Curr Gastroenterol Rep (2016) 18:43
DOI 10.1007/s11894-016-0516-y
NUTRITION AND OBESITY (S MCCLAVE AND J OBERT, SECTION EDITORS)
Sarcopenia in Patients with Chronic Liver Disease: Can It Be
Altered by Diet and Exercise?
Matthew R. Kappus 1 & Mardeli Saire Mendoza 2 & Douglas Nguyen 3 & Valentina Medici 4 &
Stephen A. McClave 5
# Springer Science+Business Media New York 2016
Abstract Sarcopenia, a loss of muscle mass, is being increas-
ingly recognized to have a deleterious effect on outcomes in
patients with chronic liver disease. Factors related to diet and
the inflammatory nature of chronic liver disease contribute to
the occurrence of sarcopenia in these patients. Sarcopenia ad-
versely influences quality of life, performance, morbidity, suc-
cess of transplantation, and even mortality. Specific deficiencies
in macronutrients (protein, polyunsaturated fatty acids) and
micronutrients (vitamins C, D, and E, carotenoids, and selenium)
have been linked to sarcopenia. Lessons learned from nutritional
therapy in geriatric patient populations may provide strategies to
manage sarcopenia in patients with liver disease. Combining diet
modification and nutrient supplementation with an organized
program of exercise may help ameliorate or even reverse the
effects of sarcopenia on an already complex disease process.
Keywords Sarcopenia . Muscle wasting . Malnutrition .
Liver disease . Cirrhosis . Portal hypertension . Protein
malnutrition
This article is part of the topical collection on Nutrition and Obesity
* Matthew R. Kappus
matthew.kappus@duke.edu
1
Department of Medicine, Duke University Medical Center, DUMS
03142, Orange Zone, Durham, NC 27710, USA
2
Department of Medicine, Ochsner Clinic, New Orleans, LA, USA
3
Department of Medicine, College of Medicine, University of
CaliforniaIrvine, Irvine, CA, USA
4
Department of Medicine, University of California-Davis, Davis, CA,
USA
5
Department of Medicine, School of Medicine, University of
Louisville, Louisville, KY, USA
Introduction
The liver transplant allocation system utilizes the model for end-
stage liver disease (MELD) score to prioritize organs to the most
ill patients. It is a validated tool that not only predicts wait-list
survival but also has successfully reduced wait-list mortality
among liver transplant candidates by prioritizing the most ill to
receive organ offers first [1]. In an effort to improve the success of
liver transplantation, measures of post-transplantation survival
such as age, hospitalization status, and medical comorbidities
are being studied [2, 3]. Due to the impact of reduced muscle
mass on survival and other measurable post-transplant outcomes,
there is renewed interest in examining the impact of sarcopenia on
the post-operative stay and survival in relation to liver transplan-
tation (LT). Sarcopenia has been identified as a contributor to
longer hospitalization, increased frequency of infections within
90 days of LT, and a lower post-transplant survival when com-
pared to non-sarcopenic patients [4]. Efforts are underway to
understand the implications of sarcopenia for developing preven-
tative strategies for early intervention.
With advanced age or chronic illness often comes sarcopenia
which is a loss of muscle mass and strength [5]. This is a com-
mon condition that is recognized as part of aging [6]. While
expected, the rate of decline varies, which suggests that factors
other than aging like chronic illness, diet, and lifestyle may in-
fluence the maintenance of healthy muscle mass and function [5,
7, 8]. This paper considers these modifiable risks that associate
diet to muscle mass and strength. Here, we review strategies to
prevent or delay sarcopenia in patients with chronic liver disease.
Sarcopenia and Chronic Liver Disease
As we age, food intake falls by almost 25 % between the ages
of 40 and 70 years old [9]. The mechanisms that explain this
43 Page 2 of 7
include the physiological and psychological, as well as social
influences on appetite and food consumption. As one ages,
there is reduced olfaction and taste, more sensation of satiety,
difficulty with mastication, and impaired gut motility [10]. In
addition to mechanisms associated with aging, patients with
chronic liver disease have additional reasons which lead to
malnutrition. The mechanisms for the Banorexia of chronic
liver disease^ are attributed to medications, metabolic and
hormonal alterations, the pro-inflammatory state, and hepatic
encephalopathy [11]. These changes which have such a neg-
ative impact on the will to eat are further compounded by the
effects of functional impairments that impact mobility and
ability to access and prepare food. As there is significant over-
lap between sarcopenia and malnutrition, sarcopenia can serve
as a marker for reduced nutritional status.
The prevalence of malnutrition varies according to the def-
inition used, but studies of patients with liver disease suggest
that potentially half to as much as 100 % may have some level
of malnutrition [12, 13]. Due to the effect of liver impairment
on muscle wasting, a significant number of patients with liver
disease are believed to be sarcopenic. This effect of liver dis-
ease on sarcopenia may persist after liver transplantation, de-
spite the reversal of the metabolic and clinical consequences
of cirrhosis [14, 15]. After transplantation factors including
the persistence of collateral blood flow, immunosuppressant
medications that inhibit the mechanistic target of rapamycin
(mTOR) and stimulate myostatin, recurrent infections which
induce catabolism, renal failure, and lifestyle changes with
reduced or no exercise all may play a role in the persistence
of sarcopenia after liver transplantation [16]. With greater
improvement in peri-operative and operative management of
patients with liver disease at the time of transplantation, nutri-
tional improvement has very tangible implications on quality
of life, morbidity, and mortality measures.
Diet as a Modifiable Influence on Sarcopenia
Diet may very well have direct influence on sarcopenia and
functional status. Declining energy intake due to reduced food
intake in the setting of maintained or increased energy expen-
diture leads to weight loss sarcopenia [9]. When patients with
liver disease consume smaller amounts of food, it becomes
difficult for patients to meet their nutrient needs. This area of
study is relatively new, but the known nutrient deficiencies
linked to this decline in muscle mass in the elderly include
protein, vitamin D, and antioxidant agents such as selenium
and vitamins E and C [17]. In the geriatrics literature, also
having a strong impact on muscle strength and functionality
in the elderly are variations in long-chain polyunsaturated fatty
acid status [18]. Even in the fatty liver disease population, we
have a better understanding that the Bquality^ of nutrition plays
a vital role in the preservation of muscle and functionality.
Curr Gastroenterol Rep (2016) 18:43
Protein
The synthesis of muscle protein requires amino acids provided
by dietary protein. At the time of feeding and absorption of
amino acids, there is a stimulation of the synthesis of muscle
tissue [19]. Previous work in the elderly and young demon-
strated that administration of a specialized amino acid formula
has an anabolic effect on muscle mass in both the elderly and
young. Essential amino acids were more responsible than non-
essential amino acid for effective protein stimulation [20, 21].
Even at higher doses, non-essential amino acids were less
effective. These amino acids are the largest proportion of die-
tary proteins in whey and egg products, the same products
often used to supplement patients who are perceived as having
a diet poor in protein. This points out that not all protein
sources are equal in their effect on effectively building muscle
mass, and that the choice of non-essential amino acids will not
appropriately stimulate muscle anabolism in elderly patients.
As previous work points towards the importance of essential
amino acids in this process of building muscle mass, it may be
reasonable to include these in a preferential manner in the diet
of liver disease patients with muscle loss [19]. It is well rec-
ognized that branched-chain amino acid (BCAA) oral nutri-
tion supplements slow the progression of hepatic failure, re-
versal of refractory hepatic encephalopathy, and improvement
in event-free survival with cirrhosis. These data are obtained
from an older uncontrolled study and two recent randomized
trials [2224]. The three most well-recognized branched chain
amino acids, isoleucine, leucine, and valine have unique prop-
erties which make these benefits tangible. The BCAAs are
metabolized by skeletal muscle in the periphery, while the
other amino acids are catabolized in the liver. This is less
efficient in patients with chronic liver illness and, therefore,
the benefit of these amino acids is reduced. They are important
regulators of mTOR signaling, which regulates both protein
synthesis and turnover. Among the other benefits aforemen-
tioned, BCAAs and the aromatic amino acids bind to the same
carrier protein to the brain and compete with one another,
which in turn changes the synthesis of specific neurotransmit-
ters that may influence specific behavior [25, 26]. With the
numerous benefits of branched-chain amino acids [27], it is
reasonable to encourage preparations high in BCAAs for liver
disease patients with sarcopenia. To have the effect of revers-
ing sarcopenia in these patients, it may be a reasonable strat-
egy to encourage supplementation with essential amino acids
based on studies done in the elderly.
Vitamin D Supplementation
Vitamin D deficiency and its association with myopathy and
osteopenia has been recognized for many years, however, re-
mains controversial on its impact on muscle strength [28].
Curr Gastroenterol Rep (2016) 18:43
Vitamin D receptors (VDR) have been identified on skeletal
muscle, indicating that muscle is a target organ. Differences in
muscle strength have been demonstrated in polymorphisms of
the VDR, and epidemiologic literature also suggests that there
is a correlation between muscle strength, functionality, and
vitamin D serum levels [29]. Data from NHANES III demon-
strated that low vitamin D levels were associated with a four-
fold increase in measures of frailty in both men and women
older than the age of 60 [30]. Follow-up meta-analysis of
supplementation studies in the elderly showed that supple-
mental vitamin D (7001000 IU per day) reduced fall risk
by 19 % [31]. While there is little direct evidence that vitamin
D supplementation can reverse sarcopenia in chronic liver
disease, this research experience in the elderly may be extrap-
olated to suggest that vitamin D supplementation may in-
crease strength and reduce frailty, thus improving exercise
tolerance and physical activity in such patients. Through this
mechanism, sarcopenia may be reduced by supplementation
of vitamin D in the appropriate clinical scenario in liver dis-
ease patients.
Antioxidants
Oxidative stress has been considered a leading component of
aging, and there is increasing interest in the nutritional litera-
ture in the impact of oxidative stress on the cause of
sarcopenia. Oxidative stress occurs when reactive oxidative
species (ROS) damage cellular DNA, lipid, and proteins in
excess. Antioxidant defense mechanisms usually counterbal-
ance the damage of ROS by mechanisms that include super-
oxide dismutase and glutathione peroxidase. Dietary antioxi-
dants like selenium, carotenoids, tocopherols, flavonoids, and
plant polyphenols also a play a protective role in counteracting
the damage inflicted by ROS [32, 33]. As a person ages, the
age-expected muscle loss and reduction in functionality may
be related to an imbalance between ROS and antioxidants,
leading to oxidative damage [32]. Several observational stud-
ies have demonstrated improved physical functionality and
strength when administering supplemental antioxidants [17].
These associations have been made in both cross-sectional
analyses as well as in longitudinal studies, tying decreased
antioxidant levels to decline in function. This literature
supporting the use of antioxidants can be found in studies
demonstrating such affects in the elderly and disabled. The
2008 InCHIANTI study looked at a population-based cohort
and demonstrated an association between lower risk for de-
veloping ambulation disabilities (odds ratio of 0.44) and in-
creased serum carotenoid levels [34]. This trial took into ac-
count confounders like physical activity and co-morbid illness
[34].
While there has been a positive association between anti-
oxidant serum levels and physical activity in certain patient
Page 3 of 7 43
populations, surprisingly, an inverse relationship between
such levels and exercise has been shown in other populations.
Perhaps this has been demonstrated most readily in healthy
individuals undergoing athletic training. During exercise,
there is a 200-fold increase in oxygen utilization by skeletal
muscle mitochondria, and this generates ROS. Lipid peroxi-
dation byproducts are increased in the exhaled air of healthy
adults. In this situation, injury to the cell and mitochondria by
ROS may actually induce cell adaptation. This results in im-
proved ability to repair DNA, increased mitochondrial biogen-
esis, and greater muscle force. Several studies have demon-
strated reduced recovery, increased fatigue, and reduced gen-
erated force with the supplementation of antioxidant agents
under these conditions [3538]. This same effect has also been
demonstrated in performance animals like greyhounds [39].
There have not been any studies which specifically target
muscle function in liver disease patients on supplemental an-
tioxidant therapy, and the benefits remain uncertain. Perhaps
in patients who are ill or debilitated, there is potential for more
benefit as compared to subjects whose bodies are in peak
physical condition and serve only to be hindered by interfering
with natural processes. In chronic illness, serum antioxidant
intake is usually low, and antioxidant defense systems may be
compromised. This is an area that can be further explored in
the future.
Late-Evening Snack
Cirrhosis is a metabolic state characterized by reduced protein
synthesis and increased protein breakdown, with a shift to
lipid utilization as source of energy following overnight star-
vation [40]. Patients with cirrhosis demonstrate reduced he-
patic glucose production only after one night of fasting, a
metabolic status that is typically shown by healthy subjects
after 3 full days of starvation [41]. The shift from glucose to
lipid sources of energy corresponds to increased rates of ke-
togenesis and gluconeogenesis. Therefore, a possible ap-
proach for improving the nutritional status of patients with
cirrhosis is to modify their timing of feeding by adding an
evening snack or meal, defined by any calorie intake provided
after 8:00 PM and before 7 AM. The goal of such a strategy is
to prolong the effect of the fed post-prandial state. Various
studies addressed the utility of this strategy using different
approaches in terms of type of snack provided, amount and
composition of calories, duration of intervention, and mea-
sured outcomes [41]. The most promising intervention is
based on the use of BCAA-enriched supplements. When com-
pared to standard diet and morning snack with similar BCAA,
supplementation with a late-evening snack with BCAA was
associated with improvement of not only lab values such as
albumin and total serum bilirubin levels but also clinical indi-
cators of liver function such as the Child-Pugh [42]. The
43 Page 4 of 7
combination of late-evening snack provision and short-term
parenteral nutrition provided for 24 h after paracentesis in
patients with recurrent ascites was associated with improved
mortality after 12-month follow-up [43]. The late-evening
snack may also improve the development of hepatic enceph-
alopathy, given that the muscle is a major site of ammonia
catabolism. Improved nutritional status and muscle mass
could ultimately improve ammonia elimination [44].
Possible concerns related to the use of a late-evening snack
are the development of hyperglycemia, particularly in patients
with known diabetes mellitus, the development or worsening
of gastroesophageal reflux disease, and in the long-term re-
duced compliance.
Long-Chain Polyunsaturated Fatty Acids
Polyunsaturated fatty acids (PUFAs) include two groups of
fatty acids, -6 and -3 fatty acids; the -3 group contains
alfa-linoleic acid (ALA), docosahexaenoic acid (DHA), and
eicosapentaenoic acid (EPA). The -3 polyunsaturated fatty
acids (-3 PUFA) are fundamental nutrients for humans as
they cannot be synthesized in the body and need to be includ-
ed in the diet [45].
Many studies have evaluated the beneficial effect of DHA
and EPA on improving lean body weight in patients with
sarcopenia. There are several trials in cancer patients with
cachexia. Murphy et al. supplemented the diet of patients with
non-small cell lung cancer with 2 g of EPA/day and was able
to sustain weight and muscle mass during chemotherapy [46].
Other studies performed in an elderly population also demon-
strated that DHA and EPA supplementation enhances the pos-
itive effects of physical training on muscle strength and func-
tional capacity [47]. Even more, supplementation alone with-
out physical activity can cause a significant gain in the muscle
anabolic signaling activity when EPA and DHA are added to
diet [48]. Another potential benefit of EPA and DHA comes
from their proven anti-inflammatory effect in skeletal muscle
[49], which could attenuate the deleterious consequences of
pro-inflammatory cytokines on protein catabolism seen in pa-
tients with liver disease [11]. Finally, EPA and DHA may
have promising effects through two other pathways: overcom-
ing a weakened anabolic response of skeletal muscle seen in
elderly patients or reducing muscle degradation and promot-
ing muscle synthesis in patients with cancer.
Despite the advantages of EPA and DHA supplementation
discussed above, there is still some disagreements regarding
their beneficial effects. A recent meta-analysis of five trials for
the treatment of cancer cachexia failed to prove that use of oral
EPA had better outcomes than placebo [50]. Therefore, more
studies are needed to help clarify the inconsistent results found
by these previous investigations.
Curr Gastroenterol Rep (2016) 18:43
Exercise and Preservation of Muscle Mass
Both sarcopenia and frailty are highly prevalent in cirrhotic
patients. Fragility is defined as unintentional weight loss as-
sociated with fatigue, weakness, and diminished physical ac-
tivity. The critical pathways for how fragility evolves in this
population are not clear. Both sarcopenia and frailty are asso-
ciated with waitlist death, waitlist removals, and transplant-
related morbidity and mortality [5160]. A program of exer-
cise and physical conditioning may preserve muscle mass and
reverse sarcopenia. In a study of patients with advanced liver
disease, low levels of physical activity and poor oral intake
were associated with sarcopenia [61]. Furthermore, in a sur-
vey of 160 subjects, patients with cirrhosis were found to have
a significantly lower hand grip strength, arm muscle area, and
calculated body mass index compared to controls, reflecting a
substantially lower muscle mass [62, 63]. The study also dem-
onstrated that the physical activity level of liver patients was
substantially lower than the control group. These findings in-
dicate that by increasing physical activity, patients with cir-
rhosis may be able to reverse sarcopenia. This is similar to
evidence which supports the use of exercise management to
improve sarcopenia in other patient populations with other
long-term illnesses [62, 63].
Exercise management studies in patients with cirrhosis
have demonstrated that a physical rehab program for as little
as 1 month may improve oxygen consumption and result in
improved health outcomes [64, 65]. Exercise management is
an essential component in the management of sarcopenia
among liver patients because it can lead to improved physical
function, greater skeletal muscle mass, and increased exercise
endurance. These changes lead to improved overall quality of
life and survival.
In patients with liver disease and cirrhosis, an important
consideration is the concern of worsening portal pressures
and portal hypertension during moderate exercise. Such a the-
ory would suggest that increased physical load may result in
higher risk for development of ascites and variceal bleeding.
This leads to a belief that patients cannot improve their phys-
ical activity. This belief, added under sufficient nutrient during
exercise intake, promotes protein catabolism resulting in fur-
ther loss of skeletal muscle [66, 67]. While these beliefs exist,
reduced exercise capacity has been associated with poor out-
comes among cirrhotics and increased mortality after liver
transplantation [68, 69]. Therefore, a comprehensive nutri-
tional and functional assessment is essential prior to the initi-
ation of any formalized nutrition support and exercise pro-
gram among patients with chronic liver disease.
The optimal exercise regimen for patients with long-
standing liver disease remains uncertain. In a recent study,
Hayashi et al. recommended a regimen of walking 5000 steps
or more with a total caloric intake of 30-kcal/ideal body
weight [61]. The combination of exercise with the
Curr Gastroenterol Rep (2016) 18:43
appropriate nutrient intake may help maintain and increase
skeletal muscle volume. In a randomized control trial among
patients with Child-Pugh A cirrhosis, an exercise regimen of
three sessions per week of 1-h treadmill and cycle exercise at a
heart rate of 6070 % of maximal heart rate for 12 weeks
along with leucine supplementation resulted in improved ex-
ercise capacity. The intervention group had improvement in 2-
min step test, increased thigh circumference, and improved
quality of life compared to no interval change in the control
group. No adverse events were seen in the intervention group
[70]. Additionally, several studies have demonstrated that for-
malized exercise regimen will improve insulin sensitivity
among patients with liver disease, which is particularly impor-
tant among patients with sarcopenic obesity [7173]. Further
studies are necessary to further define the type and duration of
exercises and their long-term effect on morbidity and mortal-
ity among chronic liver disease patients.
Conclusions
Sarcopenia is a significant problem and poses a threat to
health, functionality, quality of life, and survival in patients
with liver disease. At the current time, it is undetermined how
this problem can be prevented, minimized, or even reversed.
Current work is being conducted to examine closer whether
optimization of diet, understanding physical activity, and en-
gaging patients in order to increase their daily physical activity
can have a positive impact reversing the underlying problem
of muscle wasting. Until that question is more firmly an-
swered, there exists a host of potential interventions that
may be encouraged for patients with chronic liver disease until
more firm recommendations are available.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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