Muscle Wasting: A Nutritional Criterion to Prioritize Patients for Liver Transplantation

8/9/2019 Muscle Wasting: A Nutritional Criterion to Prioritize Patients for Liver Transplantation

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CURRENTOPINION Muscle wasting: a nutritional criterion to prioritizepatients for liver transplantation

Aldo J. Montano-Loza

Purpose of review

Cirrhosis is the result of the progression of necroinflammatory liver diseases leading to fibrosis, portalhypertension, and a catabolic state, which might cause muscle wasting or sarcopenia. In this review, weanalyze the methods for muscularity assessment, the incidence and clinical impact of muscle wasting, andpotential novel therapeutic strategies in cirrhosis. Finally, we evaluate the value of muscle wasting inclusionto conventional systems for liver transplant prioritization.

Recent findings

Muscle wasting is present in up to 45% of patients with cirrhosis and is associated with higher risk of

sepsis-related death rather than liver failure mortality. Despite the fact that muscle wasting is not included inthe scores for prognosis in cirrhotic patients, as in the case of Model for End-Stage Liver Disease (MELD) orChild-Pugh, its presence should alert clinicians to the same extent as other complications do, such asascites, hepatic encephalopathy, or variceal bleeding. Two studies have shown increased mortality riskafter liver transplantation in patients with muscle wasting, whereas one study did not. Modification of MELDto include muscle wasting is associated with a modest improvement in the prediction of mortality in patientswith cirrhosis.

Summary

Muscle wasting is a frequent complication in cirrhosis and contributes to increased risk of sepsis-relatedmortality. The impact on mortality of muscle wasting after liver transplantation is controversial and needsfurther study. The MELD-sarcopenia score is associated with improvement in mortality prediction; however,prior to the widespread use of this composite score, validation in larger cohorts of patients with cirrhosis isnecessary.

Keywordscirrhosis, liver transplant, organ allocation, sarcopenia, scores for prognosis

INTRODUCTION

Cirrhosis is the result of the progression of manyforms of necroinflammatory liver diseases leading tofibrosis, vascular remodeling, portal hypertensiondevelopment and its complications, and ultimatelyliver failure [1]. As currently there is no effective

treatment to revert cirrhosis, management is gener-ally focused on treating the primary liver disease,screening and controlling the complications of por-tal hypertension, and considering liver transplan-tation in patients with decompensated cirrhosis.Even though liver transplantation may be con-sidered curative for cirrhosis, this therapeutic optiondoes not exist for the majority of patients.

Muscle wasting or sarcopenia is one of the mostcommon complications in cirrhosis [2,36], anddespite the important role it plays in the prognosisof cirrhosis, it is frequently overlooked, mainly as

the nutrition assessment could be complex in cir-rhosis with fluid retention and/or overweight[7,8].

At present, several methods are available toevaluate the body composition and muscle massestimation of patient with cirrhosis; however, mostof these techniques have limitations, primarily

because of lack of objectivity and reproducibility.In this regard, muscularity assessment with cross-sectional imaging studies [computed tomography

Division of Gastroenterology and Liver Unit, University of Alberta

Hospital, Edmonton, Alberta, Canada

Correspondence to Aldo J. Montano-Loza, MD, MSc, PhD, Assistant

Professor, Zeidler Ledcor Centre, 130 University Campus, University of

Alberta, Edmonton, AB T6G 2X8, Canada. Tel: +1 780 248 1892;

fax: +1 780 248 1895; e-mail: [email protected]

Curr Opin Clin Nutr Metab Care 2014, 17:219225

DOI:10.1097/MCO.0000000000000046

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REVIEW
mailto:[email protected]:[email protected]



(CT) scan, or MRI] has become an attractive index ofnutritional status evaluation in cirrhosis. These CTor MRI analyses are not biased by the fluid overloadstatus that frequently presents in decompensatedcirrhosis, and muscle wasting reflects a chronicdetriment in the general physical condition, ratherthan acute severity of the liver disease [9

&

].Muscle wasting in cirrhosis is part of the frailty

complex present in these patients, characterized bya decreased reserve and resistance to stressors result-ing from cumulative declines across multiplephysiologic systems, and predisposition to poor out-comes[1012].

In this review, we discuss the currently acceptedand new potential methods to evaluate the prog-nosis in cirrhotic patients. We also discuss thecurrent evidence regarding frequency and clinical

impact of muscle wasting in cirrhosis in order topromote recognition of this complication and leadto strategies in an effort to try to improve survivaland reduce morbidity associated with cirrhosis.

PROGNOSTIC EVALUATION OF

CIRRHOSIS

The prognostic assessment of patients with cirrhosisremains a complex challenge as the natural historyis particularly variable because of several factors,including cause of the cirrhosis, liver synthetic func-

tion, presence and degree of portal hypertension,the possibility of resolution of the underlying dam-aging process, and the occurrence of hepatocellularcarcinoma[13].

Child-Pugh and Model for End-Stage LiverDisease (MELD)[14]scores constitute the most fre-quent tools to predict mortality in patients withcirrhosis. Child-Pugh score was originally designedto predict cirrhosis-related mortality during surgery,and has been shown to be useful in determiningprognosis, treatment response, and necessity forliver transplant. MELD was originally developed as

a prognostic model of early mortality in patientswith cirrhosis who received a transjugular intra-hepatic portosystemic shunt (TIPS). The originalMELD has subsequently been simplified andcurrently it is widely used to predict short-termmortality in different patient populations withcirrhosis. Moreover, in most liver transplant centers,

MELD score has replaced the Child-Pugh score forpriority organ allocation, and since 2002, the MELDscore has been used for the prioritization of poten-tial liver transplant recipients in North America,mainly because MELD was developed in a statisticalfashion and includes only objective laboratoryparameters. Since implementation of the MELDscore, there have been reports of reductions in thenumber of patients listed for liver transplantation,waiting time for liver transplant, and deaths on thewaiting list.

Although MELD score has the advantage overChild-Pugh score of being based on objective vari-ables [serum bilirubin, international normalizedratio (INR) of prothrombin time, and serum creati-nine] rather than on subjective evaluation of theseverity of clinical findings (ascites and encephal-opathy), the MELD score also has limitations, mostimportant of which are the variability of bio-chemical parameters and lack of evaluation of thenutritional and functional status.

PREVALENCE AND ORIGIN OF MUSCLE

WASTING IN CIRRHOSIS

Muscle wasting in cirrhosisseemsto be secondary to amultifactorial process and generally is more frequentas liver disease progresses as the factors that lead tomalnutrition in the first place become more prom-inent. The most important factors associated withmuscle wasting in cirrhosis include metabolic abnor-malities, insufficient oral intake (mainly because ofearly satiety in moderate-severe ascites), malabsorp-tion, and impaired capacity of the liver to metabolizeand save nutrients, among others (Fig. 1).

The frequency of malnutrition in cirrhosis hasbeen estimated to affect between 40 and 90% of

patients. This wide range is explained in part as thereare significant differences in the operational defi-nition of malnutrition in cirrhosis. For example, it isdifficult to establish the presence of calorie malnu-trition, and as adipose tissue is the largest pool ofcalories, fat malnutrition is generally defined asreduction in body fat mass. However, as mostproteins are located in the skeletal muscle, a properdefinition of clinical protein malnutrition shoulduse primarily loss of skeletal muscle [15

&

].Recent studies have found that muscle wasting,

established by cross-sectional imaging studies, is

KEY POINTS

Muscle wasting is a frequent complication in cirrhosisand contributes to increased mortality, mainly related tosepsis-related death.

Cross-sectional imaging studies with computedtomography or MRI constitute the gold standard

techniques to quantify skeletal muscle mass and identifymuscle wasting in cirrhosis.

Inclusion of muscle wasting to MELD score is associatedwith a modest improvement in the prediction ofshort-term mortality in patients with cirrhosis.

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present in up to 45% of patients with cirrhosis[2,3,5,6] (Table 1) [26,16]. Importantly, being over-weight and obesity are now endemic in Westerncountries. Patients with cirrhosis may develop sim-ultaneous loss of skeletal muscle and gain of adipose

tissue, culminating in the condition of sarcopenicobesity. Moreover, muscle depletion is characterizedby both a reduction in muscle size and increasedproportion of intermuscular and intramuscular fat[17].

Sarcopenia in

cirrhosis

Diminished

nutrient intake

Early satiety

- Impaired gastric accommodation

- Ascites

Impaired digestion and nutrient

absorption

- Portal hypertensive enteropathy

Loss of appetite

- Cytokines (TNF-)

Hospitalizations

- Lack of regular meals for examinations

and procedures

Hyperdynamic circulation

- Increase use of macronutrients and

micronutrients

Cytokine-driven hypermetabolism

- High energy expenditure and demand

Compromised gut barrier function

- Bacterial translocation

- Infections

Loss of body protein

- Inadequate synthesis

- Diminished storage capacity

- Affected enterohepatic circle

- Multiple paracentesis

Decrease hepatic glycogen reserves

- Early switch to gluconeogenesis

- Mobilization of amino acids from the

skeletal muscles

Hypermetabolic

state

Inadequate

synthesis or

absorption ormicro-

macronutrients

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

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

Author/year n

Frequency

of musclewasting (%)

Definition

of musclewasting

Method for

muscularityassessment

Clinicalsignificance

Englesbe et al.[6]2010

163 25 Lowest quartile TPA CT Low TPA was associated withmortality after liver transplant

Montano-Lozaet al.[2]2012

112 40 L3 SMI 38.5cm2/m2

for women and 52.4cm2/m2

for men

CT Sarcopenia was independentlyassociated with mortality

Meza-Junco et al.[3]2013

116 30 L3 SMI 38.5cm2/m2

for women and 52.4cm2/m2

for men

CT Sarcopenia was independentlyassociated with mortality

Kaido et al.[4]2013

124 38 Low skeletal muscle mass BIA Low skeletal mass associated withpost-transplant mortality in patientsundergoing LDLT

Krell et al.[5]2013

207 33 Lowest tertile TPA CT Lower TPA was associated with higherrisk for post-transplant infectiouscomplications and mortality

Hayashi et al.[16]2013

50 40 SMMI 6.87kg/m2 for menand 5.46kg/m2 and/or musclestrength (hand grip); 24kg formen and 14kg for women

BIA andhandgripstrength

Patients with sarcopenia had lowvalues of energy intake per idealbody weight and number of steps

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

Muscle wasting: a criterion for liver transplantMontano-Loza

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We have found that 20% of our patients withcirrhosis being evaluated for liver transplantationhad sarcopenic obesity, and low muscle attenuationreflective of muscle fat infiltration was present inmore than 50% of patients[17].

BODY COMPOSITION EVALUATION IN

CIRRHOSIS

Cirrhotic patients commonly have significantchanges in their body composition mainly charac-terized by increase in the extracellular fluids anddecrease in muscle and adipose tissue; however,clinical identification of body composition changesin cirrhotic patients with ascites and edema might bechallenging, as fluid gains hide muscle and adiposetissue losses. It seems that cirrhotic male patientshave more muscle wasting, whereas female patientstend to have more depletion of fat tissue, and thereare studies that have shown that changes in bodycomposition may progress with thecourseof the liverdisease and correlate with the Child-Pugh score.

Numerous indirect methods have been usedto quantify body composition in cirrhosis, suchas total body electrical conductivity, bioelectricalimpedance, dual energy x-ray absorptiometry, airdisplacement plethysmography, and magneticresonance spectroscopy. These methods are basedon the principle that body fat mass and lean masshave specific components, such as water, proteins,and minerals. Therefore, by establishing the totalbody weight and fat mass, the remaining weightshould be lean mass. Unfortunately, most of these

methods lack either availability and/or reproduci-bility, and their accuracy may be limited in thepresence of fluid retention.

Other techniques include the skin-fold thick-ness measurement that quantifies fat mass in theupper arm (mid-arm muscle area) using a caliper;however, there have been conflicting reports inthe accuracy for predicting malnutrition in cirrhosisbecause of interobserver variability, and thismethod does not correlate with Child-Pugh score.A recent study showed that low respiratory quotientoccurs in cirrhosis, and even this finding did not

predict mortality; the author reported a direct andsignificant relation between respiratory quotientand muscle area, which suggests that altered skeletalmuscle protein turnover contributes to this meta-bolic response [18

&

].

MUSCLE WASTING EVALUATION IN

CIRRHOSIS

CT scan and MRI are the gold standard tools toquantify skeletal muscle mass[19]and, hence, con-stitute a good resource for objective nutritionalassessment of cirrhotic patients and detection of

muscle wasting. Recently, our group performed ananalysis of the frequency and clinical impact ofmuscle wasting in cirrhotic patients being evaluatedfor liver transplant[2]. We used CT scans at the 3rdlumbar (L3) vertebrae analyzed with the SliceOmaticV4.3 software (Tomovision, Montreal, Quebec,Canada), which enables specific tissue demarca-

tion using previously reported Hounsfield unitthresholds. Skeletal muscle was identified and quan-tified by Hounsfield unit thresholds of29 to 150,and cross-sectional area of muscle and adipose tissuewas normalized for stature (cm2/m2) as reported inprevious studies[20]. The L3 skeletal muscle index(L3 SMI) was expressed as cross-sectional musclearea/height2, and cut-offs for muscle wasting werebased on a CT-based sarcopenic study for patientswith solid malignancies (L3 SMI: 38.5 cm2/m2

for women and 52.4 cm2/m2 for men) [21].In addition, we recently set up new cut-off valuesfor cirrhotic patients, and values were similar com-pared with patients with malignancies (L3 SMI:42cm2/m2 for women and 50cm2/m2 for men)[22]. We also found that muscle wasting is notexclusively present in underweight patients, andconstitutes a hidden condition that can be presentin cirrhotic patients with any BMI.

To exemplify that there is no adequate corre-lation of classical anthropometric measurement andmuscle wasting, in Fig. 2 we present images of the L3SMI analysis of two cirrhotic patients with identicalBMI, but one with and another without musclewasting.

COMPLICATIONS OF MUSCLE WASTING

IN CIRRHOSIS

Muscle wasting is associated with mortality inpatients with cirrhosis. We have reported thatmedian survival for cirrhotic patients being eval-uated for liver transplantation was significantlyworse in the presence of muscle wasting (196vs. 3411 months, log-rank, P0.005) (Fig. 3).Six-month probability of survival was 71% in sarco-penic, and 90% in nonsarcopenic patients, and thishigher mortality risk was related to sepsis-related

death rather than liver failure mortality [2]. Thismay explain why conventional scores that reflectmainly liver function, such as MELD and Child-Pugh do not detect mortality risks associated withmuscle wasting.

THERAPEUTIC OPTIONS FOR MUSCLE

WASTING IN CIRRHOSIS

In patients with cirrhosis, increased protein intakehas been demonstrated to be safe, well tolerated,and beneficial; however, the long-term effects onmuscle mass are not completely elucidated. Other

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strategies that have been evaluated include late-evening snacks, repeated snacks, branched chainamino acid, and protein supplementation in generalwith beneficial results, but their impact on musclemass needs further investigation[16,23,24].

Intake of leucine-enriched essential amino acidnutrient may be useful in the treatment of musclewasting in cirrhosis. Leucine is an essential aminoacid that serves as substrate for protein synthesis,and has a key role in the regulation of the skeletalmuscle anabolism, protein synthesis, and auto-phagy. The activation of anabolic signaling occursvia the mammalian target of rapamycin (mTOR)through an undefined mechanism [25,26]. These

data suggest a potential role for leucine-rich supple-ments in the management of muscle depletionin cirrhosis.

Exercise, including aerobic and resistancephysical activity are important for the musclemetabolism. However, patients with cirrhosis fre-quently have complications of portal hypertension,such as ascites or hepatic encephalopathy, or symp-toms associated to chronic illness, including signi-ficant fatigue and reduced maximum exercisecapacity, which significantly reduce the physicalactivity. In addition to this, even moderate exercise

augments the portal pressure and may increase therisk of variceal bleeding in patients with esophagealvarices; therefore, cirrhotic patients with portalhypertension should be advised of potential risksduring exercise, and patients who are able andwilling to enter in an exercise program may benefitfrom pharmacological or endoscopic prophylaxis.

An interesting therapeutic approach in cirrhoticmuscle wasting could be the use of TIPS. A recentstudy showed that TIPS may reverse muscle wasting,and failure to improve muscle mass after TIPS isassociated with higher mortality [27,28]; however,

the utility of TIPS as an intervention to reversemuscle wasting should be evaluated in futureprospective studies.

Myostatin is a member of the transforminggrowth factor (b) superfamily that is an extremelypotent negative regulator of muscle mass. Prelimi-nary investigations showed that myostatin plas-matic levels in cirrhotic patients compared withhealthy controls [29], and animal model studieshave shown that myostatin expression can bereversed with administration of follistatin (func-tional antagonist of myostatin) without impairmentof liver function [30]; however, new treatments toreverse muscle wasting in cirrhotic patients, includ-

ing myostatin antagonists are waiting to be eval-uated in randomized controlled trials.

MUSCLE WASTING AND LIVER

TRANSPLANTATION

The group from the University of Michigan hasreported that muscle wasting was associated witha higher risk for post-transplant infectious compli-cations and mortality[5,6]. A recent study showedthat muscle wasting measured by bioelectrical impe-dance was associated with higher post-transplant

mortality in patients undergoing living donor livertransplantation [4].

Our group recently reported that muscle wastingwas predictive of longer length of hospitalizationand higher risk of perioperative bacterial infectionafter liver transplantation, but was not associatedwith increased mortality [31]. Further prospectivestudies will be necessary to clarify the impact ofmuscle wasting after liver transplantation.

Interestingly, in a subanalysis of nonprotocolCT after liver transplant, we found that in patientswith muscle wasting before the transplant,

(a) (b)

FIGURE 2. Computed tomography images used for the L3 skeletal muscle index (L3 SMI) assessment of two patientswith cirrhosis with identical BMI of 32 kg/m2. (a) Patient at the left is sarcopenic with L3 skeletal muscle index (L3 SMI) of50cm2/m2. (b) Patient at the right is not sarcopenic with a L3 SMI of 71cm2/m2. Dark gray color indicates skeletal muscles.Reproduced with permission from[2].





sarcopenia resolved in at least 28% in a median timeof 43 months following transplantation, defined asan increase in the L3 SMI more than 38.5cm2/m2 forwomen and more than 52.4 cm2/m2 for men afterliver transplant.

Failure of reversal of muscle wasting after livertransplantation is not well elucidated. A recent

review summarizes the changes in indirect measuresof skeletal muscle mass after transplantation andsome studies reported an initial rapid postoperativeloss of muscle mass followed by incomplete recovery.Potentialreasons for failure to reverse muscle wastinginclude the use of immunosuppression that impairsskeletal muscle growth, repeated hospitalizations,and post-transplant infections, among others[32].

A recent study from our group showed thatmodification of MELD score to include muscle wast-ing is associated with a modest improvement in theprediction of 3-month and 6-month mortality inpatients with cirrhosis. The c-statistics for 3-monthand 6-month mortality were 0.72 (95% confidenceinterval, CI 0.630.82, P



17. Montano-Loza AJ, Meza-Junco J, Prado CMM, et al.Sarcopenic obesity andmuscle fat infiltration are associated with higher mortality in patients withcirrhosis. Hepatology 2013; 58 (S1):865A.

18.

&

Glass C, Hipskind P, Tsien C, et al. Sarcopenia and a physiologically lowrespiratory quotient in patients with cirrhosis: a prospective controlled study.J Appl Physiol 2013; 114:559565.

This is study that demonstrated that low respiratory quotient occurs in cirrhosis,and there is a direct and significant relation between respiratory quotient andmuscle area.19. Heymsfield SB. Development of imaging methods to assess adiposity and

metabolism. Int J Obes (Lond) 2008; 32 (Suppl 7):S76S82.20.

Mourtzakis M, Prado CM, Lieffers JR,et al.

A practical and precise approachto quantification of body composition in cancer patients using computedtomography images acquired during routine care. Appl Physiol Nutr Metab2008; 33:9971006.

21. Prado CM, Lieffers JR,McCargarLJ, et al. Prevalenceand clinical implicationsof sarcopenic obesity in patients with solid tumours of the respiratory andgastrointestinal tracts: a population-based study. Lancet Oncol 2008;9:629635.

22. Montano-Loza AJ, Meza-Junco J, Prado CMM, et al. New cutoff values forsarcopenia for predicting 6-months mortality in cirrhotic patients. J Hepatol2013; 58 (S1):95A.

23. Vaisman N, Katzman H, Carmiel-Haggai M, et al. Breakfast improves cognitivefunction in cirrhotic patients with cognitive impairment. Am J Clin Nutr 2010;92:137140.

24. Kachaamy T, Bajaj JS. Diet and cognition in chronic liver disease. Curr OpinGastroenterol 2011; 27:174179.

25. Drummond MJ, RasmussenBB. Leucine-enriched nutrientsand the regulationof mammalian target of rapamycin signalling and human skeletal muscleprotein synthesis. Curr Opin Clin Nutr Metab Care 2008; 11:222226.

26. Dreyer HC, Drummond MJ, Pennings B, et al. Leucine-enriched essentialamino acid and carbohydrate ingestion following resistance exerciseenhances mTOR signaling and protein synthesis in human muscle. Am JPhysiol Endocrinol Metab 2008; 294:E392E400.

27. Tsien C, Shah SN, McCullough AJ, Dasarathy S. Reversal of sarcopeniapredicts survival after a transjugular intrahepatic portosystemic stent. Eur JGastroenterol Hepatol 2013; 25:8593.

28. Dasarathy J, Alkhouri N, Dasarathy S. Changes in body composition after

transjugular intrahepatic portosystemic stent in cirrhosis: a critical review ofliterature. Liver Int 2013; 31:12501258.29. Garcia PS, Cabbabe A, Kambadur R,et al.Brief-reports: elevated myostatin

levelsin patients with liver disease a potentialcontributor to skeletal musclewasting. Anesth Analg 2010; 111:707709.

30. Dasarathy S, McCullough AJ, Muc S, et al. Sarcopenia associated withportosystemic shunting is reversed by follistatin. J Hepatol 2011; 54:915921.

31. Montano-Loza AJ, Meza-Junco J, Baracos VE, et al. Muscle wasting is notassociated with higher mortality after liver transplantation. Hepatology 2012;56 (S1):651A.

32. Dasarathy S. Posttransplant sarcopenia: an underrecognized early conse-quence of liver transplantation. Dig Dis Sci 2013; 58:31033111.

33. Montano-Loza AJ, Meza-Junco J, Prado CMM, et al. Inclusion of sarcopeniawithin MELD (MELD-Sarcopenia) and the prediction of mortality in patientswith cirrhosis. Hepatology 2013; 58 (S1):1041A.



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Muscle Wasting: A Nutritional Criterion to Prioritize Patients for Liver Transplantation