sarcopenia in chronic liver disease: impact on …...sarcopenia in chronic liver disease: impact on...

1422 | Review ARticle

REVIEW ARTICLE

Sarcopenia in Chronic Liver Disease: Impact on OutcomesPoh 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 1Agricultural, 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 post-LT 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 popu-lation, 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 alter-ations in dietary intake, hypermetabolism, and nutri-ent absorption and utilization.(1) Sarcopenia represents

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 sarco-penia 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 lon-gitudinal 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, inflamma-tory bowel disease [IBD], or intestinal failure) and

OOi et Al.

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;

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liveR tRAnsplAntAtiOn, vol. 25, no. 9, 2019 OOi et Al.

Review ARticle | 1423

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 tech-niques (computed tomography [CT] and magnetic resonance imaging [MRI]) have enabled the appli-cation of these methods for body composition assess-ment for patients with ESLD. These measures offer an objective measure of nutritional status and body

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 grow-ing 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 function-ality are warranted. This review evaluates the litera-ture 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 MethodsseARcH stRAteGYA literature search was completed via PubMed and Web of Science databases up to December 2018 using a systematic approach. The terms “sarcopenia,” “sar-copenic obesity,” “muscle depletion,” “muscle loss,” “reduced skeletal muscle mass,” “low muscle mass,” “reduced muscle strength” or “muscle function,” “an-thropometry,” “obesity,” “clinical outcome,” “out-comes,” “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 cRiteRiAThe inclusion criteria were primary studies that as-sessed 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 asso-ciated with sarcopenia or SO were included. All types of study designs and ESLD diagnoses were included. Articles were excluded if they were review articles, ed-itorial 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 pop-ulations with other types of transplantations and articles that did not address the concept of sarcopenia or SO were excluded at screening.

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 End-Stage 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: 780-492-2011; 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.

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OOi et Al. liveR tRAnsplAntAtiOn, september 2019


Study quality was assessed using the Newcastle-Ottawa scale (NOS).(13) The scale evaluates 3 subscales (selection of cohorts, comparability of groups, and out-come 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.

ResultsThe 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)

ADUltsThe majority of studies (n = 29/35) focused on pre-LT sarcopenia, which included stud-ies 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 retrospec-tively (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 ma-jority 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.



between body composition measurement and LT var-ied 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 inconsisten-cies 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 sar-copenia,(3-5,11,16-18,21,26,35,37,38,40-43) whereas 44% (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 mus-cle mass area [PSMA], abdominal wall muscle area [AWMA], and SMA) in defining sarcopenia,(23) whereas another study measured psoas muscle thick-ness (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 stud-ies (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 abdo-men pain (n = 1)(38) in defining sarcopenia.

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 adjust-ment 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 OUtcOMesOf 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 sarcope-nia 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 OUtcOMesOf the 20 studies that assessed pre-LT sarcopenia on postoperative mortality, 75% (n = 15/20) reported an association of sarcopenia with higher post-LT mortal-ity risk (Table 3).(1,3-6,12,19,21,24-28,30,31) In those stud-ies 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 exam-ined infection and showed a greater risk in sarcopenic liver recipients(1,3,6,25,27,33,35,39) compared with nonsar-copenic 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 hospital-ization, 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) demon-strating 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



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14%

19 (7

-41)

5

Krel

l et a

l.(33)

(201

3)Re

trosp

ectiv

e20

762

/38

52 ±

10

HCV,

24%

; HBV

, 4%

; HCC

, 23%

; alc

ohol

, 13%

; PSC

, 9%

; PBC

, 7%

; AIH

, 5%

; NAS

H, 3

%; F

HF, 2

%; A

1AD,

1%

; Wils

on’s

di

seas

e, 1

%; o

ther

s, 8

%

20 ±

76

Kim

et a

l.(32)

(201

8)Re

trosp

ectiv

e92

100/

053

(50,

57)

HBV,

85%

; HCV

, 9%

; alc

ohol

, 3%

; unk

now

n, 3

%≥2

0: 1

1%7

Unde

rwoo

d et

al.(3

9) (2

015)

Retro

spec

tive

348

62/3

852

± 1

0HC

V, 3

6%; a

lcoh

ol, 3

9%; H

CC, 2

5%19

± 8

5

Itoh

et a

l.(4) (

2016

)Re

trosp

ectiv

e15

356

/44

58 (3

4-70

)HC

C, 1

00%

≥15:

31%

7

Ham

mad

et a

l.(27)

(201

7)Re

trosp

ectiv

e20

048

/52

54 (1

8-69

)HC

C, 3

4%, H

CV/H

BV, 1

9%; P

BC/P

SC, 1

7%; A

LF, 4

%; B

A, 1

0%;

met

abol

ic, 3

%; a

lcoh

ol, 3

%; B

CS, 2

%; o

ther

s, 8

%18

(5-5

5)7

Kam

o et

al.(5

) (20

18)

Retro

spec

tive

277

48/5

254

(18-

69)

HCC,

27%

; HBV

/HCV

, 22%

; cho

lest

atic

, 20%

; oth

ers,

31%

17 (4

-55)

5

Adul

t stu

dies

that

ass

esse

d pr

e-LT

sa

rcop

enia

on

wai

t-lis

t and

pos

t-LT

outc

omes

Enge

lman

n et

al.(2

3) (2

018)

Retro

spec

tive

795

71/2

954

± 9

Alco

hol,

62%

; HBV

and

HCV

, 10%

; NAS

H, 6

%; o

ther

s, 2

2%16

± 7

6

van

Vugt

et a

l.(41)

(201

8)Re

trosp

ectiv

e22

467

/33

56 (4

8, 6

2)Al

coho

l, 13

%; H

BV, 3

%; H

CV, 7

%; P

SC/P

BC, 2

9%; H

CC, 3

3%;

chol

angi

ocar

cino

ma,

1%

; NAS

H, 3

%; c

rypt

ogen

ic, 4

%; A

IH,

2%; o

ther

, 5%

16 (1

1, 2

0)6

Adul

t stu

dies

that

ass

esse

d lo

ngitu

dina

l ev

olut

ion

of s

arco

peni

a be

fore

and

af

ter L

T

Jeon

et a

l.(29)

(201

5)Re

trosp

ectiv

e14

580

/20

50 ±

8HB

V, 8

4% a

nd/o

r HCC

, 66%

14 ±

88

Tsie

n et

al.(3

8) (2

014)

Pros

pect

ive

5377

/23

57 ±

8HC

C, 6

4%; c

irrho

sis w

ithou

t HCC

, 28%

; cho

lest

asis

, 8%

13 ±

57

Kaid

o et

al.(3

1) (2

017)

Pros

pect

ive

7253

/47

55 (2

1-68

)HC

V/HB

V, 2

2%; H

CC, 2

2%; P

BC a

nd P

SC, 2

2%; a

lcoh

ol, 1

0%;

BA, 8

%; N

ASH,

4%

; oth

ers,

12%

18 (6

-41)

6

tA

Bl

e 1

. Co

ntinued



studies consistently illustrated an association of longer ICU stay and ventilator needs with sarco-penia. Postoperative complications, such as respi-ratory, 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 con-ditions in sarcopenic patients than nonsarcopenic patients,(3,27,28,39) whereas the other study reported that SO patients had a lower incidence of neuro-logical, surgical, respiratory, and cardiovascular complications compared with those with sarcope-nia alone.(27) The presence of sarcopenia has a small effect on increased total hospital cost (n = 1).

lOnGitUDinAl evOlUtiOn OF sARcOpeniA BeFORe AnD AFteR ltOf the 5 studies that assessed longitudinal evaluation of sarcopenia, 4 studies revealed an average 24% incre-ment 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 as-sociation 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 in-cidence of cardiometabolic dysregulation (CMD) in those with SO.(20)

peDiAtRicsThree 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 chil-dren with ESLD have a lower SMM than healthy children, but no data were available regarding mea-sures 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

Refe

renc

eSt

udy D

esig

nn

Sex,

Mal

e/Fe

mal

e (%

)Ag

e, ye

ars

Live

r Etio

logy

(%)

PELD

/MEL

DSt

udy Q

ualit

y*

Berg

erso

n et

al.(1

6) (2

015)

Retro

spec

tive

4065

/35

57 ±

11

Alco

hol,

23%

; NAS

H, 5

3%; P

SC, 2

4%15

± 6

5

Caria

s et

al.(1

8) (2

016)

Retro

spec

tive

182

69/3

154

± 8

Alco

hol,

31%

; HCV

, 31%

; NAS

H, 1

8%; H

CC, 2

0%21

± 8

5Ch

oudh

ary

et a

l.(20)

(201

5)Re

trosp

ectiv

e82

84/1

651

± 1

1Al

coho

l, 30

%; H

CV, 2

2%; H

BV, 1

7%; c

rypt

ogen

ic, 2

4%; o

ther

s,

7%N

A6

NO

TE:

Dat

a are

exp

ress

ed a

s mea

n ±

SD

or m

edia

n (q

uart

ile 1

, qua

rtile

3) o

r med

ian

(rang

e) o

r per

cent

age (

%).

*Stu

dy q

ualit

y was

ass

esse

d by

NO

S ba

sed

on 3

subs

cale

s (se

lect

ion,

com

para

bilit

y, an

d ou

tcom

e) w

ith a

max

imum

scor

e of 9

.

tA

Bl

e 1

. Co

ntinued



tA

Bl

e 2

. D

efin

ition

and

pre

vale

nce

of s

arco

peni

a in

ped

iatr

ic a

nd A

dult

lt A

rtic

les

Refe

renc

e

Body

Co

mpo

sitio

n M

etho

dM

uscl

e M

easu

red

Sarc

open

ia o

r SO

Def

initi

on/C

utof

f

Tim

e Fr

ame

of

Body

Com

posi

tion

Mea

sure

men

tPr

eval

ence

of

Sarc

open

ia (%

)Pr

eval

ence

of

SO (%

)

Pedi

atric

stu

dies

that

ass

esse

d pr

e-LT

sar

cope

nia

Lurz

et a

l.(9) (

2018

)CT

; L3/

L4 a

nd

L4/L

5PM

ACo

mpa

red

with

con

trols

(tra

uma

patie

nt w

ith C

T)N

AN

AN

A

Man

gus

et a

l.(10)

(201

7)CT

; L2/

L3PM

ACo

mpa

red

with

con

trols

(tra

uma

patie

nt w

ith C

T)6

mon

ths b

efor

e LT

NA

NA

Pedi

atric

stu

dy th

at a

sses

sed

post

-LT

sarc

open

ia o

n po

st-L

T ou

tcom

es

Mag

er e

t al.(3

4) (2

019)

DEXA

SMM

SMM

z sc

ore

<–2

SD1-

13 ye

ars a

fter L

T41

NA

Adul

t stu

dies

that

ass

esse

d pr

e-LT

sa

rcop

enia

on

wai

t-lis

t out

com

es

Mon

tano

-Loz

a et

al.(1

1) (2

015)

CT, L

3SM

AFe

mal

e <4

1 cm

2 /m

2 , m

ale

<53

cm

2 /m

2N

A45

NA

Care

y et

al.(1

7) (2

017)

CT, L

3SM

AFe

mal

e <3

9 cm

2 /m

2 , m

ale

<50

cm

2 /m

23

mon

ths o

f lis

ting

45N

A

Tand

on e

t al.(3

7) (2

012)

CT/M

RI, L

3SM

AFe

mal

e <3

8.5

cm2 /

m2 ,

mal

e <

52.4

cm

2 /m

21.

5 m

onth

s of l

istin

g41

NA

Yada

v et

al.(4

3) (2

015)

CT, L

3SM

AFe

mal

e ≤

38.5

cm

2 /m

2 , m

ale

≤52

.4 c

m2 /

m2

6 m

onth

s bef

ore

LT22

NA

van

Vugt

et a

l.(40)

(201

8)CT

, L3

SMA

BMI ≥

25 kg

/m2 :

Fem

ale

≤41

cm

2 /m

2 and

mal

e ≤

53 c

m2 /

m2

3 m

onth

s of l

istin

g43

NA

BMI <

25 kg

/m2 :

≤43

cm

2 /m

2

Shira

i et a

l.(36)

(201

8)CT

, L3

PMA

mea

n <–

2 SD

: Fem

ale

3.9

cm2 /

m2 ,

mal

e 6.

4 cm

2 /m

21-

2 w

eeks

bef

ore

LTN

AN

A

Dolg

in e

t al.(2

2) (2

018)

CT, L

4PM

A>1

SD

belo

w a

vera

ge LP

A*≤

3 m

onth

s and

≥7

days

bef

ore

LT50

NA

Mal

e 14

88.4

mm

2 , fe

mal

e 97

4.8

mm

2

Wan

g et

al.(4

2) (2

016)

CT, L

3SM

ABM

I <25

kg/m

2 : F

emal

e <4

1 cm

2 /m

2 , m

ale

<43

cm2 /

m2

3 m

onth

s bef

ore

LT38

NA

BMI ≥

25 kg

/m2 :

Mal

e <

53 c

m2 /

m2

Adul

t stu

dies

that

ass

esse

d pr

e-LT

sa

rcop

enia

on

post

-LT

outc

omes

DiM

artin

i et a

l.(21)

(201

3)CT

, L3/

L4SM

AFe

mal

e <3

8.5

cm2 /

m2 ,

mal

e <

52.4

cm

2 /m

280

day

s bef

ore

LT68

NA

Mas

uda

et a

l.(6) (

2014

)CT

, L3

PMA

<5t

h pe

rcen

tile

1 m

onth

bef

ore

LT47

NA

Fem

ale

≤38

0 cm

2 , m

ale

≤80

0 cm

2

Aby

et a

l.(15)

(201

8)CT

/MRI

, L3

PMA

Fem

ale

<146

4 m

m2 ,

mal

e <1

561

mm

26

mon

ths b

efor

e LT

62N

A

Engl

esbe

et a

l.(24)

(201

0)CT

, L4

PMA

By q

uarti

le3

mon

ths b

efor

e LT

NA

NA

Refe

renc

e ar

ea 1

.9 c

m2

Mon

tano

-Loz

a et

al.(3

5) (2

014)

CT, L

3SM

ABM

I ≥25

kg/m

2 : F

emal

e ≤

41 c

m2 /

m2 ,

mal

e ≤

53 c

m2 /

m2

6 m

onth

s bef

ore

LT45

NA

BMI <

25 kg

/m2 :

≤43

cm

2 /m

2

Harim

oto

et a

l.(3) (

2017

)CT

, L3

SMA

<75%

SM

A of

hea

lthy J

apan

ese

adul

ts (s

ex-s

peci

fic fo

rmul

a)

and

wea

k mus

cle

stre

ngth

(han

dgrip

or g

ait s

peed

)Be

fore

LT24

NA

Ham

aguc

hi e

t al.(2

6) (2

017)

CT, L

3SM

A<

2 SD

of m

ean

Befo

re LT

21N

A

Fem

ale

30.9

cm

2 /m

2 , m

ale

40.3

cm

2 /m

2



Refe

renc

e

Body

Co

mpo

sitio

n M

etho

dM

uscl

e M

easu

red

Sarc

open

ia o

r SO

Def

initi

on/C

utof

f

Tim

e Fr

ame

of

Body

Com

posi

tion

Mea

sure

men

tPr

eval

ence

of

Sarc

open

ia (%

)Pr

eval

ence

of

SO (%

)

Chae

et a

l.(19)

(201

8)CT

, L3/

L4PM

APM

I cha

nge

befo

re LT

to P

OD

71

mon

th b

efor

e LT

25N

A

Cuto

ff ≤

25th

qua

rtile

/<–1

1.7%

Gol

se e

t al.(2

5) (2

017)

CT, L

3/L4

PMA

Fem

ale

1464

mm

2 , m

ale

1561

mm

24

mon

ths b

efor

e LT

22N

A

Kala

fate

li et

al.(1

) (20

17)

CT, L

3PM

ALo

wes

t sex

-stra

tifie

d qu

artil

es≤

3 m

onth

s bef

ore

LT/1

w

eek a

fter L

T25

NA

Fem

ale

264

mm

2 /m

2 , m

ale

340

mm

2 /m

2

Ham

aguc

hi e

t al.(1

2) (2

014)

CT, U

LPM

APM

I1-

2 w

eeks

bef

ore

LTN

AN

A

Fem

ale

4.1,

mal

e 6.

9

Izum

i et a

l.(28)

(201

6)CT

, L3

PMA

Less

than

the

first

qua

rtile

of P

MI o

f the

don

ors

2 m

onth

s bef

ore

LTN

AN

A

Fem

ale

442.

9 m

m2 /

m2 ,

mal

e 61

2.5

mm

2 /m

2

Kaid

o et

al.(3

0) (2

013)

BIA

SMM

<90

% o

f the

sta

ndar

d va

lue

anal

yzed

by B

IABe

fore

LT38

NA

Krel

l et a

l.(33)

(201

3)CT

, L4

PMA

Sex-

spec

ific

low

est t

ertil

e3

mon

ths b

efor

e LT

33N

A

Kim

et a

l.(32)

(201

8)CT

, L3

PMT

<15.

5 m

m/m

2 m

onth

s bef

ore

LT78

NA

Unde

rwoo

d et

al.(3

9) (2

015)

CT, L

4PM

ALo

wes

t ter

tile

3 m

onth

s bef

ore

LT34

NA

Itoh

et a

l.(4) (

2016

)CT

, L3

SMA

SO: l

owes

t qua

rtile

of S

MM

-to-V

FA ra

tioBe

fore

LTN

A25

Ham

mad

et a

l.(27)

(201

7)CT

, UL

PMA

SO: B

MI ≥

25 kg

/m2 a

nd P

MI <

−2 S

D be

low

the

mea

n of

m

atch

ed-s

ex yo

ung

heal

thy L

T don

ors

1-2

wee

ks b

efor

e LT

365

Fem

ale

<3.9

cm

2 /m

2 , m

ale

<6.4

cm

2 /m

2

Kam

o et

al.(5

) (20

18)

CT, L

3SM

ASO

: Fem

ale

<30.

9 cm

2 /m

2 , m

ale

<40.

3 cm

2 /m

2 , a

nd V

FA

≥100

cm

2 or B

MI ≥

25 kg

/m2

1 m

onth

bef

ore

LTN

A2-

3 (b

ased

on

VFA

and

BMI)

Adul

t stu

dies

that

ass

esse

d pr

e-LT

sa

rcop

enia

on

wai

t-lis

t and

pos

t-LT

outc

omes

Enge

lman

n et

al.(2

3) (2

018)

CT, L

3/L4

PSM

A,

AWM

A,

SMA

Low

er q

uarti

le20

0 da

ys o

f LT

asse

ssm

ent

NA

NA

PSM

I: fe

mal

e, 1

9.2

cm2 /

m2 ;

mal

e, 2

2.4

cm2 /

m2

AWM

I: fe

mal

e, 1

5.0

cm2 /

m2 ,

mal

e, 1

8.5

cm2 /

m2

SMI:

fem

ale,

35.

3 cm

2 /m

2 , m

ale,

41.

9 cm

2 /m

2

van

Vugt

et a

l.(41)

(201

8)CT

, L3

SMA

Low

est s

ex-s

peci

fic q

uarti

le3

mon

ths f

rom

list

ing

25N

A

Adul

t stu

dies

that

ass

esse

d

long

itudi

nal e

volu

tion

of

sarc

open

ia b

efor

e an

d af

ter L

T

Tsie

n et

al.(3

8) (2

014)

CT, L

4SM

ASe

x- a

nd a

ge-s

peci

fic 5

th p

erce

ntile

Befo

re a

nd a

fter L

TBe

fore

LT: 6

3, 1

3 m

onth

s afte

r LT

: 87

NA

Jeon

et a

l.(29)

(201

5)CT

, L4

PMA

<5t

h pe

rcen

tile:

Mal

e: 7

.7 c

m2 /

m2 (

20-5

0 ye

ars)

, 6.

6 cm

2 /m

2 (>

50 ye

ars)

0.3

mon

ths b

efor

e LT

, 12

mon

ths a

fter L

TBe

fore

LT: 3

6N

A

Fem

ale:

4.6

cm

2 /m

2 (20

-50

year

s), 4

.4 c

m2 /

m2 (

>50

year

s)1

year

afte

r LT:

46

tA

Bl

e 2

. Co

ntinued



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 depen-dency, 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.

DiscussionMalnutrition 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 pul-monary function before LT. In adults, sarcopenia was associated with increased postoperative mortality, com-plications, infection, and longer ICU stay and ventila-tor 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 sar-copenia 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 differ-ences in outcomes are likely related to nonstandardized body composition approaches, the variability of cut-offs 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 cut-offs specifically for adults with ESLD, but larger stud-ies 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 sar-copenia in adults and children before and after LT lies in the different methods used to diagnose low Re

fere

nce

Body

Co

mpo

sitio

n M

etho

dM

uscl

e M

easu

red

Sarc

open

ia o

r SO

Def

initi

on/C

utof

f

Tim

e Fr

ame

of

Body

Com

posi

tion

Mea

sure

men

tPr

eval

ence

of

Sarc

open

ia (%

)Pr

eval

ence

of

SO (%

)

Kaid

o et

al.(3

1) (2

017)

BIA

SMM

<90

% o

f low

er li

mit

of s

tand

ard

SMM

(cal

cula

ted

base

d on

se

x and

hei

ght b

y BIA

) and

low

grip

stre

ngth

(mal

e <

26

kg, f

emal

e <1

8 kg

)

Befo

re a

nd a

fter L

TBe

fore

LT: 1

4N

A

SMM

dec

lined

af

ter L

T

Berg

erso

n et

al.(1

6) (2

015)

CT, L

3SM

AFe

mal

e <3

8.5

cm2 /

m2 ,

mal

e <

52.4

cm

2 /m

2Be

fore

and

12-

48

mon

ths a

fter L

TBe

fore

LT: 5

5N

A

Afte

r LT:

30

Caria

s et

al.(1

8) (2

016)

CT, L

3SM

ASa

rcop

enia

: mus

cle

mas

s >2

SD b

elow

nor

mal

3 m

onth

s bef

ore

LTBe

fore

LT: 5

9Be

fore

LT: 4

2

Fem

ale

≤38

.5 c

m2 /

m2 ,

mal

e ≤

52.4

cm

2 /m

21

year

afte

r LT

: 100

SO: o

besi

ty c

lass

1, 2

, or 3

and

sar

cope

nia

Chou

dhar

y et

al.(2

0) (2

015)

BIA

Mus

cle

mas

sSa

rcop

enia

: mus

cle

mas

s les

s tha

n th

e no

rmal

rang

eN

AN

AAf

ter L

T: 8

8

SO: B

MI >

25 kg

/m2 a

nd vi

scer

al fa

t mas

s gre

ater

than

the

norm

al ra

nge

(nor

mal

rang

e pr

edet

erm

ined

by B

IA)

*LPA

= to

tal p

soas

are

a × [m

ean

dens

ity +

85]

/170

, uni

ts m

m2 .

tA

Bl

e 2

. Co

ntinued



tA

Bl

e 3

. c

linic

al O

utco

mes

of s

arco

peni

a in

ped

iatr

ic a

nd A

dult

lt A

rtic

les

Refe

renc

eM

orta

lity/

Surv

ival

Infe

ctio

nLO

S/Ho

spita

lizat

ion

Oth

ers

Pedi

atric

stu

dy th

at a

sses

sed

post

-LT

sarc

open

ia o

n po

st-L

T ou

tcom

es

Mag

er e

t al.(3

4) (2

019)

NA

NA

↑hos

pita

l and

ICU

stay

, re

adm

issi

on, r

eadm

issi

on LO

S↓w

eigh

t vel

ocity

SD

scor

es, ↓

wei

ght z

sco

re/

heig

ht z

scor

e, ↑

vent

ilato

r dep

ende

ncy,

↑e

mer

genc

y car

e

Adul

t stu

dies

that

ass

esse

d pr

e-LT

sa

rcop

enia

on

wai

t-lis

t out

com

es

Mon

tano

-Loz

a et

al.(1

1) (2

015)

↓sur

viva

lN

AN

AN

A

Care

y et

al.(1

7) (2

017)

↑wai

t-lis

t mor

talit

yN

AN

AN

A

Tand

on e

t al.(3

7) (2

012)

↑wai

t-lis

t mor

talit

yN

AN

AN

A

Yada

v et

al.(4

3) (2

015)

Not

a p

redi

ctor

of w

ait-l

ist m

orta

lity

NA

NA

ND

in H

RQoL

van

Vugt

et a

l.(40)

(201

8)↑1

-mon

th, 3

-mon

th, 1

-yea

r wai

t-lis

t m

orta

lity

NA

NA

NA

Shira

i et a

l.(36)

(201

8)N

AN

AN

A↓p

ulm

onar

y fun

ctio

n in

mal

es

Dolg

in e

t al.(2

2) (2

018)

NA

NA

NA

↑ris

k of b

eing

sev

erel

y im

paire

d fu

nctio

nally

*

Wan

g et

al.(4

2) (2

016)

Mus

cle

func

tion† a

nd q

ualit

y‡ wer

e as

soci

ated

with

wai

t-lis

t mor

talit

y,

but n

ot m

uscl

e m

ass

NA

NA

NA

Adul

t stu

dies

that

ass

esse

d pr

e-LT

sa

rcop

enia

on

post

-LT

outc

omes

DiM

artin

i et a

l.(21)

(201

3)Pr

edic

tor o

f sur

viva

l onl

y in

mal

esN

A↑h

ospi

tal a

nd IC

U st

ay↑v

entil

ator

dep

ende

ncy

Mas

uda

et a

l.(6) (

2014

)↓O

S, 3

-yea

r, 5-

year

surv

ival

↑rat

e of

sep

sis

NA

NA

Aby

et a

l.(15)

(201

8)N

D in

1-y

ear s

urvi

val/O

SN

AN

D in

hos

pita

l sta

yN

A

Engl

esbe

et a

l.(24)

(201

0)↑m

orta

lity

NA

NA

NA

Mon

tano

-Loz

a et

al.(3

5) (2

014)

ND

in su

rviv

al↑b

acte

rial i

nfec

tion

↑hos

pita

l and

ICU

stay

NA

ND

in o

vera

ll, vi

ral,

and

fung

al

infe

ctio

ns

Harim

oto

et a

l.(3) (

2017

)↑6

-mon

th m

orta

lity

↑pos

tope

rativ

e se

psis

↑hos

pita

l sta

y↑p

osto

pera

tive

com

plic

atio

ns§

Ham

aguc

hi e

t al.(2

6) (2

017)

↓OS

NA

NA

NA

Chae

et a

l.(19)

(201

8)↓O

SN

D in

all-

caus

e in

fect

ion

ND

in h

ospi

tal s

tay

ND

in c

ompl

icat

ions

,|| th

rom

bosi

s, ↑

vent

ilato

r du

ratio

n↑I

CU s

tay

Gol

se e

t al.(2

5) (2

017)

↓3-m

onth

, 1-y

ear,

5-ye

ar O

S ra

tes

and

↑mor

talit

y↑s

ever

e se

psis

ND

in h

ospi

tal s

tay

↑ven

tilat

or n

eed

↑ICU

sta

y

Kala

fate

li et

al.(1

) (20

17)

↑1-y

ear m

orta

lity

(n =

10)

↑in

fect

ion

(n =

10)

↑ho

spita

l and

ICU

stay

NA

Ham

aguc

hi e

t al.(1

2) (2

014)

↓OS

NA

NA

NA

Izum

i et a

l.(28)

(201

6)↓4

-mon

th su

rviv

al ra

tes

NA

NA

↑com

plic

atio

ns¶

Kaid

o et

al.(3

0) (2

013)

↓OS

NA

NA

NA



(Con

tinue

s)Re

fere

nce

Mor

talit

y/Su

rviv

alIn

fect

ion

LOS/

Hosp

italiz

atio

nO

ther

s

Krel

l et a

l.(33)

(201

3)N

A↑i

nfec

tion

NA

NA

Unde

rwoo

d et

al.(3

9) (2

015)

NA

↑sep

sis,

bac

teria

l inf

ectio

nN

A↑c

ompl

icat

ion# a

nd fa

ilure

-to-re

scue

** ra

tes

Itoh

et a

l.(4) (

2016

)↓O

SN

AN

AN

A

Ham

mad

et a

l.(27)

(201

7)Sa

rcop

enic

pat

ient

s had

↓O

S th

an

nons

arco

peni

c pa

tient

sSa

rcop

enic

pat

ient

s had

↑ba

cter

e-m

ia th

an n

onsa

rcop

enic

pat

ient

sN

ASa

rcop

enic

pat

ient

s had

↑co

mpl

icat

ions

††

than

non

sarc

open

ic p

atie

nts

SN p

atie

nts h

ad ↓

OS

than

SO

pa

tient

sSO

pat

ient

s had

↓ba

cter

emia

than

SN

pat

ient

sSO

pat

ient

s had

↓co

mpl

icat

ions

than

SN

patie

nts

Kam

o et

al.(5

) (20

18)

↓1- a

nd 5

-yea

r OS

in S

N an

d SO

pa

tient

sN

AN

AN

A

Adul

t stu

dies

that

ass

esse

d pr

e-LT

sa

rcop

enia

on

wai

t-lis

t and

pos

t-LT

outc

omes

Enge

lman

n et

al.(2

3) (2

018)

PSM

I was

a p

redi

ctor

for d

eath

with

in

1 ye

ar a

fter L

T lis

ting

Low

PSM

I pre

dict

ed b

acte

rial i

nfec

-tio

n an

d SB

P w

hile

on

the

wai

ting

list

NA

NA

PSM

I, SM

I, an

d AW

MI w

ere

not a

sso-

ciat

ed w

ith 1

-yea

r pos

t-LT

surv

ival

van

Vugt

et a

l.(41)

(201

8)N

AN

AN

D in

hos

pita

l sta

y↑t

otal

hos

pita

l cos

ts

Adul

t stu

dies

that

ass

esse

d lo

ngitu

dina

l ev

olut

ion

of s

arco

peni

a be

fore

and

af

ter L

T

Tsie

n et

al.(3

8) (2

014)

ND

in p

re-L

T sar

cope

nia

on m

orta

lity

NA

NA

NA

Post

-LT s

arco

peni

a ha

d tre

nd to

war

d ↑m

orta

lity (P

= 0

.08)

Jeon

et a

l.(29)

(201

5)N

ewly

dev

elop

ed s

arco

peni

a af

ter L

T ↑m

orta

lity

NA

NA

NA

Kaid

o et

al.(3

1) (2

017)

(pre

-LT s

arco

peni

a) ↓

OS

afte

r LT

NA

NA

NA

Caria

s et

al.(1

8) (2

016)

SO p

atie

nts h

ad a

tren

d to

war

d ↓s

urvi

val (P

= 0

.40)

NA

NA

NA

Chou

dhar

y et

al.(2

0) (2

015)

NA

NA

NA

SO p

atie

nts h

ad ↑

met

abol

ic s

yndr

ome‡‡

*Sev

erel

y im

paire

d is

indi

cate

d by

Kar

nofsk

y per

form

ance

stat

us C

.† M

uscl

e fun

ctio

n in

dica

ted

by g

rip st

reng

th a

nd sh

ort p

hysic

al p

erfo

rman

ce b

atte

ry.

‡ Mus

cle q

ualit

y def

ined

by t

he m

ean

Hou

nsfie

ld u

nits

/fat i

nfilt

ratio

n fo

r tot

al S

MA

at L

3.§ C

ompl

icat

ions

: com

plic

atio

ns o

f Cla

vien

-Din

do g

rade

4, i

nclu

ding

am

ount

of a

scite

s and

tota

l bili

rubi

n on

PO

D 1

4.|| C

ompl

icat

ions

incl

uded

acut

e cel

lula

r reje

ctio

n an

d bi

liary

com

plic

atio

ns.

¶ Com

plic

atio

ns d

efin

ed a

s gra

de ≥

3 ac

cord

ing

to th

e Cla

vien

-Din

do c

lass

ifica

tion

(con

ditio

n re

quiri

ng su

rgic

al, e

ndos

copi

c, or

radi

olog

ical

inte

rven

tion)

.# C

ompl

icat

ions

incl

uded

rena

l fai

lure

, sep

sis, b

acte

rial i

nfec

tion,

mul

tisys

tem

org

an fa

ilure

, ble

edin

g, b

ile le

ak, p

neum

onia

, res

pira

tory

failu

re, c

ardi

ac ev

ent,

bilia

ry st

rictu

re, g

raft

failu

re, t

hrom

bosis

, Clostridium

difficile

infe

ctio

n, ac

ute r

eject

ion,

and

pul

mon

ary e

mbo

lus.

**Fa

ilure

to re

scue

; if p

atie

nt e

xper

ienc

ed 1

of t

he co

mpl

icat

ions

# w

ithin

1 y

ear o

f LT

and

die

d w

ithin

1 y

ear o

f LT.

††C

ompl

icat

ions

def

ined

as C

lavi

en-D

indo

scor

e of ≥

3a, i

nclu

des n

euro

logi

cal,

surg

ical

, res

pira

tory

, car

diov

ascu

lar,

and

vasc

ular

com

plic

atio

ns.

‡‡M

etab

olic

synd

rom

e def

ined

as ≥

3 A

dult

Trea

tmen

t Pan

el II

I crit

eria

.

tA

Bl

e 3

. Co

ntinued



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 addi-tional 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 radia-tion 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 land-marks (L3-L5), muscle type/number used to measure SMM, and the potential impact of changes in total body fluid status associated with advanced liver dis-ease influencing estimates of SMM measures. Some studies indicate that L3 should be used as the land-mark 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 alter-native 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 fac-tor.(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 emerg-ing 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

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 progres-sive and generalized loss of SMM and muscle func-tion (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, highlight-ing the importance of a thorough assessment of muscle functionality.(56) We recommend a minimum of 2 mus-cle 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 mus-cle 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 per-formance,(2,59) but they may be more difficult to per-form 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 eval-uation 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 preva-lence/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 out-comes associated with sarcopenia as compared with males after LT.(17) This may due to the earlier age of sarcopenia presentation in women induced by meno-pausal hormonal changes. These changes may rapidly



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 sarcope-nia prevalence than older females.(34) Although there are limited data addressing sex differences in pediat-rics, 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 prev-alence may be due to variations in liver disease sever-ity 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 relat-ing preoperative clinical variables (eg, nutrition therapy and muscle function) and their impact on postopera-tive outcomes are needed. Preoperative nutrition and postoperative early enteral nutrition are reported to be beneficial in reducing mortality and sepsis in sarcope-nic LT recipients.(6,30) Studies in children indicate that branched-chain amino acid (BCAA) requirements before and after LT are significantly higher than in

healthy children, indicating that BCAA supplementa-tion to treat sarcopenia may be warranted.(64)

LT corrects biochemical and metabolic abnor-malities 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 con-tribute 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 physi-cal 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) signal-ing 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 mecha-nism of persistent sarcopenia before targeted longterm interventions can be developed.

FiG. 2. Mechanisms of sarcopenia before and after LT in skeletal muscle.



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 chil-dren before and after LT that would be performed on an annual basis (grade C).

This review has some limitations. The heteroge-neous liver population reviewed limits the ability to distinguish the association between specific liver dis-ease types on sarcopenia prevalence and outcomes. Conclusions could not be drawn on outcomes associ-ated with SO and post-LT sarcopenia due to limited findings and inconsistent methodology approaches in the sarcopenia diagnosis. In pediatrics, there are lim-ited data addressing sarcopenia. Despite these lim-itations, 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 foun-dation 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 sar-copenia, methodological considerations in the sarco-penia diagnosis and consistency in the approaches to assess body composition and muscle function are war-ranted. 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 out-comes and, hence, warrants further investigation. SO occurs before and after LT and may be a significant comorbid condition contributing to adverse patient outcomes. Findings highlight the need for the devel-opment of effective treatment strategies in adults and children with sarcopenia.

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