al. 1430 tABle 2. Continued Cutoff ≤25th quartile/<–11.7% Golse et al.(25) (2017) Kalafateli et al.(1) Hamaguchi et (2017) al.(12) (2014) CT, L3/L4 PMA Female 1464 mm2, male 1561 mm2 4 months before LT 22 NA CT, L3 PMA Lowest sex-stratified quartiles 25 NA Female 264 mm2/m2, male 340 mm2/m2 ≤3 months before LT/1 week after LT PMI 1-2 weeks before LT NA NA 2 months before LT NA NA Before LT 38 NA CT, UL PMA Female 4.1, male 6.9 Izumi et al.(28) (2016) CT, L3 PMA Less than the first quartile of PMI of the donors Female 442.9 mm2/m2, male 612.5 mm2/m2 Kaido et al.(30) (2013) Krell et al.(33) BIA SMM <90% of the standard value analyzed by BIA (2013) CT, L4 PMA Sex-specific lowest tertile 3 months before LT 33 NA Kim et al.(32) (2018) CT, L3 PMT <15.5 mm/m 2 months before LT 78 NA Underwood et al.(39) (2015) CT, L4 PMA Lowest tertile 3 months before LT 34 NA Itoh et al.(4) (2016) CT, L3 SMA SO: lowest quartile of SMM-to-VFA ratio Before LT NA 25 Hammad et al.(27) (2017) CT, UL PMA SO: BMI ≥25 kg/m2 and PMI <−2 SD below the mean of matched-sex young healthy LT donors 1-2 weeks before LT 36 5 Female <3.9 cm2/m2, male <6.4 cm2/m2 Kamo et al.(5) (2018) SMA SO: Female <30.9 cm2/m2, male <40.3 cm2/m2, and VFA ≥100 cm2 or BMI ≥25 kg/m2 1 month before LT NA 2-3 (based on VFA and BMI) CT, L3/L4 PSMA, AWMA, SMA Lower quartile 200 days of LT assessment NA NA 25 NA Before LT: 63, 13 months after LT: 87 NA Before LT: 36 NA Adult studies that assessed pre-LT sarcopenia on wait-list and post-LT outcomes Engelmann et al.(23) (2018) PSMI: female, 19.2 cm2/m2; male, 22.4 cm2/m2 AWMI: female, 15.0 cm2/m2, male, 18.5 cm2/m2 SMI: female, 35.3 cm2/m2, male, 41.9 cm2/m2 van Vugt et al.(41) (2018) CT, L3 SMA Lowest sex-specific quartile 3 months from listing Tsien et al.(38) (2014) CT, L4 SMA Sex- and age-specific 5th percentile Before and after LT Jeon et al.(29) (2015) CT, L4 PMA <5th percentile: Male: 7.7 cm2/m2 (20-50 years), 6.6 cm2/m2 (>50 years) 0.3 months before LT, 12 months after LT Adult studies that assessed longitudinal evolution of sarcopenia before and after LT Female: 4.6 cm2/m2 (20-50 years), 4.4 cm2/m2 (>50 years) 1 year after LT: 46 liveR tRAnsplAntAtiOn, september 2019 CT, L3 using DEXA.(34) The authors defined sarcopenia as SMM z scores <–2 and found that 41% of children had sarcopenia up to 8 years after LT (Table 2). This study showed a large effect size related to sarcopenia and perioperative LOS (ICU/total), ventilator dependency, poorer growth, and rehospitalization in the post-LT period (Table 3; Supporting Table 1).(34) None of the studies included functional measures as a part of sarcopenia assessment. SO was not identified in any of these cohorts. NA After LT: 88 Before LT: 42 1 year after LT: 100 NA *LPA = total psoas area × [mean density + 85]/170, units mm 2. SO: obesity class 1, 2, or 3 and sarcopenia Sarcopenia: muscle mass less than the normal range SO: BMI >25 kg/m2 and visceral fat mass greater than the normal range (normal range predetermined by BIA) BIA Choudhary et al.(20) (2015) Muscle mass Before LT: 59 3 months before LT Sarcopenia: muscle mass >2 SD below normal Female ≤38.5 cm2/m2, male ≤52.4 cm2/m2 CT, L3 Carias et al.(18) (2016) SMA After LT: 30 CT, L3 Bergerson et al.(16) (2015) SMA Female <38.5 cm2/m2, male <52.4 cm2/m2 Before and 12-48 months after LT Before LT: 55 NA NA Before LT: 14 SMM declined after LT Before and after LT <90% of lower limit of standard SMM (calculated based on sex and height by BIA) and low grip strength (male <26 kg, female <18 kg) SMM BIA Reference OOi et Al. Discussion Kaido et al.(31) (2017) Sarcopenia or SO Definition/Cutoff Muscle Measured Body Composition Method tABle 2. Continued Time Frame of Body Composition Measurement Prevalence of Sarcopenia (%) Prevalence of SO (%) liveR tRAnsplAntAtiOn, vol. 25, no. 9, 2019 Malnutrition and sarcopenia are common in adults with ESLD.(15) The present review indicates that the prevalence of sarcopenia in adults before and after LT ranged between 14% and 78% and between 30% and 100%, respectively. Obesity is common among adult sarcopenic patients and is also prevalent before LT (2%-42%) and after LT (88%). Sarcopenia may lead to higher mortality while on the waiting list. However, there are limited data on the effects of sarcopenia on infection risk, functional status, HRQoL, and pulmonary function before LT. In adults, sarcopenia was associated with increased postoperative mortality, complications, infection, and longer ICU stay and ventilator dependency. The implication of sarcopenia on total LOS is less consistent. There is insufficient evidence to conclude how pre- and post-LT SO impacts clinical outcomes as few studies have examined this issue. A single pediatric study revealed a high prevalence of sarcopenia after LT (41%) associated with poor growth, longer perioperative LOS (total/ICU) and ventilator dependency, and increased rehospitalization.(34) The wide range of sarcopenia prevalence and differences in outcomes are likely related to nonstandardized body composition approaches, the variability of cutoffs and definitions, and heterogeneity in liver disease types. The need to develop the liver disease population data with sex- and ethnicity-specific cutoffs for SMM is warranted. Recently, 2 studies proposed SMM cutoffs specifically for adults with ESLD, but larger studies are need before these cutoffs can be validated.(17,25) Variability in liver disease type is likely responsible for inconsistent findings related to LOS and sarcopenia, with the most consistent findings occurring in adults with HCV. One of the major challenges in understanding sarcopenia in adults and children before and after LT lies in the different methods used to diagnose low Review ARticle | 1431 Reference Mortality/Survival Infection LOS/Hospitalization Others | Review ARticle Pediatric study that assessed post-LT sarcopenia on post-LT outcomes Mager et al.(34) (2019) NA NA ↑hospital and ICU stay, readmission, readmission LOS ↓weight velocity SD scores, ↓weight z score/ height z score, ↑ventilator dependency, ↑emergency care Montano-Loza et al.(11) (2015) ↓survival NA NA NA Carey et al.(17) (2017) ↑wait-list mortality NA NA NA Tandon et al.(37) (2012) ↑wait-list mortality NA NA NA OOi et Al. 1432 tABle 3. clinical Outcomes of sarcopenia in pediatric and Adult lt Articles Adult studies that assessed pre-LT sarcopenia on wait-list outcomes Yadav et al.(43) (2015) Not a predictor of wait-list mortality NA NA ND in HRQoL van Vugt et al.(40) (2018) ↑1-month, 3-month, 1-year wait-list mortality NA NA NA Shirai et al.(36) (2018) NA NA NA ↓pulmonary function in males Dolgin et al.(22) (2018) NA NA NA ↑risk of being severely impaired functionally* Wang et al.(42) (2016) Muscle function† and quality‡ were associated with wait-list mortality, but not muscle mass NA NA NA DiMartini et al.(21) (2013) Predictor of survival only in males NA ↑hospital and ICU stay ↑ventilator dependency Masuda et al.(6) (2014) ↓OS, 3-year, 5-year survival ↑rate of sepsis NA NA Aby et al.(15) (2018) ND in 1-year survival/OS NA ND in hospital stay NA Adult studies that assessed pre-LT sarcopenia on post-LT outcomes ↑mortality NA NA NA Montano-Loza et al.(35) (2014) ND in survival ↑bacterial infection ↑hospital and ICU stay NA ↑postoperative complications§ ND in overall, viral, and fungal infections Harimoto et al.(3) (2017) ↑6-month mortality ↑postoperative sepsis ↑hospital stay Hamaguchi et al.(26) (2017) ↓OS NA NA NA Chae et al.(19) (2018) ↓OS ND in all-cause infection ND in hospital stay ↑ICU stay ND in complications,|| thrombosis, ↑ventilator duration Golse et al.(25) (2017) ↓3-month, 1-year, 5-year OS rates and ↑mortality ↑severe sepsis ND in hospital stay ↑ventilator need Kalafateli et al.(1) (2017) ↑1-year mortality (n = 10) ↑infection (n = 10) ↑hospital and ICU stay NA Hamaguchi et al.(12) (2014) ↓OS NA NA NA Izumi et al.(28) (2016) ↓4-month survival rates NA NA ↑complications¶ Kaido et al.(30) (2013) ↓OS NA NA NA ↑ICU stay liveR tRAnsplAntAtiOn, september 2019 Englesbe et al.(24) (2010) Reference Mortality/Survival Infection LOS/Hospitalization Others (Continues) Krell et al.(33) (2013) NA ↑infection NA NA Underwood et al.(39) (2015) NA ↑sepsis, bacterial infection NA ↑complication# and failure-to-rescue** rates ↓OS NA NA NA Sarcopenic patients had ↓OS than nonsarcopenic patients Sarcopenic patients had ↑bacteremia than nonsarcopenic patients NA Sarcopenic patients had ↑complications†† than nonsarcopenic patients SN patients had ↓OS than SO patients SO patients had ↓bacteremia than SN patients ↓1- and 5-year OS in SN and SO patients NA NA NA PSMI was a predictor for death within 1 year after LT listing Low PSMI predicted bacterial infection and SBP while on the waiting list NA NA NA NA ND in hospital stay ↑total hospital costs ND in pre-LT sarcopenia on mortality NA NA NA Itoh et al.(4) (2016) Hammad et al.(27) (2017) Kamo et al.(5) (2018) SO patients had ↓complications than SN patients Adult studies that assessed pre-LT sarcopenia on wait-list and post-LT outcomes Engelmann et al.(23) (2018) PSMI, SMI, and AWMI were not associated with 1-year post-LT survival van Vugt et al.(41) (2018) liveR tRAnsplAntAtiOn, vol. 25, no. 9, 2019 tABle 3. Continued Adult studies that assessed longitudinal evolution of sarcopenia before and after LT Tsien et al.(38) (2014) Post-LT sarcopenia had trend toward ↑mortality (P = 0.08) Review ARticle Jeon et al.(29) (2015) Newly developed sarcopenia after LT ↑mortality NA NA NA Kaido et al.(31) (2017) (pre-LT sarcopenia) ↓OS after LT NA NA NA Carias et al.(18) (2016) SO patients had a trend toward ↓survival (P = 0.40) NA NA NA NA NA NA SO patients had ↑metabolic syndrome‡‡ Choudhary et al.(20) (2015) 1433 OOi et Al. | *Severely impaired is indicated by Karnofsky performance status C. function indicated by grip strength and short physical performance battery. ‡Muscle quality defined by the mean Hounsfield units/fat infiltration for total SMA at L3. §Complications: complications of Clavien-Dindo grade 4, including amount of ascites and total bilirubin on POD 14. ||Complications included acute cellular rejection and biliary complications. ¶Complications defined as grade ≥3 according to the Clavien-Dindo classification (condition requiring surgical, endoscopic, or radiological intervention). # Complications included renal failure, sepsis, bacterial infection, multisystem organ failure, bleeding, bile leak, pneumonia, respiratory failure, cardiac event, biliary stricture, graft failure, thrombosis, Clostridium difficile infection, acute rejection, and pulmonary embolus. **Failure to rescue; if patient experienced 1 of the complications# within 1 year of LT and died within 1 year of LT. †† Complications defined as Clavien-Dindo score of ≥3a, includes neurological, surgical, respiratory, cardiovascular, and vascular complications. ‡‡Metabolic syndrome defined as ≥3 Adult Treatment Panel III criteria. †Muscle OOi et Al. SMM. Imaging (CT/MRI) is often performed during LT assessment and routine follow-up and, therefore, may be opportunistically applied to evaluate SMM in pediatric and adult liver populations without additional cost and radiation risk. MRI and CT are cited as the gold standard for body composition assessment, and they can be used interchangeably to quantify SMM.(2,45) The major limitation of CT is the radiation exposure, particularly in pediatrics.(46) MRI does not involve radiation, but the high cost and the need for trained analysts may limit serial measurements.(46) Other considerations include inconsistencies in landmarks (L3-L5), muscle type/number used to measure SMM, and the potential impact of changes in total body fluid status associated with advanced liver disease influencing estimates of SMM measures. Some studies indicate that L3 should be used as the landmark because this will result in better representations of whole body SMM. However, others have used L4 as a landmark.(47) Furthermore, other studies have cited SMM area as a more complete measure than PMA alone because it is closely related to total body protein and wait-list mortality.(48,49) PMT as an alternative indicator to assess for sarcopenia has also been proposed, but it requires further validation.(32) Use of cross-sectional CT/MRI, segmental DEXA using appendicular measures, and phase angle BIA have been shown to be less influenced by overhydration than whole body measures.(50-52) Although ascites may be a confounding factor in determinations of SMM, recent studies indicate that total body fluid status rather than the presence of ascites may be the determining factor.(49) Although DEXA and BIA have been reported to overestimate muscle mass due to the assumption of constant tissue hydration, use of these methods may be clinically warranted to assess for sarcopenia when CT/MRI are unavailable.(46,51,53) MRI, in particular, confers the added benefit of no radiation exposure.(46) In children, exposure to additional radiation imposed by a DEXA scan and the requirement for sedation in young children (<3 years) may outweigh the benefits of using DEXA to measure SMM. Although emerging normative data for body composition analysis using CT exists (1-20 years),(54) at present, there is no known pediatric normative data for MRI, and there is a lack of data for infants and children <18 months for DEXA. On the basis of this evidence, we propose a review of SMM using CT/MRI (where available) in children and adults with cirrhosis awaiting LT at time of LT assessment (grade B-C). For longitudinal evaluation of 1434 | Review ARticle liveR tRAnsplAntAtiOn, september 2019 bone health/body composition, we recommend using either cross-sectional/segmental DEXA on an annual basis for children (>3 years) and adults before and after LT (grade B-C). For children <3 years, there is an urgent need to develop population reference standards for determination of SMM (grade B). The EWGSOP defined sarcopenia as progressive and generalized loss of SMM and muscle function (strength or performance).(2) Because a measure of muscle function is lacking in most of the adult and pediatric studies, the presence of sarcopenia may not be adequately captured because low muscle mass is not always equivalent to low muscle strength.(2) This is particularly crucial in ESLD patients because they experience significant impairments associated with fatigue, muscle weakness, and fluid overload.(55) In children, functional impairment has been associated with higher wait-list and post-LT mortality, highlighting the importance of a thorough assessment of muscle functionality.(56) We recommend a minimum of 2 muscle tests to assess muscle function because impairments may not be captured with single measurement.(57,58) In adults and children (6-18 years), the use of validated and easy to perform tests, such as the hand grip and sit-to-stand tests, would enable the assessment of muscle strength.(59) Additional tests, such as the 6-minute walk test, Timed Up and Go, sit-to-stand, or stair climb tests, can be used to determine physical performance,(2,59) but they may be more difficult to perform in individuals with advanced ascites (grade B-C). These tests may be beneficial in identifying muscle functional deficits in adults with severe sarcopenia.(59) In younger children (<3 years), considerations of gross and fine motor skills to assess muscle function/strength are warranted. Tools used include the validated Alberta Infant Motor Scale and the Peabody Developmental Motor Scale (grade B-C).(60) Sarcopenia assessment in children should also include a comprehensive evaluation of growth, as significant differences in growth (z scores <–1.5) in children with sarcopenia were observed (grade C-D).(34) Important confounding factors on sarcopenia prevalence/expression in adults and children are sex, age, race, and liver disease etiology. Adults males have a higher incidence of sarcopenia than females after LT.(11,18,29,35) However, adult females were found to have worse outcomes associated with sarcopenia as compared with males after LT.(17) This may due to the earlier age of sarcopenia presentation in women induced by menopausal hormonal changes. These changes may rapidly liveR tRAnsplAntAtiOn, vol. 25, no. 9, 2019 and adversely influence protein turnover over shorter periods than in males where declines in testosterone may induce slower changes.(61) In contrast, female children (<10 years) after LT had a higher sarcopenia prevalence than older females.(34) Although there are limited data addressing sex differences in pediatrics, lower lean mass in young females during early life (1 year) and higher proteolysis and protein oxidation in prepuberty children may be contributing factors to increased expression of sarcopenia in young female children with chronic disease.(62,63) Healthy adults of Asian ancestry were found to have a higher risk of developing sarcopenia than Caucasians given the lower baseline SMM and lifestyle (diet and physical activity [PA]) differences.(57) Differences in sarcopenia prevalence may be due to variations in liver disease severity and/or the emergence of comorbid diseases, such as coinciding IBD with primary sclerosing cholangitis (PSC). Studies with body composition measurements taken closer to LT are likely to represent sicker patients with higher MELD scores, hence leading to a higher prevalence of sarcopenia.(21,32) More information relating preoperative clinical variables (eg, nutrition therapy and muscle function) and their impact on postoperative outcomes are needed. Preoperative nutrition and postoperative early enteral nutrition are reported to be beneficial in reducing mortality and sepsis in sarcopenic LT recipients.(6,30) Studies in children indicate that branched-chain amino acid (BCAA) requirements before and after LT are significantly higher than in OOi et Al. healthy children, indicating that BCAA supplementation to treat sarcopenia may be warranted.(64) LT corrects biochemical and metabolic abnormalities without improving sarcopenia for at least a year.(18,29,31,38) One study reported sarcopenia improved after LT.(16) These differences could be due to the exclusion of patients with confounding conditions (eg, infection and kidney failure) that may potentially contribute to postoperative SMM loss and/or the potential reversal of sarcopenia after LT.(16) The mechanism of post-LT sarcopenia is not currently well understood, with some data suggesting immunosuppressants, inflammation (eg, postoperative sepsis), and physical inactivity as contributing factors.(16,29) Sarcopenia before and after LT seems to share similar cellular mechanisms even though the underlying contributing factors may differ (Fig. 2). The common pathways are up-regulation of myostatin expression and inhibition on mammalian target of rapamycin (mTOR) signaling leading to a reduction in protein synthesis.(65,66) Concurrently, activation of the ubiquitin-proteasome pathway (UPP) by corticosteroid, inflammation, and physical inactivity has caused protein degradation.(65,66) The emerging data demonstrated that sarcopenia appears to wax and wane through the pre- and post-LT period,(16,38) which may be related to alterations to the immunosuppressive regimen or to inflammation. Future studies are needed to understand the mechanism of persistent sarcopenia before targeted longterm interventions can be developed. FiG. 2. Mechanisms of sarcopenia before and after LT in skeletal muscle. Review ARticle | 1435 OOi et Al. The diagnosis of SO is not standardized and may occur across a wide range of body fat habitus. This can be problematic in patients with fluid accumulation and could impact conclusions regarding the effects of SO on perioperative and postoperative outcomes. Although the relative risk of CMD has been associated with SO in adults after LT,(20) research is needed to determine whether SO is a feature of pediatric liver disease and CMD risk. We recommend early evaluation of lifestyle factors (eg, diet and PA) and body composition in children before and after LT that would be performed on an annual basis (grade C). This review has some limitations. The heterogeneous liver population reviewed limits the ability to distinguish the association between specific liver disease types on sarcopenia prevalence and outcomes. Conclusions could not be drawn on outcomes associated with SO and post-LT sarcopenia due to limited findings and inconsistent methodology approaches in the sarcopenia diagnosis. In pediatrics, there are limited data addressing sarcopenia. Despite these limitations, this is the first review that synthesized data related to sarcopenia and SO in adult and pediatric patients before and after LT and may serve as a foundation for future studies. In conclusion, this review found that sarcopenia in ESLD adults is highly prevalent and is associated with adverse outcomes before and after LT. To define sarcopenia, methodological considerations in the sarcopenia diagnosis and consistency in the approaches to assess body composition and muscle function are warranted. The emerging longitudinal data illustrate that sarcopenia in the post-LT period may wax and wane in its presentation, which may, in part, be related to changes in immunosuppression and highlight the need for ongoing screening and evaluation. In pediatrics, the presence of sarcopenia is an emerging and important finding that has implications for pre- and post-LT outcomes and, hence, warrants further investigation. 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