Received: 22 April 2019 | First decision: 20 May 2019 | Accepted: 13 October 2019

DOI: 10.1111/apt.15571

Review article: malnutrition/sarcopenia and frailty in patients

with cirrhosis

Chalermrat Bunchorntavakul1 | K. Rajender Reddy2

1
Division of Gastroenterology
and Hepatology, Department of
Medicine, Rajavithi Hospital, College of
Medicine, Rangsit University, Bangkok,
Thailand
2
Division of Gastroenterology
and Hepatology, Department of
Medicine, University of Pennsylvania,
Philadelphia, PA, USA
Correspondence
K. Rajender Reddy, Division of
Gastroenterology and Hepatology,
Department of Medicine, University of
Pennsylvania, 2 Dulles, 3400 Spruce Street,
Philadelphia, PA 19104, USA.
Email: reddyr@pennmedicine.upenn.edu
Summary
Background: Malnutrition/sarcopenia and frailty are common in patients with cir‐
rhosis and are associated with poor outcomes.
Aim: To provide an overview of data on the importance, assessment and manage‐
ment of malnutrition/sarcopenia and frailty in cirrhosis.
Methods: A literature search was conducted in PubMed and other sources, using
the search terms “sarcopenia,” “muscle,” “malnutrition,” “cirrhosis,” “liver” and “frailty”
from inception to April 2019, to identify the relevant studies and international
guidelines.
Results: The prevalence of malnutrition/sarcopenia in cirrhosis is 23%‐60%. Frailty
generally overlaps with malnutrition/sarcopenia in cirrhosis, leading to increased
morbidity and mortality. Rapid nutritional screening assessment should be per‐
formed in all patients with cirrhosis, and more specific tests for sarcopenia should
be performed in those at high risk. The pathogenesis of malnutrition/sarcopenia in
cirrhosis is complex/multifactorial and not just reduction in protein/calorie intake.
Hyperammonemia appears to be the main driver of sarcopenia in cirrhosis through
several molecular signalling pathways. Nutritional management in malnourished pa‐
tients with cirrhosis should be undertaken by a multidisciplinary team to achieve
adequate protein/calorie intake. While the role of branched‐chained amino acids
remains somewhat contentious in achieving a global benefit of decreasing mortality‐
and liver‐related events, they, and vitamin supplements, are recommended for those
with advanced liver disease. Novel strategies to reverse sarcopenia such as hormone
supplementation, long‐term ammonia‐lowering agents and myostatin antagonists,
are currently under investigation.
Conclusions: Malnutrition/sarcopenia and frailty are unique, inter‐related and multi‐
dimensional problems in cirrhosis which require special attention, prompt assessment
and appropriate management as they significantly impact morbidity and mortality.

The Handling Editor for this article was Dr Colin Howden, and this uncommissioned
review was accepted for publication after full peer‐review.

Aliment Pharmacol Ther. 2019;00:1–14. wileyonlinelibrary.com/journal/apt

© 2019 John Wiley & Sons Ltd | 1
2 | BUNCHORNTAVAKUL and REDDY

1 | I NTRO D U C TI O N
Malnutrition (or undernutrition) is a general term used to describe a
nutrition‐related disorder resulting from lack of intake or uptake of nu‐
trition that leads to altered body composition (decreased fat‐free mass)
1
and body cell mass. Sarcopenia is defined by generalised reduction in
muscle mass and function due to ageing (primary sarcopenia), or acute
or chronic illness (secondary sarcopenia), including cirrhosis. Frailty is
a multi‐dimensional construct that represents the end‐manifestation
of derangements of multiple physiologic systems leading to decreased
physiologic reserve and increased vulnerability to health stressors.2
These three conditions are increasingly common among patients with
cirrhosis, particularly in those with decompensated liver disease, and in
fact relatively overlap (but not identical), and all contributing to physi‐
cal deconditioning and increased mortality.1 The main components of
frailty are sarcopenia and physical impairment, which result in a cumu‐
lative decline in physiologic reserve.3 It has clearly been shown that in
those with cirrhosis and with malnutrition/sarcopenia/frailty there is
reduced quality of life and survival, increased rates of cirrhotic com‐
plications and infections and have worse outcomes following surgery
and liver transplantation (LT).1,3-5 The pathogenesis of these conditions
is complex and multifactorial and is more than just simple reduction of
5
protein and calorie intake. Hyperammonemia appears to be the main
driver of sarcopenia in cirrhosis through several molecular signalling
pathways.5,6 Prompt diagnosis and correction of malnutrition/sarcope‐
nia are very important, and have shown to improve the poor outcomes
to variable extents.1,4 Nutritional counselling and management in mal‐
nourished patients with cirrhosis should be performed by a multidisci‐
plinary team to be able to achieve adequate caloric/protein intake and
to avoid hypomobility. Branched‐chained amino acids (BCAA) and vi‐
tamin supplementations are recommended for patients with advanced
liver disease.1,4 Other and novel strategies to reverse sarcopenia are
6
currently under investigation.
2 | A S S E S S M E NT A N D D I AG N OS I S O F
M A LN U TR ITI O N/ SA RCO PE N I A A N D
FR A I LT Y I N C I R R H OS I S
The assessment of malnutrition/sarcopenia appears to be more
complicated among patients with cirrhosis as most conventional
methods may have some limitations.1,5,7-9 Estimation of nutri‐
tional status and muscle mass by anthropometry, such as body
mass index (BMI) and mid‐arm muscle circumference (MAMC),
may be influenced by features such as ascites and peripheral
fluid retention. Several laboratory tests for evaluating nutritional
status in general patients, such as serum albumin and retinol‐
binding protein, are produced by the liver and are decreased in
patients with advanced cirrhosis, with or without the presence
of malnutrition. Subjective global assessment (SGA), either gen‐
eral SGA or liver‐specific SGA, such as the Royal Free Hospital
Global Assessment, can be affected by altered laboratory tests
and physical deconditioning from advanced liver disease.1,7,10
Bioelectrical impedance analysis (BIA) also depends on stable
hydration status, which may be altered in those with cirrhosis.1
Thus, the measurement of thigh muscle thickness by ultrasound
has also been proposed.11 Despite some limitations, these con‐
ventional methods are inexpensive, widely available and practical
and therefore should be used as initial nutritional risk assessment
(screening methods) for all patients with cirrhosis, while more ac‐
curate tests, such as dual‐energy x‐ray absorptiometry (DEXA)
and computed tomographic (CT) scan to measure muscle area at
L3, can be used for the definite diagnosis of malnutrition/sarco‐
penia in cirrhosis.1,5,7-11 (Table 1 and Figure 1) In addition, frailty
has recently emerged as a strong predictor of outcomes in pa‐
tients with cirrhosis, independent of liver function, and has made
its way into decision‐making within LT. 2 Therefore, the American
Society of Transplantation has recommended risk stratification

TA B L E 1 Screening and diagnosis tools for sarcopenia in cirrhosis

Anthropometry BIA US DEXA CT/MRI

Measures Overall body size Prediction equations Thickness of muscle Whole‐body and X‐sectional area and
(BMI, MAC), to calculate lean and (thigh muscle regional integrity of specific
predicted muscle fat mass (by passing thickness) and sub‐ fat, lean, bone mineral muscle and adipose
(MAMC), predicted an electrical current cutaneous adipose content tissue groups (L3‐SMI,
visceral adipose tis‐ through the body) tissue, echogenicity and BMD muscle attenuation)
sue (WC, W:H, TSF) for tissue integrity
Simplicity +++ ++ + + +
Cost − + + ++ ++/+++
Validity + + +/++ ++ +++
Clinical ++ + + + +
application
Research −/+ + + ++/+++ +++
application

Abbreviations: BIA, bioelectrical impedance analysis; BMD, bone mass density; BMI, body mass index; CT, computed tomographic; DEXA, dual‐en‐
ergy x‐ray absorptiometry; MAC, mid‐arm circumference; MAMC, mid‐arm muscle circumference; MRI, magnetic resonance imaging; SMI, skeletal
muscle index; TSF, triceps skin fold; WC, waist circumference; W:H, waist/hip ratio; US, ultrasound.
BUNCHORNTAVAKUL and REDDY | 3

F I G U R E 1 Nutritional screening and Cirrhosis and advanced chronic liver disease

assessment in patients with cirrhosis
[adapted from EASL Clinical Practice Child C Child A or B
Guidelines on nutrition in chronic liver Assess fluid retention
disease. J Hepatol 2019;70(1):172‐193]; Estimate dry weight if needed
with permission. Abbreviations: BIA, BMI
<18.5 18.5-29.9 ≥30
bioelectrical impedance analysis; Nutritional assessment
BMI, body mass index; CT, computed Underweight Obesity and LSM
Screen for malnutrition
tomographic; DEXA, dual‐energy x‐ by screening tools* +
ray absorptiometry; LSM, lifestyle Consider assessing
modification; MAMC, mid‐arm muscle sarcopenia
High risk Medium risk Low risk
circumference; RFH, Royal Free Hospital;
SPPB, short physical performance battery;
Assess sarcopenia: Detailed nutritional
SGA, subjective global assessment • Consider CT to measure assessment (by dietician): Follow-up:
muscle area at L3 • SGA Re-assess at least
• Consider DEXA or BIA if • RFH-GA every 1 y
no fluid retention • Reported dietary intake

Sarcopenia Malnutrition No malnutrition

Treat:
• Nutritional supplementation
• Appropriate follow-up (every1-3 mo in the 1st y) *e.g. MAMC,HGS,SPPB,SGA

for LT candidates by using standardised simple frailty assessment
tools such as the Liver Frailty Index, Clinical Frailty Scale (CFS),
Six‐minute walk test, Karnofsky Performance Status scale and
Short Physical Performance Battery (SPPB). 2,12-16 Frailty tools
have been best studied in the outpatient setting (or in the pa‐
tients’ with steady state). 2
The diagnosis of sarcopenia virtually requires direct quantifica‐
tion of skeletal muscle mass by cross‐sectional imaging.1 CT scan
analysis at L3 level, reported as skeletal muscle index (L3‐SMI), is
a specific method to quantify muscle mass that has been shown
to be of higher accuracy in the diagnosis of sarcopenia in cirrhosis
than anthropometry or DEXA scan.1,5,7,17 Notably, it is currently the
most commonly utilised method in clinical studies investigating sar‐
copenia in cirrhosis. CT scan is commonly used for hepatocellular
carcinoma (HCC) surveillance in patients with cirrhosis and as such
may serve a dual purpose of calculating L3‐SMI, although special
software may be required. All measures require normal values that
are based on age, ethnicity and gender (lower predictive validity in
women).1,7,18 The mean muscle mass of Asians is approximately 15%
lower than that of Western population after height adjustments,
and ethnicity‐specific diagnostic criteria for sarcopenia may be nec‐
essary.19 Based on data from the US, the L3‐SMI cut‐off values of
less than 50 cm2/m2 in men and 39 cm2/m2 in women have been
suggested for the diagnosis of sarcopenia in patients with cirrho‐
sis as they correlated best with waitlist mortality.1,20 The Japanese
Guideline, however, has suggested using cut‐off values of 42 cm2/
2 2 2 21
m for men and 38 cm /m for women to define sarcopenia. Apart
from quantity, another consideration is the quality of skeletal mus‐
cle which can also be assessed indirectly by CT scan. CT attenuation
of the muscles in patients with cirrhosis appears to be lower (in‐
dicative of fatty infiltration or myosteatosis) than in those without
cirrhosis and such a feature has been correlated with adverse clini‐
cal outcomes.6,22
3 | PR E VA LE N C E O F M A LN U TR ITI O N/
SA RCO PE N I A A N D FR A I LT Y I N C I R R H OS I S
Malnutrition and sarcopenia are common in patients with cirrhosis
and appear to be correlated strongly with the severity of cirrhosis.
In a prospective study of 1053 patients with cirrhosis in Italy, the
prevalence of protein‐calorie malnutrition evaluated by anthropom‐
etry was 23%, 44% and 57% in patients with cirrhosis Child‐Pugh
(CP)‐A, CP‐B and CP‐C respectively. 23 Both adipose tissue and mus‐
cle tissue can be depleted; female patients more frequently develop
a depletion in fat deposits while males more rapidly lose muscle
tissue.1 In a Canadian study of 142 patients awaiting LT, the preva‐
lence of sarcopenia diagnosed by L3‐SMI was 51%. 24 Sarcopenia
was more prevalent in males vs females (54% vs 21%, P < .001) and
increased with the CP class (10%, 34% and 54% for CP‐A, CP‐B
and CP‐C, respectively, P = .007). 24 Interestingly, the prevalence
of sarcopenia increased with the advancing stages of liver disease
in males but not in females. There has been limited data regarding
the prevalence of sarcopenia in patients with cirrhosis in Asia. In a
Japanese study of 807 patients with chronic liver disease, sarcope‐
nia was encountered in 4%, 5% and 17% of patients with chronic
hepatitis, cirrhosis CP‐A and cirrhosis CP‐B/C respectively. 25
Similar to sarcopenia, frailty is common in patients with cirrho‐
sis, particularly in those with decompensated liver disease; however,
the prevalence of frailty is somewhat more difficult to report pre‐
cisely since there are several assessment tools, cut‐offs, and some‐
times being reported as a continuous index.3 In outpatient setting,
4 | BUNCHORNTAVAKUL and REDDY

the prevalence of frailty was 18% (defined by CFS > 4) among 300
16
patients with cirrhosis from various aetiologies (28% had ascites).
while the prevalence of frailty was up to 43% (defined by Fried
Frailty Index ≥ 3) among 542 patients with cirrhosis referred for LT
(52% had ascites). 26
Obesity is frequently observed in cirrhosis (20%‐40%), regard‐
less of the aetiology of liver disease, and patients with cirrhosis may
develop simultaneous loss of skeletal muscle and gain of adipose
tissue, culminating in the condition of sarcopenic obesity. 27,28 In an
analysis of 678 patients with cirrhosis (most were CP‐B), sarcopenia,
sarcopenic obesity and myosteatosis was present in 43%, 20% and
28
52% respectively.
Aetiology of cirrhosis appears to have less impact on nutrition
status, although some studies have reported that patients with al‐
coholic cirrhosis (particularly with active drinking) have higher prev‐
alence of malnutrition/sarcopenia when compared to non‐alcoholic
8,29,30
aetiologies. Apart from macronutrients, micronutrient and
vitamin deficiencies are frequently seen in patients with cirrhosis.
Patients with cholestasis are at higher risk of having fat‐soluble
vitamin deficiencies, particularly vitamin A and D.31 Vitamin D de‐
ficiency is almost universal in patients with advanced cirrhosis, par‐
32,33
ticularly from hepatitis C, cholestasis and alcohol. Deficiencies
of thiamine, folate, magnesium and zinc are commonly observed in
patients with advanced cirrhosis, especially from alcohol.34,35
4 | PATH O G E N E S I S O F M A LN U TR ITI O N
A N D SA RCO PE N I A I N C I R R H OS I S
The pathogenesis of malnutrition is cirrhosis is complex and multifac‐
torial that includes reduced nutrient intake, altered protein/energy
metabolism, maldigestion and malabsorption. In addition, frequent
fasting state and external factors, such as alcohol, infections, and
beta blockers use may further contribute to malnutrition in cirrho‐
sis7,36 (Figure 2). Alteration of macronutrient metabolism is a corner‐
stone mechanism contributing to malnutrition in cirrhosis.7 Protein
and amino acids metabolism is abnormal due to increased protein
catabolism, decreased protein synthesis, increased ureagenesis and
decreased serum BCAA/aromatic amino acids (AAA) ratio (Fischer's
ratio).8,36-38 Notably, BCAA are reduced due to increased utilisation
as the energy source and for ammonia disposal in the skeletal muscle,
while AAA are increased due to decreased metabolism from liver in‐
sufficiency and portosystemic shunting, and increased release from
protein degradation in the liver and muscle.37 The low Fischer's ratio
has been shown to be associated with the pathogenesis of compli‐
cations related to cirrhosis, such as hepatic encephalopathy (HE).38
Carbohydrate metabolism is abnormal and includes increased gluco‐
neogenesis, increased insulin resistance and glucose tolerance, and
impaired hepatic glycogen synthesis.8,36 Taken together, cirrhosis is
a state of accelerated starvation in which these effects are evident
after a short overnight fast (>6 hours) and which may resemble the
rate of fat and protein catabolism of healthy subjects undergoing
2‐3 days of starvation.39 Abnormal lipid metabolism includes in‐
creased lipolysis, oxidation of nonesterified fatty acids and ketogen‐
esis.8,36 In cirrhotic patients, the resting energy expenditure (REE)
is typically increased (~1.3‐fold higher than predicted REE) and the
total energy expenditure varies between 28 and 37.5 kcal/kg.BW/
day.1,4,6,40
The pathogenesis of sarcopenia in cirrhosis is even more complex
and is more than just reduced oral intake and negative macronutri‐
ents metabolism. Skeletal muscle mass is maintained by a balance
between protein synthesis, protein breakdown and regenerative
capacity regulated by muscle satellite cell function which involves
several metabolic‐tracer kinetics and molecular signalling pathways
(Figure 3).5,6 The two major skeletal muscle proteolytic pathways
are the ubiquitin‐proteasome pathway (UPP) and the autophagy

Reduced nutrient intake Altered protein/energy metabolism

• Anorexia, nausea/vomiting • Hypermetabolic state
• Altered taste • Altered protein and amino
• Impaired gastric expansion acids metabolism
(from ascites) • Altered CBH metabolism
• Impaired conscious state • Altered fat metabolism
• Protein/salt restriction

External factors
Malnutrition
• Infections
• SIRS
Maldigestion and
• Beta-blockers
malabsorption
• Alcohol
• Portosystematic shunting
• Bile salt and pancreatic Fasting status
enzymes deficiency
• GI bleeding F I G U R E 2 Factors contributing to
• Enteropathy malnutrition in cirrhosis. Abbreviations:
• Altered mental status
CBH, carbohydrates; GI, gastrointestinal;
• Bacterial overgrowth • Before and after SIRS, systemic inflammatory response
medical procedures
syndrome
BUNCHORNTAVAKUL and REDDY | 5

F I G U R E 3 Pathogenesis and potential Liver transplant

therapeutic options for sarcopenia in
Potential Portal HT Ammonia
cirrhosis. Abbreviations: ATB, antibiotics; treatments
BCAA, branched‐chain amino acids;
Lower
mTOR, mammalian target of rapamycin TIPS ammonia Nutrition support

Mitochodrial Nutrient
Myostatin
dysfunction intake

M Follistatin
Endotoxin ito Starvation
p Myostatin antagonists
ag rote response
Systemic en ct mTOR
ts ive
inflammation AT mTOR
B
An , pro agonists
tio bio
xid ti BCAA
Testosterone an cs
ts
Growth hormone
BCAA supplement
Hormone supplement Anaplerotic agents
Vitamin D supplement
Exe
Decreased muscle rcise Physical
Vitamin D inactivity
mass and contractile
function

system. 5 The UPP is the major muscle breakdown pathway, and in‐
volves the tagging of protein by conjugation with ubiquitin and then
subsequent degradation by the 26S proteasome, and both physical
inactivity and systemic inflammation (common in cirrhosis) activate
5
the UPP. Several potential mediators of the liver‐muscle axis have
been proposed including hyperammonemia,41-44 endotoxemia,45 de‐
46 47,48
creased follistatin, testosterone and growth hormone. In addi‐
tion, amino acid perturbations, specifically reduction in the BCAA,
l‐leucine and consequent impaired global protein synthesis has also
been reported to contribute to sarcopenia in cirrhosis. 1,37,49
Both hepatocellular dysfunction and portosystemic shunting
contribute to impaired ureagenesis and hyperammonemia in cir‐
rhosis. Apart from the liver, skeletal muscle is the main source for
ammonia disposal, which is increasingly prominent when advanced
cirrhosis evolves. In patients with cirrhosis, decreased muscle mass
compromises the place to detoxify ammonia and vice versa in that
hyperammonemia has shown to be the main driver of sarcopenia,
mainly through the myostatin‐mediated pathway. 5,6 Myostatin is
a potent autocrine growth inhibitor (member of the transforming
growth factor beta (TGF‐β) family) produced by myocytes that in‐
hibits skeletal muscle growth and reduces muscle mass through
41,50
impaired mammalian target of rapamycin (mTOR) signalling.
Hyperammonemia upregulates myostatin expression by inducing
transcriptional regulation of myostatin via NF‐κB‐mediated path‐
way.41,50 In addition, hyperammonemia also mediates muscle au‐
42 51
tophagy and impair muscle contractility. Notably, BCAA have
several potential benefits in maintaining liver‐muscle axis in cirrhosis
including the stimulation of protein synthesis, inhibition of proteoly‐
sis and autophagy, and improving insulin resistance and β‐cell func‐
tion.37,49,52,53 In the presence of hyperammonemia, serum BCAA
levels are further decreased as BCAA are important source of gluta‐
mate, which are increasingly used to detoxify ammonia by glutamine
37,49,52
synthetase in the skeletal muscle and also in the brain.
Follistatin, a negative regulator of myostatin and other muscle
growth inhibitors of TGF‐β family, has also been proposed to me‐
diate liver‐muscle axis.46,54 It is secreted by the hepatocyte and is
regulated by the glucagon‐to‐insulin ratio.46,54 Baseline plasma lev‐
els of follistatin are similar or slightly elevated in patients with cir‐
rhosis and chronic inflammatory conditions as compared to healthy
controls55-57; however, the capacity to acutely secrete follistatin is
impaired in patients with cirrhosis.46 The cause of altered follistatin
release in cirrhosis in unknown, but may be related to several factors
such as decreased hepatic synthetic function, abnormal glucose me‐
tabolism, and glucagon and insulin resistance.46
4.1 | Post‐transplant sarcopenia
Unlike other complications of cirrhosis that are generally improved
(or even reversed) after LT, the course of sarcopenia following LT is
variable with either improvement, remaining unchanged or continu‐
ing to decline.58-63 Further reduction in skeletal muscle mass follow‐
ing LT is most intense during the 1st year and may reverse thereafter,
while muscle functions generally improve early after LT and before
the improvement in muscle mass.60,61,63,64 Increased weight and BMI
are commonly observed following LT (median weight gain is 4‐6 kg at
1 year and 8‐10 kg at 3 year); however, much of this weight gain is an
increase in fat mass and sarcopenic obesity can be increasingly seen
in this population.58-61
The underlying pathogenesis and mediators of post‐LT sarco‐
penia are unclear. Several immunosuppressive agents, especially
corticosteroids and mTOR inhibitors, have negative impact on skel‐
etal muscle and appear to be the key drivers of post‐LT sarcope‐
nia (Table 2).65-70 Although hyperammonemia resolves after LT, the
reversibility of hyperammonemia‐induced signalling responses and
impaired protein synthesis following LT are not known.6 A prospec‐
tive study in 53 LT recipients (100% received calcineurin inhibitors,
6 | BUNCHORNTAVAKUL and REDDY

Agents
Corticosteroids65
Calcineurin inhibitors66,67
mTOR inhibitors68,69
MMF70
TA B L E 2 Effects of
Clinically relevant
immunosuppressive agents on skeletal
Effects of skeletal muscle strength of effect
muscle
Induce muscle protein catabolism +++
Non‐specific type II fiber atrophy
(steroid‐induced myopathy)
Inhibit muscle growth and hypertrophy ++
(intracellular calcineurin activation
regulates genes involved in skeletal
muscle growth and remodeling)
Increase myostatin expression
Prevent a switch in the type of muscle fiber
from slow to fast fibers
Block protein synthesis responses and ++
accelerate autophagy
No/minimal effects –/+
A case of reversible MMF‐induced myopa‐
thy has been reported

Abbreviations: MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin.

15% received mTOR inhibitors and 21% received corticosteroids) re‐
vealed that the skeletal muscle expression of myostatin was higher
and that of UPP components lower in LT recipients than in con‐
62
trols. This may suggest that epigenetic changes in the regulatory
molecules/mediators can result in long‐term or persistent sarcope‐
nia even after LT.6
5 | CO N S EQ U E N C E S O F M A LN U TR ITI O N
SA RCO PE N I A A N D FR A I LT Y I N C I R R H OS I S
The presence of malnutrition and/or sarcopenia in cirrhosis is associ‐
ated with worsened clinical outcomes in various (almost all) aspects,
including survival, in addition to the effects from the liver disease
itself (Figure 4).6,7,71-76 Muscle is crucial for mobility, metabolic regu‐
lation of glucose and lipids, heart and respiratory function, immune
function, and cytokine activity.7 Thus, there is a strong interplay be‐
tween malnutrition, sarcopenia, physical deconditioning and frailty
in cirrhosis. A number of cross‐sectional and longitudinal studies
using different diagnostic methods have reported that survival rates
are lower in cirrhotic patients with sarcopenia.6,7,71-74 The impact of
sarcopenia on prognosis in cirrhosis is beyond the degree of portal
hypertension and MELD score,73,74 and in fact, the modification of
MELD to include sarcopenia (Sarcopenia‐MELD) has shown to im‐
prove the prediction of mortality in patients with cirrhosis, primarily
in patients with low MELD (score < 15).77 Interestingly, in Asian pop‐
ulation‐based studies, sarcopenia in Asian populations had more im‐
pact on mortality related to sarcopenia than in Western populations

Encephalopathy* Bacterial infection Physical activity

Quality of life* Overall survival* Peri/post-operative

complications

Advanced Malnutrition
liver disease
Frailty

In LT
Sarcopenia
In HCC
Waitlist mortality*
Overall survival*
Peri-LT complications*
Treatment-related
complications* Post-LT survival
F I G U R E 4 Consequences of
malnutrition/sarcopenia/frailty in
Metabolic complications
* Supported by strong evidence cirrhosis. Abbreviation: LT, liver
(sarcopenic obesity)
transplantation
BUNCHORNTAVAKUL and REDDY | 7

TA B L E 3 Potential therapeutic strategies for malnourished/sarcopenia patients with cirrhosis

Intervention Administration Mechanism Potential outcomes

High energy and protein Ensure total calorie intake
diet1,4 of ≥ 35 kcal/kg/d and
protein intake ≥ 1.5 g/kg/d
(if oral intake is inad‐
equate, a period of EN is
recommended)
Late evening snack88-90 ≥50 g of complex carbohy‐
drate snack/meal with pro‐
tein, preferably high BCAA
BCAA supplementation BCAA 0.25 g/kg/d
53,91-93
supplementation
Exercise 102-107,130 A combination of aerobic
and resistance exercise in
moderate intensity (under
supervision)
Testosterone Testosterone IM or gel for
supplement5,48 patients with low serum
testosterone
Zinc supplement114,115 150‐200 mg of elemental
zinc/d
Vitamin D Vitamin D 600‐1000 IU/d
supplement116,117 (preferably with calcium
1000‐1500 mg/d); correct
deficiency if in vitamin D
levels <20 ng/mL, to reach
>30 ng/mL
Long‐term ammonia‐ Rifaximin, lactulose, LOLA,
lowering strategies5,43 anaplerotic agents
Reversal of portal TIPS placement
hypertension121,122
Antagonising my‐ Myostatin antagonists, fol‐
ostatin‐mediated listatin, mTOR agonists
pathway6,125-127
• Improves nitrogen balance • Improves muscle mass
• Decreases skeletal muscle proteolysis • Improves quality of life
• Improves liver functions
• Reduces liver‐related
complications
• Improves survival
• Decreases lipid oxidation and improves • Improves muscle mass,
nitrogen balance • Improves quality of life
• Decreases skeletal muscle proteolysis dur‐ • Improves liver functions
ing overnight fasting
• Activates muscle protein synthesis through • Improves muscle mass
mTOR signalling pathway • Improves quality of life
• Decreases muscle autophagy • Improves HE
• Helps detoxifying ammonia • Improves liver functions
• Improves event‐free survival
• Activates IGF‐1 → increased mTOR and • Improves functional capacity
downregulation of muscle breakdown via and fatigue,
the UPP • Increases muscle mass and
• Increased phosphatidic acid in the muscle strength
that directly stimulates mTOR signalling • Decreases body fat
• Increased expression of follistatin mRNA in • Decreases HVPG
the liver and plasma follistatin
• Activates androgen receptors in muscle • Increases muscle and bone
which inhibits myostatin, activates muscle mass
protein synthesis via the mTOR pathway • Increases haemoglobin
and downregulates the UPP • Reduces fat mass
• Reduces HbA1c
• Improves symptoms of zinc deficiency, for • Improves taste sensation
example, altered taste, loss of appetite, and • May improve liver functions
encephalopathy and mental status
• Prevents negative effects of vitamin D • Reduces bone loss
deficiency on musculoskeletal and other • May increase BMD
systems • May improve musculoskeletal
• Vitamin D deficiency is associated with functions (eg increase muscle
increased mortality in cirrhosis strength and reduced fall)
• Downregulates myostatin‐mediated • Theoretically may increase
pathway muscle mass (no human
• Decreases muscle autophagy studies)
• Improves muscle contractility • Improves HE
• Reduces HVPG • Reduces ascites
• May reduce metabolic rate • May increase muscle mass
• May improve nutrient absorption and • Can precipitate HE and ACLF
systemic inflammation
• Downregulates myostatin‐mediated • Improves muscle mass and
pathway functions in elderly (no studies
• Enhances mTOR signalling in cirrhosis)

Abbreviations: ACLF, acute‐on‐chronic liver failure; BCAA, branched‐chain amino acids; BMD, bone mass density; EN, enteral nutrition; HE, hepatic
encephalopathy; HVPG, hepatic venous portal gradient; IGF, insulin‐like growth factor; LOLA, L‐ornithine‐L‐aspartate; mTOR, mammalian target of
rapamycin; TIPS, transjugular intrahepatic portosystemic shunt; UPP, ubiquitin‐proteasome pathway.

(HR 2.45 vs HR 1.45 respectively).71 The cause(s) of higher mortal‐
ity is, however, not as evident though both increased risk of infec‐
6,72
tion and HE may be contributing factors. HE is more frequent
in sarcopenic than nonsarcopenic cirrhotic patients.78 Physical ac‐
tivity and quality of life are likely to be impaired in patients with
malnutrition/sarcopenia due to reduced muscle mass and contrac‐
tile function.79,80 Sarcopenia may also impair diaphragmatic work
due to reduced muscle mass and this event may facilitate pulmo‐
nary complications especially in the context of surgery.69 In pa‐
tients with HCC, sarcopenia is an independent prognostic factor of
8 | BUNCHORNTAVAKUL and REDDY

decreasing survival, and increasing treatment‐related complications

and mortality. 22,81 In addition, sarcopenic obesity and myosteatosis
are independently associated with a higher long‐term mortality in
cirrhosis. 28
In the setting of LT, malnutrition, sarcopenia and frailty ad‐
versely impact outcomes in patients on the waitlist, in the peri‐
LT and post‐LT period.1,2,6,12,13 The presence of sarcopenia is
predictive of waitlist mortality in addition to MELD score. 6,24
Furthermore, the presence of frailty is associated with waitlist
mortality independent of MELD and CP scores. 2,12,13,82 Of note,
frailty appears to be a more useful indicator for functional ca‐
pacity or quality of life in LT candidates, than the presence of
sarcopenia.14 During peri‐LT period, malnourished/sarcopenic
patients commonly have prolonged the length of intensive care
unit and hospital stay, longer time of mechanical ventilation
and higher rate of infections compared with those who are well
7,12,62,63,73,83
nourished.
Following LT, pre‐LT sarcopenia is associated with decreased
medium‐term survival. 61,62,84,85 The severity of pre‐LT frailty has
been shown to be an independent predictor of patient and graft
survival. 86,87 LT recipients who have low performance status be‐
fore LT and do not show an improvement in performance status
between 3 and 12 months after liver transplant have very poor
survival. 86 Notably, sarcopenic obesity has been increasingly re‐
ported in LT recipients and may contribute to the development of
metabolic consequences of insulin resistance, diabetes mellitus,
hyperlipidemia and possibly recurrent or de novo fatty liver, which
may eventually increase cardiovascular morbidity in the long
6,61,85
term. It should be noted that the degree of frailty and sar‐
copenia should not be used as the sole criterion for delisting a pa‐
tient for LT, but rather should be considered one of many criteria
when evaluating transplant candidacy and suitability. 2 Currently,
whether or not patients with low MELD and sarcopenia should
be prioritised for LT (MELD exception) is debatable at this stage.
6 | M A N AG E M E NT O F M A LN U TR ITI O N
A N D SA RCO PE N I A I N C I R R H OS I S
6.1 | Nutritional support and BCAA
supplementation
Nutritional counselling should be provided for malnourished cir‐
rhotic patients, when possible, by a multidisciplinary team, and thus
helping patients to achieve adequate caloric and protein intake.1,4
General nutritional recommendations and potential therapeutic
strategies for malnutrition/sarcopenia in patients with cirrhosis are
summarised in Figure 5 and Table 3. It should be emphasised that the
optimal daily energy intake should not be lower than 35 kcal/kg/d (in
non‐obese individuals) and protein intake should not be lower than
1.2‐1.5 g/kg/d (amount of protein > 1.5 g/kg/d should be ingested
to replenish malnourished and/or sarcopenic state).1,4 The daily in‐
take should be divided into frequent small meals and/or snack (5‐6
times/d) and, of importance, late evening oral nutritional supplemen‐
tation containing ≥ 50 g of complex carbohydrates must be included,
as it has been shown to be more effective on substrate utilisa‐
tion and nitrogen retention than daytime calorie supplementation
alone.1,4,88-90 Several studies have demonstrated that late evening
snack or meal is an effective intervention to prevent and to reverse
sarcopenia in cirrhosis, resulting in an improvement in quality of life
and also liver functions. 88-90 Notably, when prescribing a low sodium
(<2‐3 g/d) diet, the increased risk of even lower food intake (due to
unpalatability) should be balanced against its moderate advantage in
the treatment of ascites.4
The decreased levels of BCAA in the blood plasma (also
Fischer's ratio) is the hallmark of cirrhosis and which plays a role
in pathogenesis of HE, sarcopenia and impaired liver regenera‐
tion. 37,38,52 Therefore, BCAA are a preferred source of amino acids
in cirrhotic patients and BCAA supplementation seems theoreti‐
cally rationale. 37,52 (Figure 6) Among the BCAAs (leucine, isoleucine

Recommended total energy intake: 35-40 kcal/kg/d

Frequent meals and snacks (5-6 times/d)

Protein >1.2-1.5 g/kg/d
• Encourage vegetable proteins
• BCAA (0.25 g/kg/d) and leucine
enriched AA supplementation for
decompensated cirrhosis
CBH 50-70%
• Consider BCAA if encephalopathy
• Late-evening snack/meal
(>50 g complex CBH)
• Low glycemic index and high-fiber
CBH sources are preferred
• Reduce simple sugars, esp. fructose F I G U R E 5 General nutritional
• Restrict CBH if NAFLD and/or DM
recommendations for malnourished
Fat 10-20% patients with cirrhosis. Abbreviations: AA,
• High unsaturated fat
Sodium restriction <2-3 g/d, amino acids; BCAA, branched‐chain amino
is preferred acids; CBH, carbohydrates; DM, diabetes
if ascites and/or edema
• Include adequate mellitus; NAFLD, non‐alcoholic fatty liver
essential fatty acids Water restriction, if Na <130
disease
BUNCHORNTAVAKUL and REDDY | 9

F I G U R E 6 Possible targets and Prevention and Prevention and Repair and

outcomes of BCAA supplementation in treatment of
the management of malnourished patients sarcopenia
with cirrhosis. Abbreviations: AAA,
aromatic amino acids; BCAA, branched‐ • Activates mTOR
chain amino acids; HCC, hepatocellular signaling pathway –
carcinoma; HGF, hepatocyte growth stimulates protein
factor; mTOR, mammalian target of synthesis (improves
muscle mass)
rapamycin
• Inhibits proteolysis
Improves insulin
•
resistance and β-cell
function
treatment of
encephalopathy
• Facilitates ammonia
detoxification (through
glutamine synthetase)
in skeletal muscle and
brain
• Normalizes Fischer’s
ratio – decrease brain
influx of AAA
• Improves cerebral
blood flow
regeneration of
injured liver
• Energy/protein source
• Stimulates HGF
production by hepatic
stellate cells
• Enhances production
of glutamine –
stimulates liver
regeneration
• Suppresses HCC
carcinogenesis

Muscle mass Encephalopathy* Liver functions

Muscle strength Quality of life* Liver biomarkers
Serum albumin Hospital stay
Liver events The grey boxes represent
*Supported by strong evidence
Survival potential modes of action
(there is low-moderate evidence
based on experimental evidence
for the other outcomes)

and valine), leucine is particularly crucial in increasing muscle pro‐
tein synthesis. 38,44,53 Several clinical trials, including three RCTs
(n = 174,91 n = 64692 and n = 11693) and one large prospective study
94
(n = 267), have demonstrated the positive effects of BCAA sup‐
plementation in malnourished cirrhotic patients, such as improve‐
ment in nutritional status, liver functions, HE, quality of life and
37,38,52
event‐free survival. There were few unique observations
among these BCAA trials that included: (a) the BCAA dose ranged
from 12 to 30 g/d; (b) beneficial effects were predominantly seen
in those with advanced liver disease and/or previous HE and (c) ad‐
herence to BCAA supplementation was moderate (75%‐90%) even
in the context of RCT which may be partly explained by its unpalat‐
ability for some patients. Accordingly, the European Guidelines on
nutrition in liver disease have recommended long‐term oral BCAA
supplement (0.25 g/kg/d) in patients with advanced cirrhosis in
order to improve event‐free survival or quality of life, particularly
when adequate nitrogen intake is not achieved by oral diet (grade
of recommendation B by ESPEN and evidence and Grade II‐1, C1
by EASL).1,4
In patients with chronic HE, the optimal daily protein and en‐
ergy intake should not be lower than the general recommenda‐
tions for patients with cirrhosis. Diets rich in vegetables and dairy
protein are encouraged as they have higher Fischer's ratio and
possibly prebiotic properties (eg decreased intestinal transit time,
reduced intraluminal pH and increased faecal ammonia excre‐
tion).1,95 BCAA supplementation should be considered to improve
neuropsychiatric performance and to reach the recommended ni‐
trogen intake, particularly in those who are intolerant to dietary
1
proteins. It should be emphasised that protein intake should not
be restricted in patients with episodic HE admitted to hospital as
it increases protein catabolism rate.4 A small RCT in this context
showed that the normal content of protein intake is metabolically
more adequate than low‐protein diets, and without negative im‐
pact on HE recovery.96
In malnourished patients with cirrhosis who are unable to
achieve adequate dietary intake (even with oral supplements), a pe‐
riod of enteral nutrition (EN) is recommended.1 Oesophageal varices
are not an absolute contraindication for placing a nasogastric tube.4
Some, however, recommend withholding EN for 48‐72 h after acute
variceal bleeding because EN may increase splanchnic blood flow,
which in turn may increase portal pressure and the risk of re‐bleed‐
ing.1,97 Percutaneous endoscopic gastrostomy placement is associ‐
ated with a higher risk of complications and should only be used in
exceptional cases.4 Parenteral nutrition (PN) should be used in cir‐
rhotic patients in whom oral and/or EN are ineffective or not fea‐
sible.1,4 A meta‐analysis of nutrition therapy in cirrhosis (13 RCT; 9
EN, 4 PN) revealed significant beneficial effects on clinical outcomes
including mortality, overt HE and infections, although all included
trials were classed as having a high risk of bias.98 In general, stan‐
dard nutrition regimens can be utilised since specialised regimens (eg
BCAA‐enriched, immune‐enhancing diets) have not been shown to
improve morbidity or mortality in intervention trials.1 Meta‐analyses
of BCAA‐enriched EN formula and PN solution showed an improve‐
ment in mental state, but no definite benefit in survival and other
outcomes.99,100
Nutritional management of obese cirrhotic patients, particu‐
larly with sarcopenia, is even more complicated and often requires
a specialised multidisciplinary team.1,27,101 In general, a nutritional
and lifestyle program to achieve progressive weight loss (>5%‐10%)
should be implemented.1 A tailored, moderately hypocaloric
(−500‐800 kcal/d) diet, including adequate protein intake (>1.5 g/
kg/d) can be adopted to achieve weight loss without compromising
protein stores in obese cirrhotic patients.1,101 Furthermore, obese
cirrhotic patients can be given EN and/or PN with a target energy
10 | BUNCHORNTAVAKUL and REDDY
of 25 kcal/kg/d and an increased target protein intake of 2.0‐2.5 g/
4
kg/d.
6.2 | Exercise
Physical inactivity and frailty are highly prevalent, independent pre‐
dictors of morbidity and mortality in patients with cirrhosis.102,103
Consistent with the broader chronic disease literature, the experi‐
mental and clinical evidence for a benefit of exercise in cirrhosis is
promising. Several small clinical trials have demonstrated significant
improvements in muscle health (mass, strength, functional capacity),
quality of life, fatigue, cardiopulmonary fitness and reductions in
the hepatic venous pressure gradient, without adverse events.102-107
Unfortunately, most patients (63%‐92%) included in these trials were
cirrhosis CP‐A, while patients at the lower end of physical decondi‐
tioning (CP‐B/C) have not been evaluated systematically so far.102,103
Patients with cirrhosis, whenever possible, can be encouraged to
avoid hypomobility and to progressively increase physical activity
to prevent and/or ameliorate sarcopenia.1 It is reasonable to recom‐
mend 30‐to‐60‐minute sessions of supervised moderated intensity
exercise combining both aerobic and resistance training to achieve
≥150 min/wk for cirrhotic patients.102,103 Aerobic training would
be particularly relevant to improve overall fitness, while resistance
training would help reverse sarcopenia, improve strength and bal‐
ance, and bone mineral density.102,103 Whether the use of weights
is appropriate for patients with varices is unclear, and thus weight‐
bearing exercises or repetitions with small weights (eg 0.5‐1 kg) may
be advised.103
6.3 | Hormones and micronutrient replacement
Testosterone and growth hormone have been evaluated in chronic
liver disease to improve nutritional status and, potentially, muscle
mass in cirrhosis but have not been consistently beneficial.6,48,108-110
It is possible that the effects of testosterone may be blunted by
increased aromatase activity in patients with cirrhosis which then
enhances the conversion of testosterone to estradiol.6 Thus, admin‐
istration of an aromatase inhibitor has shown to improve nutritional
and endocrine abnormalities in rats with portocaval anastomosis.111
A RCT (n = 101) has demonstrated that testosterone therapy for
1 year in men with cirrhosis and low serum testosterone safely in‐
creases muscle mass, bone mass and haemoglobin, and reduces fat
mass.48 Nevertheless, despite controversies, cautions should be ex‐
ercised when using long‐term testosterone replacement therapy due
to the possibility of increased risk of cardiovascular events, poly‐
cythemia, cholestasis, prostate cancer and HCC.1,112,113
Specific evidence about the beneficial effect, especially on mus‐
cle mass, of micronutrients and vitamin supplementation in cirrhotic
patients is not available. However, confirmed clinically suspected
deficiency should be treated based on accepted general recom‐
1
mendations. Zinc and vitamin D deficiency are being increasingly
recognised to contribute to worse clinical outcomes in patients with
cirrhosis. Zinc deficiency may manifest several ways in cirrhosis,
including altered taste and smell, poor appetite, hair loss, skin lesions,
poor wound healing/liver regeneration, altered mental status or al‐
tered immune function.34,114 Zinc supplementation (150‐200 mg/d
taken with a meal to decrease the potential side effect of nausea) has
shown to at least improve taste sensation in cirrhosis.114,115 Likewise,
the data on vitamin D supplementation in improving outcomes are
not robust but the data regarding poor outcomes in cirrhosis with
vitamin D deficiency are compelling.116,117 Research experience in
the elderly suggests that vitamin D supplementation may have ben‐
efits on musculoskeletal system (eg increased bone density, mus‐
cle strength and physical activity)118,119; however, whether these
findings can be extrapolated for those with cirrhosis is unknown.
Vitamin D level should be checked in all malnourished patients with
cirrhosis and supplemental vitamin D orally in those with vitamin D
levels < 20 ng/mL, to reach serum 25(OH) vitamin D > 30 ng/mL is
recommended.1
6.4 | Other strategies
Long‐term ammonia‐lowering strategies may result in increased
muscle mass and strength; however, apart from indirectly by BCAA
supplementation, the data are derived from preclinical studies and
require further validation in humans.6,43 A 4‐week ammonia‐lower‐
ing therapy by L‐ornithine‐L‐aspartate and rifaximin has shown to
improve skeletal muscle mass and functions in hyperammonemic
portacaval anastomosis rats.43 Potential novel strategies to lower
muscle ammonia include the use of cell permeable esters of a alpha‐
ketoglutarate that can provide a direct anaplerotic influx with the
removal of ammonia as glutamine.6 In addition, isoleucine and va‐
line may help detoxifying ammonia as anaplerotic substrates but the
molecular and functional responses to these interventions have not
been evaluated in clinical studies to lower muscle ammonia or re‐
verse sarcopenia.6 Similarly, long‐term ammonia lowering by rifaxi‐
min plus lactulose has shown to improve HE and survival in patients
with cirrhosis and overt HE,120 but its impact on skeletal muscle has
not been directly investigated.
Reducing portal pressure by transjugular intrahepatic portosys‐
temic shunt (TIPS) placement may have beneficial effects on muscle
mass.121 A small uncontrolled trial demonstrated a significant in‐
crease in 72% of patients following successful TIPS placement.122
Furthermore, the improvement of sarcopenia after TIPS was accom‐
panied by lower mortality (43.5%) compared with patients in whom
sarcopenia had not improved (9.8% vs 43.5%, P = .007).122 It is to be
recognised that apart from reduce portal pressure, many other fac‐
tors such as reduced ascites, reduced metabolic rate and improved
nutrition could have contributed to the beneficial effects.5,121 Of
note, caution is needed when performing TIPS in malnourished pa‐
tients with cirrhosis as sarcopenia is a risk factor for the develop‐
ment of HE and acute‐on‐chronic liver failure after TIPS.123,124
Novel approaches, such as myostatin antagonists,125-127 folli‐
statin,128 direct mTORC1 activators,53,129 antioxidants6 and mito‐
chondrial protective agents,6 theoretically have potential benefits
on liver‐muscle axis, but have not been adequately evaluated in
BUNCHORNTAVAKUL and REDDY
clinical studies. In sarcopenic rats with portocaval anastomosis, the
inhibitory effect of myostatin is abolished by injections of follista‐
tin, resulting in increased skeletal muscle mass and muscle synthetic
rate.128 Notably, small RCTs (Phase II) evaluating myostatin antibody
have demonstrated positive effects on muscle mass in older and
weak fallers126 and patients undergoing elective total hip arthro‐
plasty.127 Further clinical studies are required before these interven‐
tions can be translated to clinical practice, especially for those with
cirrhosis.
AC K N OW L E D G E M E N T
Declaration of personal interests: None.
AU T H O R S H I P
Guarantor of the article: K. R. Reddy.
Author contributions: C. Bunchorntavakul: conceptualised,
searched and reviewed literature, created the tables and drafted the
manuscript. KR Reddy: conceptualised and critically reviewed the
paper.
Both authors approved the final version of the manuscript.
ORCID
Chalermrat Bunchorntavakul https://orcid.
org/0000-0002-8842-032X
K. Rajender Reddy https://orcid.org/0000-0002-4898-7778
REFERENCES
1. Merli M, Berzigotti A, Zelber‐Sagi S, et al. Practice guidelines on
nutrition in chronic liver disease. J Hepatol. 2019;70:172‐193.
2. Lai JC, Sonnenday CJ, Tapper EB, et al. Frailty in liver transplan‐
tation: an expert opinion statement from the American Society of
Transplantation Liver and Intestinal Community of Practice. Am J
Transplant. 2019;19:896‐1906.
3. Ebadi M, Montano‐Loza AJ. Sarcopenia and frailty in the progno‐
sis of patients on the liver transplant waiting list. Liver Transplant.
2019;25:7‐9.
4. Plauth M, Bernal W, Dasarathy S, et al. ESPEN guideline on clinical
nutrition in liver disease. Clin Nutr. 2019;38:485‐521.
5. Sinclair M, Gow PJ, Grossmann M, Angus PW. Review article: sar‐
copenia in cirrhosis–aetiology, implications and potential thera‐
peutic interventions. Aliment Pharmacol Ther. 2016;43:765‐777.
6. Dasarathy S, Merli M. Sarcopenia from mechanism to diag‐
nosis and treatment in liver disease. J Hepatol. 2016;65:1232‐
1244.
7. Tandon P, Raman M, Mourtzakis M, Merli M. A practical approach
to nutritional screening and assessment in cirrhosis. Hepatology.
2017;65:1044‐1057.
8. Zhao VM, Ziegler TR. Nutrition support in end‐stage liver disease.
Crit Care Nurs Clin North Am. 2010;22:369‐380.
9. Santos LAA, Lima TB, Ietsugu MDV, Nunes HRC, Qi X, Romeiro
FG. Anthropometric measures associated with sarcopenia in
outpatients with liver cirrhosis. Nutr Diet. 2019. https​://doi.
org/10.1111/1747-0080.12523​. [Epub ahead of print.]
| 11
10. Morgan MY, Madden AM, Soulsby CT, Morris RW. Derivation and
validation of a new global method for assessing nutritional status
in patients with cirrhosis. Hepatology. 2006;44:823‐835.
11. Tandon P, Low G, Mourtzakis M, et al. A model to identify sar‐
copenia in patients with cirrhosis. Clin Gastroenterol Hepatol.
2016;14:1473‐1480; e1473.
12. Wang CW, Feng S, Covinsky KE, et al. A comparison of muscle
function, mass, and quality in liver transplant candidates: results
from the functional assessment in liver transplantation study.
Transplantation. 2016;100:1692‐1698.
13. Lai JC, Covinsky KE, Dodge JL, et al. Development of a novel
frailty index to predict mortality in patients with end‐stage liver
disease. Hepatology. 2017;66:564‐574.
14. Yadav A, Chang Y‐H, Carpenter S, et al. Relationship between sar‐
copenia, six‐minute walk distance and health‐related quality of life
in liver transplant candidates. Clin Transplant. 2015;29:134‐141.
15. Carey EJ, Steidley DE, Aqel BA, et al. Six‐minute walk distance
predicts mortality in liver transplant candidates. Liver Transplant.
2010;16:1373‐1378.
16. Tandon P, Tangri N, Thomas L, et al. A rapid bedside screen to
predict unplanned hospitalization and death in outpatients with
cirrhosis: a prospective evaluation of the clinical frailty scale. Am J
Gastroenterol. 2016;111:1759‐1767.
17. Giusto M, Lattanzi B, Albanese C, et al. Sarcopenia in liver cirrho‐
sis: the role of computed tomography scan for the assessment of
muscle mass compared with dual‐energy X‐ray absorptiometry
and anthropometry. Eur J Gastro Hepatol. 2015;27:328‐334.
18. Peng S, Plank LD, McCall JL, Gillanders LK, McIlroy K, Gane EJ.
Body composition, muscle function, and energy expenditure in pa‐
tients with liver cirrhosis: a comprehensive study. Am J Clin Nutr.
2007;85:1257‐1266.
19. Chen L‐K, Liu L‐K, Woo J, et al. Sarcopenia in Asia: consensus re‐
port of the Asian Working Group for Sarcopenia. J Am Med Dir
Assoc. 2014;15:95‐101.
20. Carey EJ, Lai JC, Wang CW, et al. A multicenter study to define sar‐
copenia in patients with end‐stage liver disease. Liver Transplant.
2017;23:625‐633.
21. Nishikawa H, Shiraki M, Hiramatsu A, Moriya K, Hino K, Nishiguchi
S. Japan Society of Hepatology guidelines for sarcopenia in liver
disease (1st edition): Recommendation from the working group
for creation of sarcopenia assessment criteria. Hepatol Res.
2016;46:951‐963.
22. Fujiwara N, Nakagawa H, Kudo Y, et al. Sarcopenia, intramuscular
fat deposition, and visceral adiposity independently predict the
outcomes of hepatocellular carcinoma. J Hepatol. 2015;63:131‐140.
23. Merli M, Riggio O, Dally L. Does malnutrition affect survival in cir‐
rhosis? PINC (Policentrica Italiana Nutrizione Cirrosi). Hepatology.
1996;23:1041‐1046.
24. Tandon P, Ney M, Irwin I, et al. Severe muscle depletion in patients
on the liver transplant wait list: its prevalence and independent
prognostic value. Liver Transplant. 2012;18:1209‐1216.
25. Hiraoka A, Michitaka K, Ueki H, et al. Sarcopenia and two types of
presarcopenia in Japanese patients with chronic liver disease. Eur
J Gastro Hepatol. 2016;28:940‐947.
26. Cron DC, Friedman JF, Winder GS, et al. Depression and frailty in
patients with end‐stage liver disease referred for transplant evalu‐
ation. Am J Transplant. 2016;16:1805‐1811.
27. Berzigotti A, Garcia‐Tsao G, Bosch J, et al. Obesity is an indepen‐
dent risk factor for clinical decompensation in patients with cirrho‐
sis. Hepatology. 2011;54:555‐561.
28. Montano‐Loza AJ, Angulo P, Meza‐Junco J, et al. Sarcopenic obe‐
sity and myosteatosis are associated with higher mortality in pa‐
tients with cirrhosis. J Cachexia Sarcopenia Muscle. 2016;7:126‐135.
29. Tai ML, Goh KL, Mohd‐Taib SH, Rampal S, Mahadeva S.
Anthropometric, biochemical and clinical assessment of
12 | BUNCHORNTAVAKUL and REDDY
malnutrition in Malaysian patients with advanced cirrhosis. Nutr J.
2010;9:27.
30. Roongpisuthipong C, Sobhonslidsuk A, Nantiruj K,
Songchitsomboon S. Nutritional assessment in various stages of
liver cirrhosis. Nutrition. 2001;17:761‐765.
31. Phillips JR, Angulo P, Petterson T, Lindor KD. Fat‐soluble vitamin
levels in patients with primary biliary cirrhosis. Am J Gastroenterol.
2001;96:2745‐2750.
32. Konstantakis C, Tselekouni P, Kalafateli M, Triantos C. Vitamin
D deficiency in patients with liver cirrhosis. Ann Gastroenterol.
2016;29:297‐306.
33. Lim LY, Chalasani N. Vitamin d deficiency in patients with chronic
liver disease and cirrhosis. Curr Gastroenterol Rep. 2012;14:67‐73.
34. Mohammad MK, Zhou Z, Cave M, Barve A, McClain CJ. Zinc and
liver disease. Nutr Clin Pract. 2012;27:8‐20.
35. Katayama K, Kawaguchi T, Shiraishi K, et al. The prevalence and
implication of zinc deficiency in patients with chronic liver disease.
J Clin Med Res. 2018;10:437‐444.
36. Cheung K, Lee SS, Raman M. Prevalence and mechanisms of malnu‐
trition in patients with advanced liver disease, and nutrition man‐
agement strategies. Clin Gastroenterol Hepatol. 2012;10:117‐125.
37. Holecek M. Three targets of branched‐chain amino acid sup‐
plementation in the treatment of liver disease. Nutrition.
2010;26:482‐490.
38. Ooi PH, Gilmour SM, Yap J, Mager DR. Effects of branched chain
amino acid supplementation on patient care outcomes in adults
and children with liver cirrhosis: A systematic review. Clin Nutr
ESPEN. 2018;28:41‐51.
39. Owen OE, Reichle FA, Mozzoli MA, et al. Hepatic, gut, and renal
substrate flux rates in patients with hepatic cirrhosis. J Clin Investig.
1981;68:240‐252.
40. Greco AV, Mingrone G, Benedetti G, Capristo E, Tataranni PA,
Gasbarrini G. Daily energy and substrate metabolism in patients
with cirrhosis. Hepatology. 1998;27:346‐350.
41. Qiu J, Thapaliya S, Runkana A, et al. Hyperammonemia in cir‐
rhosis induces transcriptional regulation of myostatin by an
NF‐kappaB‐mediated mechanism. Proc Natl Acad Sci USA.
2013;110:18162‐18167.
42. Qiu J, Tsien C, Thapalaya S, et al. Hyperammonemia‐mediated au‐
tophagy in skeletal muscle contributes to sarcopenia of cirrhosis.
Am J Physiol Endocrinol Metab. 2012;303:E983‐993.
43. Kumar A, Davuluri G, Silva RNE, et al. Ammonia lowering reverses
sarcopenia of cirrhosis by restoring skeletal muscle proteostasis.
Hepatology. 2017;65:2045‐2058.
44. Davuluri G, Krokowski D, Guan B‐J, et al. Metabolic adaptation of
skeletal muscle to hyperammonemia drives the beneficial effects
of l‐leucine in cirrhosis. J Hepatol. 2016;65:929‐937.
45. Kovarik M, Muthny T, Sispera L, Holecek M. The dose‐dependent
effects of endotoxin on protein metabolism in two types of rat
skeletal muscle. J Physiol Biochem. 2012;68:385‐395.
46. Rinnov AR, Plomgaard P, Pedersen BK, Gluud LL. Impaired
follistatin secretion in cirrhosis. J Clin Endocrinol Metab.
2016;101:3395‐3400.
47. Mowat NA, Edwards CR, Fisher R, McNeilly AS, Green JR, Dawson
AM. Hypothalamic‐pituitary‐gonadal function in men with cirrho‐
sis of the liver. Gut. 1976;17:345‐350.
48. Sinclair M, Grossmann M, Hoermann R, Angus PW, Gow PJ.
Testosterone therapy increases muscle mass in men with cirrho‐
sis and low testosterone: a randomised controlled trial. J Hepatol.
2016;65:906‐913.
49. Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched‐chain
amino acids as pharmacological nutrients in chronic liver disease.
Hepatology. 2011;54:1063‐1070.
50. Garcia PS, Cabbabe A, Kambadur R, Nicholas G, Csete M. Brief‐
reports: elevated myostatin levels in patients with liver disease:
a potential contributor to skeletal muscle wasting. Anest Analg.
2010;111:707‐709.
51. McDaniel J, Davuluri G, Hill EA, et al. Hyperammonemia results in
reduced muscle function independent of muscle mass. Am J Physiol
Gastrointest Liver Physiol. 2016;310:G163‐170.
52. Holecek M. Branched‐chain amino acid supplementation in treat‐
ment of liver cirrhosis: Updated views on how to attenuate their
harmful effects on cataplerosis and ammonia formation. Nutrition.
2017;41:80‐85.
53. Tsien C, Davuluri G, Singh D, et al. Metabolic and molecular re‐
sponses to leucine‐enriched branched chain amino acid supple‐
mentation in the skeletal muscle of alcoholic cirrhosis. Hepatology.
2015;61:2018‐2029.
54. Hansen JS, Rutti S, Arous C, et al. Circulating follistatin is liver‐
derived and regulated by the glucagon‐to‐insulin ratio. J Clin
Endocrinol Metab. 2016;101:550‐560.
55. Sakamoto Y, Shintani Y, Harada K, Abe M, Shitsukawa K, Saito
S. Determination of free follistatin levels in sera of normal
subjects and patients with various diseases. Eur J Endocrinol.
1996;135:345‐351.
56. Yuen MF, Norris S, Evans LW, Langley PG, Hughes RD. Transforming
growth factor‐beta 1, activin and follistatin in patients with hepa‐
tocellular carcinoma and patients with alcoholic cirrhosis. Scand J
Gastroenterol. 2002;37:233‐238.
57. Tomoda T, Nouso K, Miyahara K, et al. Prognotic impact of serum
follistatin in patients with hepatocellular carcinoma. J Gastroenterol
Hepatol. 2013;28:1391‐1396.
58. Pravisani R, Soyama A, Isola M, et al. Chronological changes in
skeletal muscle mass following living‐donor liver transplantation:
An analysis of the predictive factors for long‐term post‐transplant
low muscularity. Clin Transplant. 2019;33:e13495.
59. Schütz T, Hudjetz H, Roske A‐E, et al. Weight gain in long‐term
survivors of kidney or liver transplantation–another paradigm of
sarcopenic obesity? Nutrition. 2012;28:378‐383.
60. Bergerson JT, Lee J‐G, Furlan A, et al. Liver transplantation arrests
and reverses muscle wasting. Clin Transplant. 2015;29:216‐221.
61. Kallwitz ER. Sarcopenia and liver transplant: the relevance of too
little muscle mass. World J Gastroenterol. 2015;21:10982‐10993.
62. Tsien C, Garber A, Narayanan A, et al. Post‐liver transplantation
sarcopenia in cirrhosis: a prospective evaluation. J Gastroenterol
Hepatol. 2014;29:1250‐1257.
63. Bhanji RA, Takahashi N, Moynagh MR, et al. The evolution and
impact of sarcopenia pre‐ and post‐liver transplantation. Aliment
Pharmacol Ther. 2019;49:807‐813.
64. Kaido T, Tamai Y, Hamaguchi Y, et al. Effects of pretransplant sar‐
copenia and sequential changes in sarcopenic parameters after
living donor liver transplantation. Nutrition. 2017;33:195‐198.
65. Gupta A, Gupta Y. Glucocorticoid‐induced myopathy:
Pathophysiology, diagnosis, and treatment. Indian J Endocrinol
Metab. 2013;17:913‐916.
66. Michel RN, Chin ER, Chakkalakal JV, Eibl JK, Jasmin BJ. Ca2+/calm‐
odulin‐based signalling in the regulation of the muscle fibre pheno‐
type and its therapeutic potential via modulation of utrophin A and
myostatin expression. Appl Physiol Nutr Metab. 2007;32:921‐929.
67. Semsarian C, Wu M‐J, Ju Y‐K, et al. Skeletal muscle hypertrophy
is mediated by a Ca2+‐dependent calcineurin signalling pathway.
Nature. 1999;400:576‐581.
68. Bodine SC, Stitt TN, Gonzalez M, et al. Akt/mTOR pathway is a
crucial regulator of skeletal muscle hypertrophy and can prevent
muscle atrophy in vivo. Nat Cell Biol. 2001;3:1014‐1019.
69. Dasarathy S. Consilience in sarcopenia of cirrhosis. J Cachexia
Sarcopenia Muscle. 2012;3:225‐237.
70. Galindo M, Cabello A, Joven B, et al. Mycophenolate mofetil in‐
duced myopathy in a patient with lupus nephritis. J Rheumatol.
2005;32:188‐190.
BUNCHORNTAVAKUL and REDDY
71. Kim G, Kang SH, Kim MY, Baik SK. Prognostic value of sarcopenia
in patients with liver cirrhosis: A systematic review and meta‐anal‐
ysis. PLoS ONE. 2017;12:e0186990.
72. van Vugt JL, Levolger S, de Bruin RW, van Rosmalen J, Metselaar
HJ, IJzermans JNM. Systematic review and meta‐analysis of the
impact of computed tomography‐assessed skeletal muscle mass
on outcome in patients awaiting or undergoing liver transplanta‐
tion. Am J Transplant. 2016;16:2277‐2292.
73. Kalafateli M, Mantzoukis K, Choi Yau Y, et al. Malnutrition and
sarcopenia predict post‐liver transplantation outcomes inde‐
pendently of the model for end‐stage liver disease score. J
Cachexia Sarcopenia Muscle. 2017;8:113‐121.
74. Kang SH, Jeong WK, Baik SK, Cha SH, Kim MY. Impact of sarco‐
penia on prognostic value of cirrhosis: going beyond the hepatic
venous pressure gradient and MELD score. J Cachexia Sarcopenia
Muscle. 2018;9:860‐870.
75. Bunchorntavakul C, Supanun R, Atsawarungruangkit A. Nutritional
status and its impact on clinical outcomes for patients admitted to
hospital with cirrhosis. J Med Assoc Thai. 2016;99(Suppl 2):S47‐55.
76. Bhanji RA, Carey EJ, Watt KD. Review article: maximising quality
of life while aspiring for quantity of life in end‐stage liver disease.
Aliment Pharmacol Ther. 2017;46:16‐25.
77. Montano‐Loza AJ, Duarte‐Rojo A, Meza‐Junco J, et al. Inclusion
of sarcopenia within MELD (MELD‐sarcopenia) and the prediction
of mortality in patients with cirrhosis. Clin Transl Gastroenterol.
2015;6:e102.
78. Merli M, Giusto M, Lucidi C, et al. Muscle depletion increases the
risk of overt and minimal hepatic encephalopathy: results of a pro‐
spective study. Metab Brain Dis. 2013;28:281‐284.
79. Ohashi K, Ishikawa T, Hoshi A, et al. Relationship between sar‐
copenia and both physical activity and lifestyle in patients with
chronic liver disease. J Clin Med Res. 2018;10:920‐927.
80. Hayashi F, Matsumoto Y, Momoki C, et al. Physical inactivity and
insufficient dietary intake are associated with the frequency of
sarcopenia in patients with compensated viral liver cirrhosis.
Hepatol Res. 2013;43:1264‐1275.
81. Levolger S, van Vledder MG, Muslem R, et al. Sarcopenia impairs
survival in patients with potentially curable hepatocellular carci‐
noma. J Surg Oncol. 2015;112:208‐213.
82. Lai JC, Rahimi RS, Verna EC, et al. Frailty associated with waitlist
mortality independent of ascites and hepatic encephalopathy in a
multicenter study. Gastroenterology. 2019;156:1675‐1682.
83. Merli M, Giusto M, Gentili F, et al. Nutritional status: its influence
on the outcome of patients undergoing liver transplantation. Liver
Int. 2010;30:208‐214.
84. Hamaguchi Y, Kaido T, Okumura S, et al. Impact of quality as well
as quantity of skeletal muscle on outcomes after liver transplanta‐
tion. Liver Transplant. 2014;20:1413‐1419.
85. Kamo N, Kaido T, Hamaguchi Y, et al. Impact of sarcopenic obesity
on outcomes in patients undergoing living donor liver transplanta‐
tion. Clin Nutr. 2019;38:2202‐2209.
86. Thuluvath PJ, Thuluvath AJ, Savva Y. Karnofsky performance sta‐
tus before and after liver transplantation predicts graft and patient
survival. J Hepatol. 2018;69:818‐825.
87. Dolgin NH, Martins PN, Movahedi B, Lapane KL, Anderson FA,
Bozorgzadeh A. Functional status predicts postoperative mortal‐
ity after liver transplantation. Clin Transplant. 2016;30:1403‐1410.
88. Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploit‐
ing a period of anabolic opportunity in cirrhosis. J Gastroenterol
Hepatol. 2012;27:430‐441.
89. Plank LD, Gane EJ, Peng S, et al. Nocturnal nutritional supplemen‐
tation improves total body protein status of patients with liver cir‐
rhosis: a randomized 12‐month trial. Hepatology. 2008;48:557‐566.
90. Chen CJ, Wang LC, Kuo HT, Fang YC, Lee HF. Late‐evening
snacking improves liver functions in patients with liver cirrhosis:
| 13
a meta‐analysis of randomized controlled trials. J Gastroenterol
Hepatol. 2019;34:1143‐1152.
91. Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementa‐
tion with branched‐chain amino acids in advanced cirrhosis: a dou‐
ble‐blind, randomized trial. Gastroenterology. 2003;124:1792‐1801.
92. Muto Y, Sato S, Watanabe A, et al. Effects of oral branched‐chain
amino acid granules on event‐free survival in patients with liver
cirrhosis. Clin Gastroenterol Hepatol. 2005;3:705‐713.
93. Les I, Doval E, García‐Martínez R, et al. Effects of branched‐chain
amino acids supplementation in patients with cirrhosis and a pre‐
vious episode of hepatic encephalopathy: a randomized study. Am
J Gastroenterol. 2011;106:1081‐1088.
94. Kawaguchi T, Shiraishi K, Ito T, et al. Branched‐chain amino acids
prevent hepatocarcinogenesis and prolong survival of patients
with cirrhosis. Clin Gastroenterol Hepatol. 2014;12:1012‐1018;
e1011.
95. Amodio P, Bemeur C, Butterworth R, et al. The nutritional man‐
agement of hepatic encephalopathy in patients with cirrhosis:
International Society for Hepatic Encephalopathy and Nitrogen
Metabolism Consensus. Hepatology. 2013;58:325‐336.
96. Córdoba J, López‐Hellı́n J, Planas M, et al. Normal protein diet for
episodic hepatic encephalopathy: results of a randomized study. J
Hepatol. 2004;41:38‐43.
97. de Ledinghen V, Beau P, Mannant PR, et al. Early feeding or enteral
nutrition in patients with cirrhosis after bleeding from esophageal
varices? A randomized controlled study. Dig Dis Sci. 1997;42:536‐541.
98. Fialla AD, Israelsen M, Hamberg O, Krag A, Gluud LL. Nutritional
therapy in cirrhosis or alcoholic hepatitis: a systematic review and
meta‐analysis. Liver Int. 2015;35:2072‐2078.
99. Naylor CD, O'Rourke K, Detsky AS, Baker JP. Parenteral nutrition
with branched‐chain amino acids in hepatic encephalopathy. A
meta‐analysis. Gastroenterology. 1989;97:1033‐1042.
100. Gluud LL, Dam G, Les I, et al. Branched‐chain amino acids for
people with hepatic encephalopathy. Cochrane Database Syst Rev.
2017;5:Cd001939.
101. Everhart JE, Lok AS, Kim H, et al. Weight‐related effects on dis‐
ease progression in the hepatitis C antiviral long‐term treatment
against cirrhosis trial. Gastroenterology. 2009;137:549‐557.
102. Tandon P, Ismond KP, Riess K, et al. Exercise in cirrhosis:
translating evidence and experience to practice. J Hepatol.
2018;69:1164‐1177.
103. Duarte‐Rojo A, Ruiz‐Margain A, Montano‐Loza AJ, Macias‐
Rodriguez RU, Ferrando A, Kim WR. Exercise and physical activ‐
ity for patients with end‐stage liver disease: Improving functional
status and sarcopenia while on the transplant waiting list. Liver
Transplant. 2018;24:122‐139.
104. Berzigotti A, Albillos A, Villanueva C, et al. Effects of an inten‐
sive lifestyle intervention program on portal hypertension in pa‐
tients with cirrhosis and obesity: the SportDiet study. Hepatology.
2017;65:1293‐1305.
105. Román E, García‐Galcerán C, Torrades T, et al. Effects of an exer‐
cise programme on functional capacity, body composition and risk
of falls in patients with cirrhosis: a randomized clinical trial. PLoS
ONE. 2016;11:e0151652.
106. Zenith L, Meena N, Ramadi A, et al. Eight weeks of exercise train‐
ing increases aerobic capacity and muscle mass and reduces
fatigue in patients with cirrhosis. Clin Gastroenterol Hepatol.
2014;12:1920‐1926.e1922.
107. Kruger C, McNeely ML, Bailey RJ, et al. Home exercise training
improves exercise capacity in cirrhosis patients: role of exercise
adherence. Sci Rep. 2018;8(1):99.
108. Matsumoto R, Fukuoka H, Iguchi G, et al. Long‐term effects of
growth hormone replacement therapy on liver function in adult
patients with growth hormone deficiency. Growth Hormone IGF
Res. 2014;24:174‐179.
14 | BUNCHORNTAVAKUL and REDDY
109. Rambaldi A, Gluud C. Anabolic‐androgenic steroids for alcoholic
liver disease. Cochrane Database Syst Rev. 2006;4:Cd003045.
110. Yurci A, Yucesoy M, Unluhizarci K, et al. Effects of testosterone gel
treatment in hypogonadal men with liver cirrhosis. Clin Res Hepatol
Gastroenterol. 2011;35:845‐854.
111. Dasarathy S, Mullen KD, Dodig M, Donofrio B, McCullough AJ.
Inhibition of aromatase improves nutritional status following por‐
tacaval anastomosis in male rats. J Hepatol. 2006;45:214‐220.
112. Grech A, Breck J, Heidelbaugh J. Adverse effects of testosterone
replacement therapy: an update on the evidence and controversy.
Ther Adv Drug Saf. 2014;5:190‐200.
113. Johnson FLeonard, Lerner KennethG, Siegel M, et al. Association
of androgenic‐anabolic steroid therapy with development of hepa‐
tocellular carcinoma. Lancet. 1972;2:1273‐1276.
114. Grungreiff K, Reinhold D, Wedemeyer H. The role of zinc in liver
cirrhosis. Ann Hepatol. 2016;15:7‐16.
115. Weismann K, Christensen E, Dreyer V. Zinc supplementation in
alcoholic cirrhosis. A double‐blind clinical trial. Acta Med Scand.
1979;205:361‐366.
116. Bjelakovic G, Nikolova D, Bjelakovic M, Gluud C. Vitamin D supple‐
mentation for chronic liver diseases in adults. Cochrane Database
Syst Rev. 2017;11:Cd011564.
117. Yang F, Ren H, Gao Y, Zhu Y, Huang W. The value of severe vitamin
D deficiency in predicting the mortality risk of patients with liver cir‐
rhosis: a meta‐analysis. Clin Res Hepatol Gastroenterol. 2019. https​://
doi.org/10.1016/j.clinre.2019.03.001. [Epub ahead of print.]
118. Bischoff‐Ferrari HA, Dawson‐Hughes B, Staehelin HB, et al.
Fall prevention with supplemental and active forms of vita‐
min D: a meta‐analysis of randomised controlled trials. BMJ.
2009;339:b3692.
119. Wintermeyer E, Ihle C, Ehnert S, et al. Crucial Role of Vitamin D in
the Musculoskeletal System. Nutrients. 2016;8(6):319.
120. Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK.
A randomized, double‐blind, controlled trial comparing rifaximin
plus lactulose with lactulose alone in treatment of overt hepatic
encephalopathy. Am J Gastroenterol. 2013;108:1458‐1463.
121. Dasarathy J, Alkhouri N, Dasarathy S. Changes in body composi‐
tion after transjugular intrahepatic portosystemic stent in cirrho‐
sis: a critical review of literature. Liver Int. 2011;31:1250‐1258.
122. Tsien C, Shah SN, McCullough AJ, Dasarathy S. Reversal of sarco‐
penia predicts survival after a transjugular intrahepatic portosys‐
temic stent. Eur J Gastro Hepatol. 2013;25:85‐93.
123. Nardelli S, Lattanzi B, Torrisi S, et al. Sarcopenia is risk factor for
development of hepatic encephalopathy after transjugular intra‐
hepatic portosystemic shunt placement. Clin Gastroenterol Hepatol.
2017;15:934‐936.
124. Praktiknjo M, Clees C, Pigliacelli A, et al. Sarcopenia is associated
with development of acute‐on‐chronic liver failure in decompen‐
sated liver cirrhosis receiving transjugular intrahepatic portosys‐
temic shunt. Clin Transl Gastroenterol. 2019;10(4):e00025.
125. Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin path‐
way antagonism: molecular basis and therapeutic potential. Int J
Biochem Cell Biol. 2013;45:2333‐2347.
126. Becker C, Lord SR, Studenski SA, et al. Myostatin antibody
(LY2495655) in older weak fallers: a proof‐of‐concept, randomised,
phase 2 trial. Lancet Diabetes Endocrinol. 2015;3:948‐957.
127. Woodhouse L, Gandhi R, Warden SJ, et al. A phase 2 randomized
study investigating the efficacy and safety of myostatin antibody
LY2495655 versus placebo in patients undergoing elective total
hip arthroplasty. J Frailty Aging. 2016;5:62‐70.
128. Dasarathy S, McCullough AJ, Muc S, et al. Sarcopenia associated
with portosystemic shunting is reversed by follistatin. J Hepatol.
2011;54:915‐921.
129. Carroll B, Korolchuk VI, Sarkar S. Amino acids and autophagy:
cross‐talk and co‐operation to control cellular homeostasis. Amino
Acids. 2015;47:2065‐2088.
130. Hansen J, Brandt C, Nielsen AR, et al. Exercise induces a marked
increase in plasma follistatin: evidence that follistatin is a contrac‐
tion‐induced hepatokine. Endocrinology. 2011;152:164‐171.
How to cite this article: Bunchorntavakul C, Reddy KR.
Review article: malnutrition/sarcopenia and frailty in patients
with cirrhosis. Aliment Pharmacol Ther. 2019;00:1–14. https​://
doi.org/10.1111/apt.15571​