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REVIEW

URRENT
C
OPINION

Muscle wasting: a nutritional criterion to prioritize


patients for liver transplantation
Aldo J. Montano-Loza

Purpose of review
Cirrhosis is the result of the progression of necroinflammatory liver diseases leading to fibrosis, portal
hypertension, and a catabolic state, which might cause muscle wasting or sarcopenia. In this review, we
analyze the methods for muscularity assessment, the incidence and clinical impact of muscle wasting, and
potential novel therapeutic strategies in cirrhosis. Finally, we evaluate the value of muscle wasting inclusion
to conventional systems for liver transplant prioritization.
Recent findings
Muscle wasting is present in up to 45% of patients with cirrhosis and is associated with higher risk of
sepsis-related death rather than liver failure mortality. Despite the fact that muscle wasting is not included in
the scores for prognosis in cirrhotic patients, as in the case of Model for End-Stage Liver Disease (MELD) or
Child-Pugh, its presence should alert clinicians to the same extent as other complications do, such as
ascites, hepatic encephalopathy, or variceal bleeding. Two studies have shown increased mortality risk
after liver transplantation in patients with muscle wasting, whereas one study did not. Modification of MELD
to include muscle wasting is associated with a modest improvement in the prediction of mortality in patients
with cirrhosis.
Summary
Muscle wasting is a frequent complication in cirrhosis and contributes to increased risk of sepsis-related
mortality. The impact on mortality of muscle wasting after liver transplantation is controversial and needs
further study. The MELD-sarcopenia score is associated with improvement in mortality prediction; however,
prior to the widespread use of this composite score, validation in larger cohorts of patients with cirrhosis is
necessary.
Keywords
cirrhosis, liver transplant, organ allocation, sarcopenia, scores for prognosis

INTRODUCTION
Cirrhosis is the result of the progression of many
forms of necroinflammatory liver diseases leading to
fibrosis, vascular remodeling, portal hypertension
development and its complications, and ultimately
liver failure [1]. As currently there is no effective
treatment to revert cirrhosis, management is generally focused on treating the primary liver disease,
screening and controlling the complications of portal hypertension, and considering liver transplantation in patients with decompensated cirrhosis.
Even though liver transplantation may be considered curative for cirrhosis, this therapeutic option
does not exist for the majority of patients.
Muscle wasting or sarcopenia is one of the most
common complications in cirrhosis [2,36], and
despite the important role it plays in the prognosis
of cirrhosis, it is frequently overlooked, mainly as

the nutrition assessment could be complex in cirrhosis with fluid retention and/or overweight [7,8].
At present, several methods are available to
evaluate the body composition and muscle mass
estimation of patient with cirrhosis; however, most
of these techniques have limitations, primarily
because of lack of objectivity and reproducibility.
In this regard, muscularity assessment with crosssectional imaging studies [computed tomography
Division of Gastroenterology and Liver Unit, University of Alberta
Hospital, Edmonton, Alberta, Canada
Correspondence to Aldo J. Montano-Loza, MD, MSc, PhD, Assistant
Professor, Zeidler Ledcor Centre, 130 University Campus, University of
Alberta, Edmonton, AB T6G 2X8, Canada. Tel: +1 780 248 1892;
fax: +1 780 248 1895; e-mail: aldo.montanoloza@ualberta.ca
Curr Opin Clin Nutr Metab Care 2014, 17:219225
DOI:10.1097/MCO.0000000000000046

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Translational research in wasting diseases

KEY POINTS
 Muscle wasting is a frequent complication in cirrhosis
and contributes to increased mortality, mainly related to
sepsis-related death.
 Cross-sectional imaging studies with computed
tomography or MRI constitute the gold standard
techniques to quantify skeletal muscle mass and identify
muscle wasting in cirrhosis.
 Inclusion of muscle wasting to MELD score is associated
with a modest improvement in the prediction of
short-term mortality in patients with cirrhosis.

(CT) scan, or MRI] has become an attractive index of


nutritional status evaluation in cirrhosis. These CT
or MRI analyses are not biased by the fluid overload
status that frequently presents in decompensated
cirrhosis, and muscle wasting reflects a chronic
detriment in the general physical condition, rather
than acute severity of the liver disease [9 ].
Muscle wasting in cirrhosis is part of the frailty
complex present in these patients, characterized by
a decreased reserve and resistance to stressors resulting from cumulative declines across multiple
physiologic systems, and predisposition to poor outcomes [1012].
In this review, we discuss the currently accepted
and new potential methods to evaluate the prognosis in cirrhotic patients. We also discuss the
current evidence regarding frequency and clinical
impact of muscle wasting in cirrhosis in order to
promote recognition of this complication and lead
to strategies in an effort to try to improve survival
and reduce morbidity associated with cirrhosis.
&

PROGNOSTIC EVALUATION OF
CIRRHOSIS
The prognostic assessment of patients with cirrhosis
remains a complex challenge as the natural history
is particularly variable because of several factors,
including cause of the cirrhosis, liver synthetic function, presence and degree of portal hypertension,
the possibility of resolution of the underlying damaging process, and the occurrence of hepatocellular
carcinoma [13].
Child-Pugh and Model for End-Stage Liver
Disease (MELD) [14] scores constitute the most frequent tools to predict mortality in patients with
cirrhosis. Child-Pugh score was originally designed
to predict cirrhosis-related mortality during surgery,
and has been shown to be useful in determining
prognosis, treatment response, and necessity for
liver transplant. MELD was originally developed as
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a prognostic model of early mortality in patients


with cirrhosis who received a transjugular intrahepatic portosystemic shunt (TIPS). The original
MELD has subsequently been simplified and
currently it is widely used to predict short-term
mortality in different patient populations with
cirrhosis. Moreover, in most liver transplant centers,
MELD score has replaced the Child-Pugh score for
priority organ allocation, and since 2002, the MELD
score has been used for the prioritization of potential liver transplant recipients in North America,
mainly because MELD was developed in a statistical
fashion and includes only objective laboratory
parameters. Since implementation of the MELD
score, there have been reports of reductions in the
number of patients listed for liver transplantation,
waiting time for liver transplant, and deaths on the
waiting list.
Although MELD score has the advantage over
Child-Pugh score of being based on objective variables [serum bilirubin, international normalized
ratio (INR) of prothrombin time, and serum creatinine] rather than on subjective evaluation of the
severity of clinical findings (ascites and encephalopathy), the MELD score also has limitations, most
important of which are the variability of biochemical parameters and lack of evaluation of the
nutritional and functional status.

PREVALENCE AND ORIGIN OF MUSCLE


WASTING IN CIRRHOSIS
Muscle wasting in cirrhosis seems to be secondary to a
multifactorial process and generally is more frequent
as liver disease progresses as the factors that lead to
malnutrition in the first place become more prominent. The most important factors associated with
muscle wasting in cirrhosis include metabolic abnormalities, insufficient oral intake (mainly because of
early satiety in moderate-severe ascites), malabsorption, and impaired capacity of the liver to metabolize
and save nutrients, among others (Fig. 1).
The frequency of malnutrition in cirrhosis has
been estimated to affect between 40 and 90% of
patients. This wide range is explained in part as there
are significant differences in the operational definition of malnutrition in cirrhosis. For example, it is
difficult to establish the presence of calorie malnutrition, and as adipose tissue is the largest pool of
calories, fat malnutrition is generally defined as
reduction in body fat mass. However, as most
proteins are located in the skeletal muscle, a proper
definition of clinical protein malnutrition should
use primarily loss of skeletal muscle [15 ].
Recent studies have found that muscle wasting,
established by cross-sectional imaging studies, is
&

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Muscle wasting: a criterion for liver transplant Montano-Loza

Early satiety
- Impaired gastric accommodation
- Ascites
Impaired digestion and nutrient
absorption
- Portal hypertensive enteropathy

Diminished
nutrient intake

Loss of appetite
- Cytokines (TNF-)
Hospitalizations
- Lack of regular meals for examinations
and procedures
Hyperdynamic circulation
- Increase use of macronutrients and
micronutrients

Sarcopenia in
cirrhosis
Hypermetabolic
state

Cytokine-driven hypermetabolism
- High energy expenditure and demand
Compromised gut barrier function
- Bacterial translocation
- Infections
Loss of body protein
- Inadequate synthesis
- Diminished storage capacity
- Affected enterohepatic circle
- Multiple paracentesis

Inadequate
synthesis or
absorption or
micromacronutrients

Decrease hepatic glycogen reserves


- Early switch to gluconeogenesis
- Mobilization of amino acids from the
skeletal muscles

FIGURE 1. Factors associated with muscle wasting development in patients with cirrhosis.

present in up to 45% of patients with cirrhosis


[2,3,5,6] (Table 1) [26,16]. Importantly, being overweight and obesity are now endemic in Western
countries. Patients with cirrhosis may develop simultaneous loss of skeletal muscle and gain of adipose

tissue, culminating in the condition of sarcopenic


obesity. Moreover, muscle depletion is characterized
by both a reduction in muscle size and increased
proportion of intermuscular and intramuscular fat
[17].

Table 1. Clinical studies describing the prevalence and clinical significance of muscle wasting in patients with cirrhosis

Frequency
of muscle
wasting (%)

Englesbe et al. [6]


2010

163

25

Lowest quartile TPA

CT

Low TPA was associated with


mortality after liver transplant

Montano-Loza et al. [2]


2012

112

40

CT

Sarcopenia was independently


associated with mortality

Meza-Junco et al. [3]


2013

116

30

L3 SMI 38.5 cm2/m2


for women and 52.4 cm2/m2
for men
L3 SMI 38.5 cm2/m2
for women and 52.4 cm2/m2
for men

CT

Sarcopenia was independently


associated with mortality

Kaido et al. [4]


2013

124

38

Low skeletal muscle mass

BIA

Low skeletal mass associated with


post-transplant mortality in patients
undergoing LDLT

Krell et al. [5]


2013

207

33

Lowest tertile TPA

CT

Lower TPA was associated with higher


risk for post-transplant infectious
complications and mortality

50

40

SMMI 6.87 kg/m2 for men


and 5.46 kg/m2 and/or muscle
strength (hand grip); 24 kg for
men and 14 kg for women

BIA and
handgrip
strength

Patients with sarcopenia had low


values of energy intake per ideal
body weight and number of steps

Author/year

Hayashi et al. [16]


2013

Definition
of muscle
wasting

Method for
muscularity
assessment

Clinical
significance

BIA, bioelectrical impedance analysis; CT, computed tomography; HR, hazard ratio; LDLT, living donor liver transplantation; SMMI, skeletal muscle mass index;
TPA, total psoas area.

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Translational research in wasting diseases

We have found that 20% of our patients with


cirrhosis being evaluated for liver transplantation
had sarcopenic obesity, and low muscle attenuation
reflective of muscle fat infiltration was present in
more than 50% of patients [17].

BODY COMPOSITION EVALUATION IN


CIRRHOSIS
Cirrhotic patients commonly have significant
changes in their body composition mainly characterized by increase in the extracellular fluids and
decrease in muscle and adipose tissue; however,
clinical identification of body composition changes
in cirrhotic patients with ascites and edema might be
challenging, as fluid gains hide muscle and adipose
tissue losses. It seems that cirrhotic male patients
have more muscle wasting, whereas female patients
tend to have more depletion of fat tissue, and there
are studies that have shown that changes in body
composition may progress with the course of the liver
disease and correlate with the Child-Pugh score.
Numerous indirect methods have been used
to quantify body composition in cirrhosis, such
as total body electrical conductivity, bioelectrical
impedance, dual energy x-ray absorptiometry, air
displacement plethysmography, and magnetic
resonance spectroscopy. These methods are based
on the principle that body fat mass and lean mass
have specific components, such as water, proteins,
and minerals. Therefore, by establishing the total
body weight and fat mass, the remaining weight
should be lean mass. Unfortunately, most of these
methods lack either availability and/or reproducibility, and their accuracy may be limited in the
presence of fluid retention.
Other techniques include the skin-fold thickness measurement that quantifies fat mass in the
upper arm (mid-arm muscle area) using a caliper;
however, there have been conflicting reports in
the accuracy for predicting malnutrition in cirrhosis
because of interobserver variability, and this
method does not correlate with Child-Pugh score.
A recent study showed that low respiratory quotient
occurs in cirrhosis, and even this finding did not
predict mortality; the author reported a direct and
significant relation between respiratory quotient
and muscle area, which suggests that altered skeletal
muscle protein turnover contributes to this metabolic response [18 ].
&

muscle wasting. Recently, our group performed an


analysis of the frequency and clinical impact of
muscle wasting in cirrhotic patients being evaluated
for liver transplant [2]. We used CT scans at the 3rd
lumbar (L3) vertebrae analyzed with the SliceOmatic
V4.3 software (Tomovision, Montreal, Quebec,
Canada), which enables specific tissue demarcation using previously reported Hounsfield unit
thresholds. Skeletal muscle was identified and quantified by Hounsfield unit thresholds of 29 to 150,
and cross-sectional area of muscle and adipose tissue
was normalized for stature (cm2/m2) as reported in
previous studies [20]. The L3 skeletal muscle index
(L3 SMI) was expressed as cross-sectional muscle
area/height2, and cut-offs for muscle wasting were
based on a CT-based sarcopenic study for patients
with solid malignancies (L3 SMI: 38.5 cm2/m2
for women and 52.4 cm2/m2 for men) [21].
In addition, we recently set up new cut-off values
for cirrhotic patients, and values were similar compared with patients with malignancies (L3 SMI:
42 cm2/m2 for women and 50 cm2/m2 for men)
[22]. We also found that muscle wasting is not
exclusively present in underweight patients, and
constitutes a hidden condition that can be present
in cirrhotic patients with any BMI.
To exemplify that there is no adequate correlation of classical anthropometric measurement and
muscle wasting, in Fig. 2 we present images of the L3
SMI analysis of two cirrhotic patients with identical
BMI, but one with and another without muscle
wasting.

COMPLICATIONS OF MUSCLE WASTING


IN CIRRHOSIS
Muscle wasting is associated with mortality in
patients with cirrhosis. We have reported that
median survival for cirrhotic patients being evaluated for liver transplantation was significantly
worse in the presence of muscle wasting (19  6
vs. 34  11 months, log-rank, P 0.005) (Fig. 3).
Six-month probability of survival was 71% in sarcopenic, and 90% in nonsarcopenic patients, and this
higher mortality risk was related to sepsis-related
death rather than liver failure mortality [2]. This
may explain why conventional scores that reflect
mainly liver function, such as MELD and ChildPugh do not detect mortality risks associated with
muscle wasting.

MUSCLE WASTING EVALUATION IN


CIRRHOSIS

THERAPEUTIC OPTIONS FOR MUSCLE


WASTING IN CIRRHOSIS

CT scan and MRI are the gold standard tools to


quantify skeletal muscle mass [19] and, hence, constitute a good resource for objective nutritional
assessment of cirrhotic patients and detection of

In patients with cirrhosis, increased protein intake


has been demonstrated to be safe, well tolerated,
and beneficial; however, the long-term effects on
muscle mass are not completely elucidated. Other

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Muscle wasting: a criterion for liver transplant Montano-Loza

(a)

(b)

FIGURE 2. Computed tomography images used for the L3 skeletal muscle index (L3 SMI) assessment of two patients
with cirrhosis with identical BMI of 32 kg/m2. (a) Patient at the left is sarcopenic with L3 skeletal muscle index (L3 SMI) of
50 cm2/m2. (b) Patient at the right is not sarcopenic with a L3 SMI of 71 cm2/m2. Dark gray color indicates skeletal muscles.
Reproduced with permission from [2].

strategies that have been evaluated include lateevening snacks, repeated snacks, branched chain
amino acid, and protein supplementation in general
with beneficial results, but their impact on muscle
mass needs further investigation [16,23,24].
Intake of leucine-enriched essential amino acid
nutrient may be useful in the treatment of muscle
wasting in cirrhosis. Leucine is an essential amino
acid that serves as substrate for protein synthesis,
and has a key role in the regulation of the skeletal
muscle anabolism, protein synthesis, and autophagy. The activation of anabolic signaling occurs
via the mammalian target of rapamycin (mTOR)
through an undefined mechanism [25,26]. These
data suggest a potential role for leucine-rich supplements in the management of muscle depletion
in cirrhosis.
Exercise, including aerobic and resistance
physical activity are important for the muscle
metabolism. However, patients with cirrhosis frequently have complications of portal hypertension,
such as ascites or hepatic encephalopathy, or symptoms associated to chronic illness, including significant fatigue and reduced maximum exercise
capacity, which significantly reduce the physical
activity. In addition to this, even moderate exercise
augments the portal pressure and may increase the
risk of variceal bleeding in patients with esophageal
varices; therefore, cirrhotic patients with portal
hypertension should be advised of potential risks
during exercise, and patients who are able and
willing to enter in an exercise program may benefit
from pharmacological or endoscopic prophylaxis.
An interesting therapeutic approach in cirrhotic
muscle wasting could be the use of TIPS. A recent
study showed that TIPS may reverse muscle wasting,
and failure to improve muscle mass after TIPS is
associated with higher mortality [27,28]; however,

the utility of TIPS as an intervention to reverse


muscle wasting should be evaluated in future
prospective studies.
Myostatin is a member of the transforming
growth factor (b) superfamily that is an extremely
potent negative regulator of muscle mass. Preliminary investigations showed that myostatin plasmatic levels in cirrhotic patients compared with
healthy controls [29], and animal model studies
have shown that myostatin expression can be
reversed with administration of follistatin (functional antagonist of myostatin) without impairment
of liver function [30]; however, new treatments to
reverse muscle wasting in cirrhotic patients, including myostatin antagonists are waiting to be evaluated in randomized controlled trials.

MUSCLE WASTING AND LIVER


TRANSPLANTATION
The group from the University of Michigan has
reported that muscle wasting was associated with
a higher risk for post-transplant infectious complications and mortality [5,6]. A recent study showed
that muscle wasting measured by bioelectrical impedance was associated with higher post-transplant
mortality in patients undergoing living donor liver
transplantation [4].
Our group recently reported that muscle wasting
was predictive of longer length of hospitalization
and higher risk of perioperative bacterial infection
after liver transplantation, but was not associated
with increased mortality [31]. Further prospective
studies will be necessary to clarify the impact of
muscle wasting after liver transplantation.
Interestingly, in a subanalysis of nonprotocol
CT after liver transplant, we found that in patients
with muscle wasting before the transplant,

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Translational research in wasting diseases

sarcopenia resolved in at least 28% in a median time


of 43 months following transplantation, defined as
an increase in the L3 SMI more than 38.5 cm2/m2 for
women and more than 52.4 cm2/m2 for men after
liver transplant.
Failure of reversal of muscle wasting after liver
transplantation is not well elucidated. A recent
review summarizes the changes in indirect measures
of skeletal muscle mass after transplantation and
some studies reported an initial rapid postoperative
loss of muscle mass followed by incomplete recovery.
Potential reasons for failure to reverse muscle wasting
include the use of immunosuppression that impairs
skeletal muscle growth, repeated hospitalizations,
and post-transplant infections, among others [32].
A recent study from our group showed that
modification of MELD score to include muscle wasting is associated with a modest improvement in the
prediction of 3-month and 6-month mortality in
patients with cirrhosis. The c-statistics for 3-month
and 6-month mortality were 0.72 (95% confidence
interval, CI 0.630.82, P <0.001) and 0.71 (95% CI
0.630.79, P <0.001) for MELD, and 0.76 (95% CI
0.690.84, P <0.001) and 0.75 (95% CI 0.680.83,
P <0.001) for MELD-sarcopenia, respectively [33].
However, prior to the widespread use of MELDsarcopenia, additional validation in larger cohorts
of patients with cirrhosis is necessary.

CONCLUSION
Over the past years, the role of muscle wasting as one
of the most important factors that can influence
overall morbidity and mortality in cirrhosis has been
understood and appreciated. Despite the fact that
muscle wasting is not included in the conventional
scores for prognosis in cirrhosis, such as MELD or

100

88%

82%

Survival (%)

80
73%

60

63%
Log rank, P < 0.001

40
20

No sarcopenia (median survival 5822 months)


Sarcopenia (median survival 202 months)

0
0

10

12

14

16

18

20

22

24

Follow-up (months)

Pt followed (no.)
293

245

221

200

185

176

162

142

133

127

113

108

98

235

159

127

111

94

82

76

68

59

58

51

48

43

FIGURE 3. KaplanMeier curve indicating the survival of


cirrhotic patients with () and without () muscle wasting.
The 6-month probability of survival was 73 and 88%,
respectively (P <0.001, log-rank test).
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Child-Pugh, its presence should make clinicians


aware to the same extent as other complications,
such as ascites, jaundice, hepatic encephalopathy,
variceal bleeding, or hepatocellular carcinoma.
Modification of MELD score to include muscle
wasting (MELD-sarcopenia) is associated with a
modest improvement in the prediction of mortality
in patients with cirrhosis; however, additional validation in larger cohorts of patients with cirrhosis is
necessary. Because of the worldwide shortage of
organs for transplants, one of the imperative clinical
questions is the feasibility to treat muscle wasting in
cirrhosis without the need of liver transplantation.
Acknowledgements
The present study showed research results funded by a
Clinical Research Award from the American College of
Gastroenterology Institute.
Conflicts of interest
There are no conflicts of interest.

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