701400

research-article2017
PENXXX10.1177/0148607117701400Journal of Parenteral and Enteral NutritionBelarmino et al

2017 Research Workshop

Journal of Parenteral and Enteral
Nutrition
Diagnosing Sarcopenia in Male Patients With Cirrhosis Volume XX Number X
Month 201X 1­–12
by Dual-Energy X-Ray Absorptiometry Estimates of © 2017 American Society

Appendicular Skeletal Muscle Mass for Parenteral and Enteral Nutrition

DOI: 10.1177/0148607117701400
https://doi.org/10.1177/0148607117701400
journals.sagepub.com/home/pen

Giliane Belarmino, PhD¹; Maria Cristina Gonzalez, PhD2,3; Priscila Sala, PhD1;
Raquel Susana Torrinhas, PhD¹; Wellington Andraus, PhD¹;
Luiz Augusto Carneiro D’Albuquerque, PhD¹; Rosa Maria R. Pereira, PhD4;
Valéria F. Caparbo, PhD4; Eduardo Ferrioli, PhD5; Karina Pfrimer, PhD5;
Lucas Damiani, MSc6; Steven B. Heymsfield, PhD3; and Dan L. Waitzberg, PhD¹

Abstract
Background: Ascites in cirrhotic patients interfere with accurate assessment of skeletal muscle when diagnosing sarcopenia. We
hypothesized measurement of appendicular skeletal muscle index (ASMI) with dual-energy x-ray absorptiometry (DXA) improves the
diagnosis of sarcopenia in cirrhotic patients as ASMI does not include the fluid-filled abdominal compartment. Objective: To evaluate if
ASMI is influenced by ascites, lower limb edema (LLE) and predicts mortality alone or combined with handgrip strength (HGS) in cirrhotic
patients. Design: ASMI, HGS, and 36-month mortality were obtained in 144 men with cirrhosis. ASMI was compared before and after
paracentesis in 20 men with ascites and to results from 20 matched controls. The prognostic value of ASMI alone and with HGS was tested
in a survival. Survival probabilities were obtained for sarcopenia diagnosed by standard ASMI and HGS European Working Group on
Sarcopenia in Older People (EWGSOP) cutoffs and a new cutoff calculated from our ASMI + HGS tertiles. Results: ASMI did not change
after paracentesis, was lower in patients than in controls (P < .001), and was not influenced by LLE (D = 0.30 kg/m2, P = .068; R2 = 2.40%).
Mortality was influenced by ASMI and HGS (Pinteraction = 0.028). Sarcopenia diagnosed by EWGSOP was also diagnosed by our new cutoff;
both predicted mortality with the latter more sensitive for mortality risk prediction (P = .011). Conclusions: DXA-measured ASMI is not
influenced by ascites or LLE in cirrhotic patients; can diagnose low skeletal muscle/sarcopenia; and predicts mortality, particularly when
combined with HGS. (JPEN J Parenter Enteral Nutr. XXXX;xx:xx-xx)

Keywords
body composition; cirrhosis; dual-energy x-ray absorptiometry; liver disease; mortality; muscle loss; muscle strength; nutrition assessment;
sarcopenia; edema; ascites

Clinical Relevancy Statement
This article describes pioneer data displaying the use of dual-
energy x-ray absorptiometry to estimate muscle mass from the
appendicular skeletal muscle index. This safe and reliable
method for clinically estimating skeletal muscle mass in patients
with cirrhosis is not affected by the hydric changes that are
commonly found in this population. Moreover, the method can
be applied for sarcopenia diagnosis with prognostic value.
Introduction
Cirrhosis is accompanied by severe hepatocellular dysfunc-
tion and abnormal vascularization as a consequence of
advanced chronic liver fibrosis.1 Liver transplantation (LT) is
often the most effective treatment for patients with advanced
cirrhosis, but the low availability of organ donors, risk of
organ rejection, and high cost limit the clinical application of
this approach. Consequently, the control and treatment of cir-
rhosis-associated complications remain the mainstays of ther-
apy for these patients.2,3
From the 1Department of Gastroenterology (LIM 35), Surgical Division,
Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil;
2
Postgraduate Program in Health and Behavior, Universidade Católica
de Pelotas, Rio Grande do Sul, Brazil; 3Pennington Biomedical Research
Center, Baton Rouge, Louisiana, USA; 4Laboratory of Bone Metabolism,
Rheumatology Division, Faculdade de Medicina da Universidade de São
Paulo, São Paulo, Brazil; 5Department of Medical Clinic, Faculdade de
Medicina de Ribeirão Preto da Universidade de São Paulo, São Paulo, Brazil;
and 6Research Institute, Hospital do Coração de São Paulo, São Paulo, Brazil.
Financial disclosure: This work was supported by the Fundação de
Amparo à Pesquisa do Estado de São Paulo (project no. 2011/13243-3,
DD 2012/15677-3 [GB]) and the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (no. 300559/2009-7 [RMRP]).
Conflicts of interest: None declared.
Received for publication December 13, 2016; accepted for publication
February 21, 2017.
Corresponding Author:
Giliane Belarmino, PhD, Laboratory of Nutrition and Metabolic Surgery
of the Digestive Tract, LIM 35 Faculdade de Medicina da Universidade de
São Paulo, Avenida Dr. Arnaldo, 455, Cerqueira César, 01246-903, São
Paulo, Brazil.
Email: giliane85@hotmail.com
2 Journal of Parenteral and Enteral Nutrition XX(X)
Severe muscle mass loss (sarcopenia) is one of the most
common cirrhosis-associated complications. In patients with
cirrhosis, sarcopenia adversely affects survival and quality of
life, imposes clinical complications, and may impair post-LT
survival.4–7 Early diagnosis is important, as prompt manage-
ment can prevent further complications and improve quality of
life.8 Seven sets of criteria have been proposed for the general
diagnosis of sarcopenia. All of these criteria include low skel-
etal muscle mass (alone [n = 3] or combined with low muscle
strength and/or performance [n = 4]), as a result of aging (pri-
mary sarcopenia) or chronic disease (secondary sarcopenia).9,10
Secondary sarcopenia, present in patients with cirrhosis, is
associated with nutrition disturbances, including inadequate
dietary intake of energy and/or protein, malabsorption, gastro-
intestinal disorders, and use of medications that cause anorexia
or protein restriction.10
A reference method for the estimation of skeletal muscle
mass in cirrhosis is lacking.11 Patients with cirrhosis often dis-
play circulatory dysfunctions that culminate in ascites or
edema.12 These fluid imbalances impair the performance of
available methods for skeletal muscle evaluation (ie, bioelec-
trical impedance analysis, anthropometry). Consequently, tra-
ditional and even more sophisticated methods for skeletal
muscle mass estimation usually overestimate this compartment
in patients with end-stage liver disease.13,14
In this scenario, the accurate diagnosis of sarcopenia in
patients with cirrhosis often remains elusive, and a suitable
method for skeletal muscle assessment that is not influ-
enced by body fluid changes, such as edema and ascites, is
clearly needed.15–20 Recently, dual-energy x-ray absorpti-
ometry (DXA) was reported to be useful for the detection
of low skeletal muscle mass in populations other than
patients with cirrhosis, as it enables the estimation of
appendicular skeletal muscle (ASM) mass and the diagno-
sis of sarcopenia in combination with nondominant hand-
grip strength (ND-HGS).21,22 Because the abdominal
compartment is excluded from ASM measurements, this
approach may not be influenced by ascites and thus may be
useful for skeletal muscle mass estimation in cirrhosis.
This study tested the performance of appendicular skeletal
muscle index assessed by dual-energy x-ray absorptiometry
(DXA-ASMI) in diagnosing sarcopenia in patients with
cirrhosis.
Patients and Methods
Protocol Design
To test the performance of DXA-ASMI in diagnosing sarcope-
nia in patients with cirrhosis, our protocol was designed to
answer 4 main questions: (1) whether the presence of ascites
influences DXA-ASMI measurement in cirrhosis, assessed by
comparing DXA-ASMI values obtained from patients with cir-
rhosis and ascites before and after paracentesis; (2) whether the
DXA-ASMI identifies low skeletal muscle mass in cirrhosis,
assessed by comparing DXA-ASMI values obtained from
patients with cirrhosis and healthy volunteers; (3) whether the
skeletal muscle estimation by DXA-ASMI can be influenced
by clinically detectable edema, assessed by comparing the
DXA-ASMI values obtained from patients with and without
lower limb edema; and (4) whether the DXA-ASMI, alone or
in combination with ND-HGS, has prognostic value for mor-
tality and compliance with a diagnosis of sarcopenia, assessed
in mortality models adjusted for different variables potentially
affecting estimation of skeletal muscle mass and/or grade of
disease.
To test the compliance of the DXA-ASMI in diagnosing
sarcopenia, we applied the cutoffs of DXA-ASMI + ND-HGS
suggested by the European Working Group on Sarcopenia in
Older People (EWGSOP) for this purpose22 and correlated our
findings with mortality rates. Furthermore, we compared the
sarcopenia identified by these reference cutoffs with the sarco-
penia identified by a specific DXA-ASMI + ND-HGS cutoff
obtained from our sample.
Before starting the study, a pilot study with 15 patients with
cirrhosis who met the inclusion and exclusion criteria and did
not undergo our study protocol procedures was performed.
Data from these patients were used exclusively to determine
the coefficient of variation (CV) and device error of the DXA-
ASMI for our patient population (see Supplementary Material).
This information was used to calculate the sample size needed
to test the influence of ascites on DXA-ASMI values.
All body measurements were performed in the hepatol-
ogy clinic at 7:00 am, after a 4-hour fast.23 Studied patients
were verbally instructed to refrain from physical activity
(except light walking), diuretic use, and alcohol consump-
tion for 24 hours before the body composition assessment.23
Demographic data were recorded for all patients. Death
events were recorded for all patients with cirrhosis during
the 36-month follow-up period. A single trained technician
performed all study procedures according to the ethical stan-
dards of the Declaration of Helsinki of the World Medical
Association. The protocol was approved by the Institutional
Ethics Review Board (0646/11) and registered at www.clini-
calTrials.gov (NCT02421848).
Patients
This study included 144 male patients with cirrhosis, diag-
nosed by hepatic biopsy, recruited prospectively from the
Digestive Tract Surgery Service at the Hospital das Clínicas of
the University of São Paulo Medical School (HC-FMUSP)
between January 2012 and December 2014. Exclusion criteria
were alcohol abuse; human immunodeficiency virus positivity;
diagnosis of cancer, acute liver failure, or chronic or acute dis-
ease of the lung, kidney, or heart, determined by the medical
staff from our department; previous LT; orthopedic prosthesis
use; and dementia.
Belarmino et al 3
The influence of ascites on the DXA-ASMI values was
tested before and immediately after paracentesis in the first 20
consecutively included patients who required this procedure.
Among these 20 patients undergoing paracentesis, the last 3
patients also underwent DXA assessment with DXA-ASMI cal-
culation at different intervals until 7 days after paracentesis.
The capacity of the DXA-ASMI to identify low skeletal muscle
mass in cirrhosis was tested by comparing the values of DXA-
ASMI obtained from these 20 patients before paracentesis with
values of DXA-ASMI obtained from 20 sex- age-, weight-, and
height-matched healthy volunteers recruited from the general
staff of the HC-FMUSP. The influence of edema on the skeletal
muscle mass estimation by DXA-ASMI was assessed in the
total sample. The ability of the DXA-ASMI, alone or in combi-
nation with ND-HGS, to predict cirrhosis-related mortality was
assessed in patients who had all of the measurements for the
variables tested in the mortality models (n = 129).
All patients and healthy volunteers provided written
informed consent before trial participation.
Demographic and Clinical Data Collection
The following demographic and clinical data were collected:
age, liver cirrhosis etiology, presence of hepatic encephalopa-
thy, diuretic use, infection, renal function, esophageal varices,
Child-Pugh (CP) and model for end-stage liver disease
(MELD) scores, lower limb edema, ascites, body weight and
height, body mass index (BMI), and LT.24 Presence of lower
limb edema and ascites was evaluated by physical examina-
tion, immediately before the DXA-ASMI measurement.
During this procedure, ascites grade was assessed by a hepa-
tologist, according to the criteria of the International Club of
Ascites.25 Body weight was measured with the participant
standing in the center of a single electronic scale platform
while barefoot and wearing only light clothes. Height was
measured with a single stadiometer (Sanny, São Paulo, Brazil)
with the individual standing barefoot with the heels together,
back upright, and arms extended next to the body. BMI was
calculated as weight divided by height squared (kg/m2).
DXA
Body composition was estimated by DXA (Discovery model;
Hologic, Bedford, MA) with APEX software (version 4.02;
Hologic). Participants removed all metal objects and other
items that might interfere with the scan and were instructed to
empty the bladder. They were positioned supine in the center
of the scanning table with the palms down and the arms beside
the body. Age, height, weight, sex, and ethnicity were entered
into the computer. The device’s default software was used to
determine body composition indices. The DXA system was
calibrated at the start of the study using the manufacturer’s
body composition phantom.26 All individuals underwent
whole-body DXA scans to measure the total lean mass
(including the trunk), regional lean mass (in the 4 limbs), and
total body fat. The DXA-ASMI value was calculated by divid-
ing the sum of lean mass in all 4 limbs by the body height
squared (kg/m2).27
Paracentesis
After DXA, patients undergoing paracentesis (n = 20) were
asked to urinate. Thereafter, they were placed in a supine posi-
tion with the head elevated at 30° to allow fluid accumulation
in the lower abdomen. After anesthesia, paracentesis was per-
formed as previously described elsewhere.28 Ascites fluid was
collected and its volume was measured in a graduated flask.
When this volume exceeded 2 L, it was replaced by intrave-
nous administration of 20% human albumin (Alburex 20, 50
mL/2 L withdrawn ascites fluid; CSL Behring, Marburg,
Germany). Patients remained in bed during and for 30 minutes
after paracentesis.28
Handgrip Strength
ND-HGS was measured using a digital dynamometer (Charder
Co. Ltd., Taichung City, Taiwan), as previously described else-
where.20,21 A single test instructor encouraged patients to pro-
duce their maximal grip strength. The best result of 3 attempts
(with 1-minute pauses between attempts) was recorded in kilo-
grams, when the test instructor was convinced that the partici-
pant had squeezed with maximal effort based on previously
described criteria.29
Survival and Sarcopenia Diagnosis
Death events were assessed by telephone calls at the end of the
study. Only deaths related directly to cirrhosis complications
were counted. A longitudinal analysis of mortality was used to
assess the prognostic value of low skeletal muscle mass, identi-
fied by the DXA-ASMI. The effect of possible interaction
between the DXA-ASMI and ND-HGS on survival and the
ability of these combined measures to predict mortality in
patients with cirrhosis were also evaluated in mortality models
adjusted for variables potentially affecting skeletal muscle
mass and/or cirrhosis severity (CP score, LT, lower limb
edema, MELD score, and age).24
A specific cutoff for mortality prediction was obtained from
tertiles of the DXA-ASMI and ND-HGS values. The survival
probability of patients with sarcopenia, diagnosed by this cut-
off, was calculated and compared with the use of the cutoff
proposed by the EWGSOP (DXA-ASMI <7.26 kg/m2 +
ND-HGS <30 kg).22
Sample Size and Statistical Analyses
We calculated the sample size required to analyze the influence
of ascites on DXA-ASMI values using the G Power software
4 Journal of Parenteral and Enteral Nutrition XX(X)
package (version 3.1.9.2; Heinrich Heine University,
Dusseldorf, Germany). Considering a variability of 0.27 kg/m2
between preparacentesis and postparacentesis DXA measures,
we estimated that we would need 20 patients to achieve 80%
power at the 5% significance level, with a t test equivalence
region similarity of 0.20 kg/m2 (2.77 times the estimated mean
device error of 0.07 kg/m2).
Differences between DXA-ASMI values obtained before
and after paracentesis were compared by paired Student t tests.
Agreement between the 2 values was assessed by Lin’s concor-
dance correlation coefficient (CCC), the Bland-Altman
graphic, 95% confidence intervals (CIs), and CV. An equiva-
lence test was performed to determine whether the mean differ-
ence (MD) before and after paracentesis was within the
machine’s CV.26
To analyze when the DXA-ASMI can be used to identify
low skeletal muscle mass in cirrhosis, the sample of 20 patients
was suitable to identify differences of 1.40 kg/m2 for DXA-
ASMI values and 7.20 kg for ND-HGS values with the same
80% power and 5% significance level, considering the stan-
dard deviations of DXA-ASMI (≅8.0) and ND-HGS (≅1.5)
values. Differences in DXA-ASMI values obtained from cir-
rhotic patients and healthy volunteers were assessed by
unpaired Student t tests.
To analyze whether the skeletal muscle estimation by
DXA-ASMI can be influenced by clinically detectable lower
limb edema, a minimum sample size of 140 individuals has
approximately 90% power, with a 5% significance level, to
detect a difference of 0.60 kg/m2 in DXA-ASMI according to
lower limb edema considering the standard deviations of
DXA-ASMI 1.20 kg/m2. That mean comparison was assessed
by an unpaired Student t test and reported with a coefficient of
determination (R2).
To analyze the ability of the DXA-ASMI to predict mor-
tality, a minimum sample size of 120 patients has 80% power
to detect a hazard ratio (HR) of 2.50 for mortality using a Cox
proportional hazards regression model, considering a signifi-
cance level of 5% and event rate of 36% at 36 months of fol-
low-up. Survival probabilities were estimated by the
Kaplan-Meier method, compared using the log-rank test, and
estimated in terms of the failure rate according to indepen-
dent and multiple models of Cox proportional hazards. The
mortality models included DXA-ASMI values, ND-HGS val-
ues, and DXA-ASMI/ND-HGS interaction and were adjusted
for CP score, LT, lower limb edema, MELD score, and age.24
The influence of lower limb edema on the ability of DXA-
ASMI to estimate skeletal muscle was tested considering the
interaction effect (DXA-ASMI/lower limb edema) in this
model. The final model included only variables shown to be
significant for mortality prediction. The correlation of DXA-
ASMI and ND-HGS in predicting mortality among these
remaining variables was tested by the Pearson correlation and
pairs of dispersion analyses. A specific cutoff for mortality
prediction was obtained from the combined lowest tertiles of
the DXA-ASMI and ND-HGS values at the study’s end. The
cumulative survival rates for sarcopenia obtained from this
cutoff were tested using the Kaplan-Meier method and com-
pared with those only obtained using the EWGSOP-suggested
cutoffs for DXA-ASMI and ND-HGS values using the log-
rank test.22
Data are expressed as means ± standard deviations, medi-
ans, interquartile ranges (IQRs; 25th–75th percentile), or per-
centages, depending on the normality of distribution and type
of variable. Data were analyzed using the R software package
(version 3.1.3, 2015; R Core Team, Vienna, Austria). A signifi-
cance level of 5% was used for all analyses.
Results
Patient Characteristics
Figure 1 shows the distribution of patients and healthy volun-
teers included in the study. Patients (median age, 54.50 years;
IQR, 48–62 years) with cirrhosis of different etiologies (59%
alcoholic, 20% viral, 12% cryptogenic, and 9% other) were
enrolled in the study. Characteristics of the studied sample are
presented in Table 1. Patient distribution according to CP des-
ignation was 17% Child A, 54% Child B, and 29% Child C; the
mean MELD score was 14.38 (IQR, 11–17). Ascites was
absent or controlled in 63% of patients and moderate, volumi-
nous, or refractory in 37% of patients; 72 (50%) patients pre-
sented lower limb edema; and 16 (11.10%) patients underwent
LT, at an interval of 38–1001 days (median, 530 days; IQR,
226–652 days) after enrollment. Table 2 provides demographic
and preparacentesis body composition (ND-HGS and DXA)
data for the 20 patients assessed separately and corresponding
healthy volunteers.
Influence of Ascites on Skeletal Muscle
Estimation by DXA-ASMI
On average, 7.40 ± 2.73 L ascites fluid was removed by para-
centesis. DXA-ASMI values obtained before and after paracen-
tesis did not differ (Table 3), with a CCC of 0.99 (Figure 2A), MD
of −0.01 kg/m2 (95% CI, –0.09 to 0.07), and 95% limits of indi-
vidual agreement of −0.33 and 0.31 kg/m2 (Figure 2B). No sig-
nificant change in DXA-ASMI values was observed between
before and up to 7 days after paracentesis in the 3 patients eval-
uated (Figure 2C). According to the equivalence test, the MD
before and after paracentesis was within the CV of the machine
(MD = 0.01, standard deviation = 0.16; P < .001).
Capacity of DXA-ASMI to Identify Low
Skeletal Muscle Mass in Cirrhosis
Among patients and healthy volunteers who were similar in
age (53.80 ± 10.37 vs 55.35 ± 9.84 years), weight (79.84 ± 8.22
vs 79.63 ± 12.23 kg), and height (1.67 ± 0.04 vs 1.70 ± 0.07 m),
Belarmino et al 5

Figure 1.  Distribution of included patients and healthy volunteers according to study procedures and aims. CV, coefficient of variation;
DXA-ASMI, appendicular skeletal muscle index estimated by dual-energy x-ray absorptiometry; SM, skeletal muscle.

Table 1.  Baseline Characteristics and Body Composition of muscle mass and strength were significantly lower in the cir-
Patients With Cirrhosis (N = 144).a rhosis group than in healthy volunteers (25.00 kg and 7.76 kg/
m2 vs 39.69 kg and 9.29 kg/m2, P < .001). Figure 3 shows the
Variable Value
difference in DXA-ASMI values between the cirrhosis and
Age, y 54 ± 9.90 healthy volunteer groups. The body fat value was lower (P <
Weight, kg 76.70 ± 13.90 .001) and total lean mass values were higher (P = .021) in
Height, m 1.70 ± 0.10 patients with cirrhosis and ascites (Table 2).
Child-Pugh score 8.33 ± 2.00
MELD score 14.38 ± 5.40
Diuretic use, % 85.92 Influence of Lower Limb Edema on Skeletal
Absent ascites, % 26.00 Muscle Estimation by DXA-ASMI
Controlled ascites, % 37.20
The MD of DXA-ASMI values obtained from patients with
Moderate ascites, % 14.00
edema and patients without edema was not significant (0.30
Refractory ascites, %  7.80
Voluminous ascites, % 15.00 kg/m2, P = .068). In addition, the DXA-ASMI variability
Hepatic encephalopathy, % 16.70 explained by edema was insignificant, as demonstrated by the
Chronic or recurrent infection, %  1.00 R2 value (R2 = 2.40%).
Renal function (good), % 99.00
Esophagus varices, % 30.83 Prognostic Value of DXA-ASMI for Mortality
BMI, kg/m2 26.60 ± 4.50
ND-HGS, kg 28.70 ± 8.90
and Compliance for Sarcopenia Diagnosis
Body fat, kg 16.40 ± 8.70 Of the 144 patients included in the mortality prediction analy-
Lean mass, kg 57.90 ± 10.90 sis, 88 (61%) survived and 55 (38%) died due to cirrhosis, with
Body fat, % 22.80 ± 7.30 a mean of 16 months of follow-up until death (median, 32
ASMI, kg/m2 7.66 ± 6.89 months; IQR, 17.52–33.96 months). Seven (12.70%) of the
ASMI, appendicular skeletal muscle index; BMI, body mass index;
patients who died underwent LT. One patient died due to a car
MELD, model for end-stage liver disease; ND-HGS, nondominant accident, and his death event was not counted.
handgrip strength. Only 129 of the 144 patients had both DXA-ASMI and
a
Body composition data were obtained by dual-energy x-ray ND-HGS measures and were applied in the mortality models.
absorptiometry from 144 patients, except DXA-ASMI and ND-HGS
obtained from 129 patients. Data are presented as mean ± standard The initial multiple Cox regression model for mortality was
deviation unless otherwise indicated. not influenced by CP score (HR, 1.10; 95% CI, 0.93–1.31;
6 Journal of Parenteral and Enteral Nutrition XX(X)

Table 2.  Body Composition and Handgrip Strength Data From Patients With Cirrhosis and Ascites Before Paracentesis and Healthy
Volunteers.a

Variable Cirrhosis Group (n = 20) Control Group (n = 20) P Valueb

BMI, kg/m2 27.80 ± 4.07 28.87 ± 2.78 .338
ND-HGS, kg 25.00 ± 8.40 39.69 ± 6.27 <.001
Body fat, kg 13.23 ± 4.44 20.57 ± 4.22 <.001
Lean mass, kg 66.27 ± 9.50 60.00 ± 6.73 .021
Body fat, % 16.41 ± 4.35 25.64 ± 3.66 <.001
DXA-ASMI, kg/m2 7.76 ± 1.45 9.29 ± 0.95 <.001

BMI, body mass index; DXA-ASMI, appendicular skeletal muscle index assessed by dual-energy x-ray absorptiometry; ND-HGS, nondominant
handgrip strength.
a
Data were collected by dual-energy x-ray absorptiometry and handgrip strength tests and are expressed as mean ± standard deviation.
b
Unpaired Student t test.

Table 3.  Body Composition Data From Patients With Cirrhosis and Ascites Before and After Paracentesis.a

Before Paracentesis After Paracentesis

Variable (n = 20) (n = 20) MD 95% CI P Valueb
Weight, kg 79.60 ± 12.26 73.32 ± 11.80 6.28 5.34–7.29 <.001
BMI, kg/m2 27.80 ± 4.07 25.67 ± 3.95 2.13 1.82–2.45 <.001
Body fat, kg 13.23 ± 4.44 12.20 ± 4.16 1.03 0.51–1.56 .001
Lean mass, kg 66.27 ± 9.50 61.16 ± 9.56 5.11 4.36–5.87 <.001
Body fat, % 16.41 ± 4.35 16.41 ± 4.54 0.00 –0.46 to 0.46 1
DXA-ASMI, kg/m2 7.76 ± 1.45 7.77 ± 1.46 –0.01 –0.09 to 0.07 .786

BMI, body mass index; DXA-ASMI, appendicular skeletal muscle index assessed by dual-energy x-ray absorptiometry; MD, mean difference.
a
Data were collected by dual-energy x-ray absorptiometry from 20 patients and are expressed as mean ± standard deviation.
b
Paired Student t test.

Figure 2.  Appendicular skeletal muscle index values obtained by dual-energy x-ray absorptiometry (DXA-ASMI) in patients with
cirrhosis and ascites before and after paracentesis. (A) Correlation between DXA-ASMI values obtained before and after paracentesis
(r = 0.99, P < .001; n = 20). (B) Bland-Altman plot of the difference in DXA-ASMI values obtained before and after paracentesis (n =
20). Solid horizontal line represents the mean difference (MD = −0.01; 95% confidence interval, –0.09 to 0.07). Dashed lines indicate
the 95% limits of agreement (–0.33 to 0.31). (C) DXA-ASMI behavior before, immediately after (n = 3), and at 1 (n = 2) or 4 (n = 1)
days and 7 days (n = 3) after paracentesis (P = .364). ASMI, appendicular skeletal muscle index; CCC, Lin’s concordance correlation
coefficient.

P = .255) or LT as a time-dependent covariate (HR, 1.26; 95% on the mortality model but no significant DXA-ASMI: lower
CI, 0.47–3.36; P = .63). Lower limb edema showed an indepen- limb edema interaction affecting mortality prediction was
dent significant effect (HR, 1.95; 95% CI, 1.46–3.65; P = .036) detected and the model was adjusted without this parameter
Belarmino et al 7

Figure 3.  Boxplot of mean of appendicular skeletal muscle index values obtained by dual-energy x-ray absorptiometry (DXA-ASMI)
in patients with cirrhosis and ascites (n = 20) before and after paracentesis and from healthy matched controls (n = 20). Bottom and
top of each box represent the 25th and 75th percentiles (interquartile range), respectively. P values were determined by the Student t
test: P < .001, cirrhotic group vs control group; P = .786, cirrhotic group before vs after paracentesis.

Table 4.  Hazard Ratio Estimates for Patients With Cirrhosis adjusted for MELD score and age. In addition, Pearson correla-
From a Multiple Cox Regression Model.a tion and pairs of dispersion analyses showed that the effects of
DXA-ASMI and ND-HGS in this model were independent of
Multiple Cox Regression Model
MELD score and age for mortality prediction (Figure 4).
Variable HR (95% CI) P Value From the tertiles of DXA-ASMI and ND-HGS measures,
we observed that 73.70% of patients with DXA-ASMI ≤7 kg/
Age, y 1.04 (1.01–1.08) .017
m2 + ND-HGS ≤25 kg died, compared with 28.20% of patients
MELD score 1.15 (1.10–1.21) <.001
who did not fall into this category. Patients who presented with
LLE (yes/no) 1.95 (1.46–3.65) .036
ND-HGS, kg 0.78 (0.65–0.93) .005
DXA-ASMI and ND-HGS values below this cutoff were sig-
DXA-ASMI, kg/m2 0.44 (0.21–0.92) .029 nificantly more likely to die, as demonstrated by Kaplan-Meier
DXA-ASMI/ND-HGS 1.03 (1.00–1.05) .019 curves (Figure 5). Among the 129 patients with DXA-ASMI
interaction and ND-HGS measurements, 19 (14.70%) were diagnosed as
sarcopenic by applying this cutoff. These 19 patients and
DXA-ASMI, appendicular skeletal muscle index obtained by dual-energy another 12 patients were diagnosed as sarcopenic by applying
x-ray absorptiometry; HR, hazard ratio; LLE, lower limb edema; MELD,
model for end-stage liver disease; ND-HGS, nondominant handgrip the cutoff recommended by the EWGSOP (n = 31; 24%).
strength. Fourteen of the 19 patients diagnosed as sarcopenic by both
a
Data were collected from 129 patients. P values for independent Cox cutoffs died, and 3 of the 12 patients diagnosed as sarcopenic
regression models refer to three models explained by age, MELD score, only by the EWGSOP cutoff died. The frequency of mortality
and DXA-ASMI/ND-HGS interaction.
predicted by our cutoff was 73.70%. The frequency of mortal-
ity predicted by the EWGSOP cutoff was 54.80%. The Kaplan-
(Table 4). The final independent and multiple Cox regression Meier curve of cumulative survival rates showed that our
model for mortality (Table 5) included DXA-ASMI, ND-HGS, sarcopenia cutoff identified patients with greater mortality risk
DXA-ASMI/ND-HGS interaction, age, and MELD score. All relative to the EWGSOP cutoff (log-rank test, P = .011; Figure
of the variables included in the model were associated indepen- 6). The 12 patients diagnosed as sarcopenic only by the
dently with mortality. Significant DXA-ASMI/ND-HGS inter- EWGSOP cutoff were not significantly different from the
action in mortality prediction was found (P = .028), and these group of patients diagnosed as nonsarcopenic by both cutoffs
measures combined significantly affected the mortality model (n = 98; P > .05).
8 Journal of Parenteral and Enteral Nutrition XX(X)

Table 5.  Mortality Estimates for Patients With Cirrhosis From Independent and Multiple Cox Regression Models.a

Independent Model Multiple Model

Variable HR (95% CI) P Value HR (95% CI) P Value

Age, y 1.03 (1.00–1.06) .039 1.04 (1.00–1.07) .023
MELD score 1.11 (1.07–1.15) <.001 1.14 (1.09–1.20) <.001
ND-HGS, kg 0.78 (0.67–0.91) .002 0.78 (0.66–0.93) .006
DXA-ASMI, kg/m2 0.41 (0.20–0.82) .012 0.49 (0.23–1.00) .053
DXA-ASMI/ND-HGS 1.03 (1.00–1.05) .008 1.03 (1.00–1.05) .028
interaction

DXA-ASMI, appendicular skeletal muscle index obtained by dual-energy x-ray absorptiometry; HR, hazard ratio; MELD, model for end-stage liver
disease; ND-HGS, nondominant handgrip strength.
a
Data were collected from 129 patients. P values for independent Cox regression models refer to three models explained by age, MELD score, and DXA-
ASMI/ND-HGS interaction.

Figure 4.  Dispersion in pairs (left lower corner) and Pearson correlations (upper right corner) between age, appendicular skeletal
muscle index obtained by dual-energy x-ray absorptiometry (DXA-ASMI), model for end-stage liver disease (MELD) score, and
nondominant handgrip strength (ND-HGS). Data were obtained from patients with cirrhosis (n = 129) and included in univariate and
multivariate models of mortality prediction. No variable included in these 2 models was related to the MELD score.
Belarmino et al 9

Figure 5.  Kaplan-Meier survival curves for 129 patients with cirrhosis, obtained by applying the new cutoff created from the tertiles
of appendicular skeletal muscle index obtained by dual-energy x-ray absorptiometry (DXA-ASMI) and nondominant handgrip strength
(ND-HGS) values. The percentages of deaths were 73.70% for patients within the new cutoff (DXA-ASMI ≤7 kg/m2 + ND-HGS ≤25
kg) and 28.20% for patients with DXA-ASMI and/or ND-HGS values above this new cutoff. The corresponding 18-month survival
rates were 45.10% and 90.60%, respectively.

Discussion we found that the DXA-ASMI did not change up to 7 days

Diagnosing sarcopenia in patients with cirrhosis can be diffi-
cult because the clinically available methods for skeletal mus-
cle mass estimation are affected strongly by ascites.8,9,17,30–33
Here, we showed that the use of the DXA-ASMI for skeletal
muscle mass estimation is not influenced by ascites in patients
with cirrhosis, as DXA-ASMI values obtained before and after
paracentesis were similar. Furthermore, DXA-ASMI values
were significantly lower in patients with cirrhosis than in
healthy volunteers, were not influenced by lower limb edema,
predicted mortality, and were able to diagnose sarcopenia,
mainly when associated with ND-HGS.
DXA-ASMI estimates are obtained from the arms and legs,
which are composed mainly of muscle (with small amounts of
connective tissue and skin); this method excludes the abdomi-
nal region.21 When studying the compartmentalization of
ascitic and nonascitic fluid in patients with cirrhosis, Shear
et al33 found that paracentesis initiated rapid fluid reform,
resulting largely from a shift of nonascitic fluid to the abdomi-
nal compartment. Draining of abdominal ascites can redistrib-
ute retained fluid in the appendages, which could affect DXA
performance for skeletal muscle mass estimation. However,
after paracentesis, suggesting that changes in appendicular
edema do not significantly affect this measurement in patients
with cirrhosis.
We identified 2 studies comparing DXA performance
before and after paracentesis in patients with cirrhosis, but this
procedure was applied to assess total body composition. In
those studies, DXA provided lower total lean mass values after
paracentesis, proportional to or correlated with the amount of
drained ascites.32,34 Similarly, in our study, total lean mass val-
ues decreased significantly after paracentesis. Taken together,
these findings suggest that ascites leads to the overestimation
of total lean mass by DXA because this variable includes the
abdominal region for measuring. Accordingly, in our study,
cirrhotic patients before paracentesis presented with greater
total lean mass than healthy volunteers.
One main question is whether DXA-ASMI values could
adequately identify low skeletal muscle mass in patients with
cirrhosis. Riggio et al35 reported that the individual assessment
of ASM by DXA can identify lower skeletal muscle mass in
cirrhotic patients compared with healthy volunteers. Our
DXA-ASMI findings also showed lower skeletal muscle val-
ues in patients with cirrhosis than in healthy volunteers,
10 Journal of Parenteral and Enteral Nutrition XX(X)

Figure 6.  Kaplan-Meier survival curves for 31 patients with sarcopenia, obtained using cutoff scores based on appendicular skeletal
muscle index obtained by dual-energy x-ray absorptiometry (DXA-ASMI) ≤7 kg/m2 + nondominant handgrip strength (ND-HGS) ≤25
kg (new cirrhosis cutoff, n = 19) and DXA-ASMI <7.26 kg/m2 + ND-HGS <30 kg (European Working Group on Sarcopenia in Older
People [EWGSOP] cutoff, n = 31) and patients diagnosed as nonsarcopenic (DXA-ASMI >7.26 kg/m2 + ND-HGS >30 kg (EWGSOP
cutoff, n = 98).

suggesting that DXA-ASMI application for this purpose has
clinical value.
The performance of the DXA-ASMI for skeletal muscle
mass estimation in cirrhosis has not been sufficiently well
explored to enable comparative discussion of our data. To our
knowledge, the only exception is a study by Giusto et al36 com-
paring the performance of computed tomography (CT), DXA
(including the DXA-ASMI), HGS, and mid-arm muscle cir-
cumference for the diagnosis of sarcopenia in patients with cir-
rhosis. The authors found a higher frequency of CT-diagnosed
sarcopenia than that diagnosed by the DXA-ASMI (76% vs
42%), but the first was even higher than that reported previ-
ously by other authors applying the same CT technique for cir-
rhosis.37–40 Furthermore, unlike these previous studies, Giusto
et al36 did not find a significant correlation of CT-diagnosed
sarcopenia with mortality.36–40
In cirrhosis, decreased muscle strength reflects decreased
skeletal muscle mass.41 Therefore, HGS is currently consid-
ered a useful marker of low skeletal muscle mass in cirrhotic
patients, with prognostic value in this population.42
Accordingly, we found significantly lower ND-HGS values in
cirrhotic patients than in matched healthy volunteers. Giusto
et al36 found that HGS and the DXA-ASMI identified sarcope-
nia with similar frequency (46%) and that HGS values were
not correlated significantly with their CT findings for the diag-
nosis of this syndrome in patients with cirrhosis. Although CT
is considered a gold-standard tool for skeletal muscle estima-
tion, it is possible that skeletal muscle assessment by CT in
cirrhosis suffers from ascites, as the abdominal region is
included in the analysis. A study comparing the performance of
CT for skeletal muscle estimation before and after paracentesis
is lacking to scientifically eliminate this hypothesis.
Giusto et al36 did not examine the possible correlation of
sarcopenia diagnosed by HGS or DXA-ASMI with mortality.
In this study, we found that the DXA-ASMI can predict mor-
tality, mainly when combined with ND-HGS, given the signifi-
cant interaction between these tools when used for this purpose.
Furthermore, our data showed that clinically detectable lower
limb edema also did not influence the skeletal muscle estima-
tion by DXA-ASMI. No DXA-ASMI/lower limb edema inter-
action was found in our mortality model, reinforcing this
impression. Accordingly, elderly patients also may experience
edema (mainly in the lower limbs, due to venous insuffi-
ciency), and the DXA-ASMI is a reference method for skeletal
muscle mass estimation in this population.21,22,43
Due to the lack of consensus on the definition of sarcopenia,
available studies have involved the application of various cutoffs
designed for populations other than cirrhotic patients to diagnose
this syndrome in cirrhosis.44,45 We chose to apply the EWGSOP
cutoff for the DXA-ASMI and ND-HGS values proposed to
identify sarcopenia, as a reference to assess DXA-ASMI compli-
ance in diagnosing sarcopenia. In our study, death events occurred
mainly in patients with DXA-ASMI ≤7 kg/m2 + ND-HGS ≤25 k,
which corresponded to a new cutoff calculated based on the ter-
tiles of DXA-ASMI + ND-HGS values obtained in our sample.
Therefore, we also compared the EWGSOP cutoff with this new
cutoff obtained from our patients with cirrhosis.
The frequency of sarcopenia in patients with cirrhosis has
varied widely among studies (ranging from 17%–70%),
according to patient sex, grade of disease, the criterion applied
Belarmino et al 11
to diagnose this syndrome (low muscle mass alone, and/or low
muscle strength, and/or low muscle performance), and the clin-
ical toll applied to assess muscle mass.36,44,46 According to our
data, both studied cutoffs provided sarcopenia frequencies
close to that reported recently by Augusti et al,45 who used the
DXA-ASMI to correlate sarcopenia with encephalopathy in
cirrhosis. However, our new cutoff was more sensitive than the
EWGSOP criterion for mortality prediction. This result proba-
bly occurred because the EWGSOP cutoff was developed for
the diagnosis of sarcopenia in populations other than patients
with cirrhosis.22 A validated cutoff for sarcopenia diagnosis in
cirrhosis is of clinical interest. The new cutoff found here is
specific for our population, and an independent validation
study will be required to confirm any clinical value.
Our study protocol was designed to circumvent the main
limitations of studies evaluating muscle wasting in cirrhotic
patients, many of which have involved the analysis of retro-
spective data collected for purposes other than skeletal muscle
mass estimation and the application of nonspecific cutoffs for
mortality prediction.4,6,37,46 To this end, we sequentially and
prospectively included patients with the exclusive purpose of
assessing low skeletal muscle mass and the influence of asci-
tes on skeletal muscle mass measurement by DXA. At the end
of the study, we calculated specific cutoffs for our population
to mortality using the lowest tertiles of DXA-ASMI and
ND-HGS values, in addition to a reference cutoff.22
Furthermore, before the study began, we calculated the CV of
DXA specifically for ASMI estimation in our patient popula-
tion. This procedure ensured that observed ASMI variations
were not influenced by the DXA device.23 Nonetheless, this
study was limited by the inability to control for changes in
lower limb edema before and after paracentesis. However, our
data suggest that edema did not significantly influence skele-
tal muscle mass measurement by the DXA-ASMI. We also
chose to examine exclusively male patients, who comprise a
more uniform and susceptible cirrhotic population. The inci-
dence of cirrhosis is higher and sarcopenia appears to have
greater prognostic value for disease progression in men than
in women.47,48
In summary, our findings suggest that the DXA-ASMI may
be useful for sarcopenia diagnosis in patients with cirrhosis, as
DXA-ASMI estimates of skeletal muscle mass were not influ-
enced by ascites and edema, and this index enabled identifica-
tion of low skeletal muscle mass values in this population
compared with healthy volunteers. DXA-ASMI values seem to
be correlated positively with ND-HGS values, a marker of low
muscle strength. Furthermore, the DXA-ASMI enabled mor-
tality prediction when combined with ND-HGS and corrected
by age and MELD score, the 2 main variables associated with
sarcopenia and cirrhosis, respectively. In addition, the predic-
tive ability of the DXA-ASMI and ND-HGS was not influ-
enced by age or MELD score, indicating additional and
independent effects of these tools in mortality prediction in
patients with cirrhosis. DXA presents several advantages for
ASMI measurement, as it uses minimal and safe radiation lev-
els for skeletal muscle estimation and allows sequential mea-
surement solely for this purpose without risks.26,49,50 Therefore,
we suggest the combined use of the DXA-ASMI and ND-HGS
for sarcopenia diagnosis in cirrhotic patients, regardless of the
presence of ascites and edema.
Acknowledgments
We thank the patients and nurses who participated in the study.
Statement of Authorship
G. Belarmino, M. C. Gonzalez, D. L. Waitzberg, R. M. R. Pereira,
L. A. C. D’Albuquerque, and W. Andraus contributed to the
conception/design of the research; G. Belarmino, R. S. Torrinhas,
M. C. Gonzalez, D. L. Waitzberg, P. Sala, V. F. Caparbo, S. B.
Heymsfield, and R. M. R. Pereira were responsible for the acquisi-
tion, analysis, and/or interpretation and of the data; and G.
Belarmino, R. S. Torrinhas, S. B. Heymsfield, M. C. Gonzalez, D.
L. Waitzberg, P. Sala, E. Ferrioli, K. Pfrimer, and W. Andraus
drafted the manuscript. All authors critically revised the manu-
script, agree to be fully accountable for ensuring the integrity and
accuracy of the work, and read and approved the final manuscript.
Supplementary Material
Supplementary material is available with the online article at
http://journals.sagepub.com/home/pen.
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