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EASL Clinical Practice Guidelines on nutrition in chronic liver disease

Published:August 22, 2018DOI:https://doi.org/10.1016/j.jhep.2018.06.024

      Summary

      A frequent complication in liver cirrhosis is malnutrition, which is associated with the progression of liver failure, and with a higher rate of complications including infections, hepatic encephalopathy and ascites. In recent years, the rising prevalence of obesity has led to an increase in the number of cirrhosis cases related to non-alcoholic steatohepatitis. Malnutrition, obesity and sarcopenic obesity may worsen the prognosis of patients with liver cirrhosis and lower their survival. Nutritional monitoring and intervention is therefore crucial in chronic liver disease. These Clinical Practice Guidelines review the present knowledge in the field of nutrition in chronic liver disease and promote further research on this topic. Screening, assessment and principles of nutritional management are examined, with recommendations provided in specific settings such as hepatic encephalopathy, cirrhotic patients with bone disease, patients undergoing liver surgery or transplantation and critically ill cirrhotic patients.

      Introduction

      Malnutrition is frequently a burden in patients with liver cirrhosis, occurring in 20–50% of patients. The progression of malnutrition is associated with that of liver failure. While malnutrition may be less evident in patients with compensated cirrhosis it is easily recognisable in those with decompensated cirrhosis. Malnutrition has been reported in 20% of patients with compensated cirrhosis and in more than 50% of patients with decompensated liver disease.
      • Nutritional status in cirrhosis
      Italian multicentre cooperative project on nutrition in liver cirrhosis.
      Both adipose tissue and muscle tissue can be depleted; female patients more frequently develop a depletion in fat deposits while males more rapidly lose muscle tissue.
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      Malnutrition in alcoholic and virus-related cirrhosis.
      • Nutritional status in cirrhosis
      Italian multicentre cooperative project on nutrition in liver cirrhosis.
      As detailed in these clinical practice guidelines (CPGs), malnutrition and muscle mass loss (sarcopenia), which has often been used as an equivalent of severe malnutrition,
      • Dasarathy S.
      Consilience in sarcopenia of cirrhosis.
      are associated with a higher rate of complications
      • Huisman E.J.
      • Trip E.J.
      • Siersema P.D.
      • van Hoek B.
      • van Erpecum K.J.
      Protein energy malnutrition predicts complications in liver cirrhosis.
      such as susceptibility to infections,
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      • Giusto M.
      • Riggio O.
      • Falcone M.
      • et al.
      Cirrhotic patients are at risk for health care-associated bacterial infections.
      hepatic encephalopathy (HE)
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      • Giusto M.
      • Lucidi C.
      • Giannelli V.
      • Pentassuglio I.
      • Di Gregorio V.
      • et al.
      Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study.
      and ascites,
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      • Trip E.J.
      • Siersema P.D.
      • van Hoek B.
      • van Erpecum K.J.
      Protein energy malnutrition predicts complications in liver cirrhosis.
      as well as being independent predictors of lower survival in cirrhosis
      • Gunsar F.
      • Raimondo M.L.
      • Jones S.
      • Terreni N.
      • Wong C.
      • Patch D.
      • et al.
      Nutritional status and prognosis in cirrhotic patients.
      • Montano-Loza A.J.
      • Meza-Junco J.
      • Prado C.M.
      • Lieffers J.R.
      • Baracos V.E.
      • Bain V.G.
      • et al.
      Muscle wasting is associated with mortality in patients with cirrhosis.
      and in patients undergoing liver transplantation.
      • Englesbe M.J.
      • Patel S.P.
      • He K.
      • Lynch R.J.
      • Schaubel D.E.
      • Harbaugh C.
      • et al.
      Sarcopenia and mortality after liver transplantation.
      Given these observations, malnutrition and sarcopenia should be recognised as complications of cirrhosis, which in turn worsen the prognosis of cirrhotic patients.
      Whether malnutrition can be reversed in cirrhotic patients is controversial. Although there is general agreement about the need to improve the dietary intake of these patients, by avoiding limitations and restrictions that are not evidence based, amelioration of the nutritional status and muscle mass is not always achievable.
      • Ney M.
      • Vandermeer B.
      • van Zanten S.J.
      • Ma M.M.
      • Gramlich L.
      • Tandon P.
      Meta-analysis: oral or enteral nutritional supplementation in cirrhosis.
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      Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis.
      • Koretz R.L.
      • Avenell A.
      • Lipman T.O.
      Nutritional support for liver disease.
      Although the term “malnutrition” refers both to deficiencies and to excesses in nutritional status, in the present CPGs “malnutrition” refers to “undernutrition”. More recently, in addition to undernutrition, overweight or obesity are increasingly observed in cirrhotic patients because of the increasing number of cirrhosis cases related to non-alcoholic steatohepatitis (NASH). Muscle mass depletion may also occur in these patients, but due to the coexistence of obesity, sarcopenia might be overlooked. Obesity and sarcopenic obesity may worsen the prognosis of patients with liver cirrhosis.
      • Berzigotti A.
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      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Morillas R.
      • et al.
      Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis.
      • Montano-Loza A.J.
      • Angulo P.
      • Meza-Junco J.
      • Prado C.M.
      • Sawyer M.B.
      • Beaumont C.
      • et al.
      Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis.
      • Nishikawa H.
      • Nishiguchi S.
      Sarcopenia and sarcopenic obesity are prognostic factors for overall survival in patients with cirrhosis.
      • Dasarathy S.
      Consilience in sarcopenia of cirrhosis.
      No previous guidelines released by the European Association for the Study of Liver Disease (EASL) have dealt with nutrition in advanced liver disease and/or have evaluated the relationship between nutritional status and the clinical outcome of patients. Therefore, the EASL Governing Board has asked a panel of experts in the field of nutrition and hepatology to produce the present CPGs.

      Methodology

      The panel initially established the most relevant questions to answer, considering relevance, urgency and completeness of the topics to be covered. The main questions addressed were: How can nutritional problems be recognised? In which conditions are nutritional assessments recommended? What are the available methods of evaluation? What are the consequences of malnutrition and its correction? Different clinical scenarios have been considered with special attention paid to nutrition in HE and before and after liver transplantation. A section devoted to bone metabolism in chronic liver disease has also been included. Each expert took responsibility and made proposals for statements for a specific section of the guideline.
      The literature search was performed in different databases (PubMed, Embase, Google Scholar, Scopus) and a list of pertinent articles was derived from this “first line” search The initial key words were: “Nutrition” OR “Nutritional status” OR “Malnutrition” OR “Sarcopenia” AND “Liver cirrhosis” OR “Chronic liver Disease”. Further, more specific key words were also utilised: “nutritional assessment”, “nutrition risk”, “hepatic encephalopathy”, “osteoporosis”, “liver transplantation” for each specific topic of the guideline. The selection of references was then based on appropriateness of study design, number of patients, and publication in peer-reviewed journals. Original data were prioritised. The resulting literature database was made available to all members of the panel.
      All recommendations were discussed and approved by all participants. The Committee met on two occasions during international meetings with experts who were available to participate, two ad hoc teleconferences also took place for discussion and voting.
      The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.
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      • Guyatt G.
      • Oxman A.D.
      • Alderson P.
      • Dahm P.
      • Falck-Ytter Y.
      • et al.
      GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations.
      The classifications and recommendations are therefore based on three categories: the source of evidence in levels I through III; the quality of evidence designated by high (A), moderate (B), or low quality (C); and the strength of recommendations classified as strong (1) or weak (2) (Table 1). All recommendations based on expert opinion because of the lack of available data were graded as III. The recommendations were peer-reviewed by external expert reviewers and approved by the EASL Governing Board.
      Table 1Evidence quality according to the GRADE scoring system.
      Level of evidence
      IRandomised, controlled trials
      II-1Controlled trials without randomisation
      II-2Cohort or case-control analytical studies
      II-3Multiple time series, dramatic uncontrolled experiments
      IIIOpinions of respected authorities, descriptive epidemiology
      Quality of evidence
      AHigh: Further research is very unlikely to change our confidence in the estimated effect
      BModerate: Further research is likely to have an important impact on our confidence in the estimated effect and may change the estimate
      CLow: Further research is likely to have an important impact on our confidence in the estimated effect and is likely to change the estimate. Any change of estimate is uncertain
      Grade of recommendation
      1Strong: Factors influencing the strength of recommendation included the quality of evidence, presumed patient-important outcomes, and costs
      2Weak: Variability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher costs, or resource consumption
      These guidelines are directed at consultant hepatologists, specialists in training, and general practitioners and refer specifically to adult patients with cirrhosis. Their purpose is to provide guidance on the best available evidence to deal with nutritional problems in patients with chronic liver disease. A few schemes were produced by the panel and are included in these guidelines to help with the management of nutritional problems in patients with liver cirrhosis.
      For clarity, the terms and definitions used in the present CPGs are summarised (Box 1).

      Screening and assessment for malnutrition and obesity in liver cirrhosis: Who, when and how

      Given the worse prognosis associated with malnutrition, all patients with advanced chronic liver disease, and in particular patients with decompensated cirrhosis are advised to undergo a rapid nutritional screen. Those at risk of malnutrition should complete a more detailed nutritional assessment to confirm the presence and severity of malnutrition,
      • Tandon P.
      • Raman M.
      • Mourtzakis M.
      • Merli M.
      A practical approach to nutritional screening and assessment in cirrhosis.
      • Teitelbaum D.
      • Guenter P.
      • Howell W.H.
      • Kochevar M.E.
      • Roth J.
      • Seidner D.L.
      Definition of terms, style, and conventions used in A.S.P.E.N. guidelines and standards.
      • Charney P.
      Nutrition screening vs. nutrition assessment: how do they differ?.
      in order to actively manage this complication.

      Nutrition screening tools

      Two simple criteria stratify patients at high risk of malnutrition: being underweight, defined as a body mass index (BMI) (kg.body weight [BW]/[height in meters]2) < 18.5 kg/m2,
      • Cederholm T.
      • Bosaeus I.
      • Barazzoni R.
      • Bauer J.
      • Van Gossum A.
      • Klek S.
      • et al.
      Diagnostic criteria for malnutrition – An ESPenteral nutrition Consensus Statement.
      in which the vast majority of cirrhotic patients have sarcopenia, and having advanced decompensated cirrhosis (Child-Pugh C patients).
      • Tandon P.
      • Raman M.
      • Mourtzakis M.
      • Merli M.
      A practical approach to nutritional screening and assessment in cirrhosis.
      • Tandon P.
      • Ney M.
      • Irwin I.
      • Ma M.M.
      • Gramlich L.
      • Bain V.G.
      • et al.
      Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value.
      There are several possible scoring tools to classify patients who are at risk of malnutrition. Most have not been validated in cirrhotic patients, and are prone to bias in cases of fluid retention, which should be accounted for. There are two liver disease-specific tools, however, both need further validation. The Royal Free Hospital-nutritional prioritizing tool (RFH-NPT) score was reported to correlate with clinical deterioration, severity of disease (Child-Pugh score, model for end-stage liver disease [MELD] score), and clinical complications such as ascites, hepatorenal syndrome, and episodes of HE.
      • Borhofen S.M.
      • Gerner C.
      • Lehmann J.
      • Fimmers R.
      • Gortzen J.
      • Hey B.
      • et al.
      The royal free hospital-nutritional prioritizing tool is an independent predictor of deterioration of liver function and survival in cirrhosis.
      Furthermore, improvement in RFH-NPT score was associated with improved survival.
      • Borhofen S.M.
      • Gerner C.
      • Lehmann J.
      • Fimmers R.
      • Gortzen J.
      • Hey B.
      • et al.
      The royal free hospital-nutritional prioritizing tool is an independent predictor of deterioration of liver function and survival in cirrhosis.
      This scheme takes less than 3 mins to be completed and can be used by non-specialist staff. The liver disease undernutrition screening tool is based on six patient-directed questions regarding: nutrient intake, weight loss, subcutaneous fat loss, muscle mass loss, fluid accumulation and decline in functional status. However, it relies almost completely on the patient’s subjective judgment and has low negative predictive value.
      • Booi A.N.
      • Menendez J.
      • Norton H.J.
      • Anderson W.E.
      • Ellis A.C.
      Validation of a screening tool to identify undernutrition in ambulatory patients with liver cirrhosis.
      If the initial screening using these tools is negative, it is recommended that the evaluation be repeated over time.

      Detailed nutritional assessment

      It is advisable that patients who are at risk of malnutrition during screening undergo a detailed nutritional assessment for the diagnosis of malnutrition, preferably by a registered dietitian or nutrition expert. In patients with cirrhosis whose screening results indicate a high risk of malnutrition, it is suggested that each component be assessed and documented every 1–6 months in the outpatient setting and for inpatients, at admission and periodically throughout the hospital stay.
      • Tandon P.
      • Raman M.
      • Mourtzakis M.
      • Merli M.
      A practical approach to nutritional screening and assessment in cirrhosis.
      The components of a detailed nutritional assessment include evaluation of: muscle mass, global assessment tools and a detailed dietary intake assessment, as described below.

      Sarcopenia: How to assess

      Sarcopenia is a major component of malnutrition. Direct quantification of skeletal muscle mass requires cross-sectional imaging.
      • Cruz-Jentoft A.J.
      • Baeyens J.P.
      • Bauer J.M.
      • Boirie Y.
      • Cederholm T.
      • Landi F.
      • et al.
      Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People.
      Computed tomographic (CT) image analysis at the L3 vertebra is almost universally recognised as a specific method to quantify muscle loss. Psoas muscle and possibly para spinal and abdominal wall muscles are considered core skeletal muscles that are relatively independent of activity and water retention, but are consistently altered by the metabolic and molecular perturbations of cirrhosis. Any of the several possible image analysis software packages can be used to analyse the total cross-sectional area (cm2) of abdominal skeletal muscles at L3. This area is then normalised to height to calculate the skeletal muscle index (cm2/m2). Even though magnetic resonance imaging has also been suggested, data in patients with liver cirrhosis are scarce and normal values are still required.
      The routine use of CT imaging for nutritional assessment, especially for repeated assessments, is obviously limited in clinical practice, due to cost and exposure to radiation. However, since CT scanning is frequently available in cirrhotic patients (second line imaging for screening hepatocellular carcinoma, evaluation for liver transplant, evaluation of vascular shunts or portal thrombosis), it can be utilised at least once for assessment of sarcopenia.
      All measures require normal values that are based on age, gender and ethnicity. In addition, there are gender differences in the interpretation of muscle mass and function, indicating lower predictive validity in women.
      • Tandon P.
      • Ney M.
      • Irwin I.
      • Ma M.M.
      • Gramlich L.
      • Bain V.G.
      • et al.
      Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value.
      • Peng S.
      • Plank L.D.
      • McCall J.L.
      • Gillanders L.K.
      • McIlroy K.
      • Gane E.J.
      Body composition, muscle function, and energy expenditure in patients with liver cirrhosis: a comprehensive study.
      Normal CT measures and cut-off values to define sarcopenia were initially derived from an oncologic population.
      • Martin L.
      • Birdsell L.
      • Macdonald N.
      • Reiman T.
      • Clandinin M.T.
      • McCargar L.J.
      • et al.
      Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index.
      Cut-off values derived from cirrhotic patients on the liver transplant list and based on clinical outcomes have only recently been suggested (50 cm2/m2 for men and 39 cm2/m2 for women),
      • Carey E.J.
      • Lai J.C.
      • Wang C.W.
      • Dasarathy S.
      • Lobach I.
      • Montano-Loza A.J.
      • et al.
      A multicenter study to define sarcopenia in patients with end-stage liver disease.
      and still need to be further validated. The predictive role of CT-assessed skeletal muscle mass in liver transplant candidates was demonstrated in a meta-analysis, showing an independent association between low muscle mass and post-transplantation mortality (pooled hazard ratios of sarcopenia 1.84, 95% CI 1.11–3.05), independent of the MELD score.
      • van Vugt J.L.
      • Levolger S.
      • de Bruin R.W.
      • van Rosmalen J.
      • Metselaar H.J.
      • IJzermans J.N.
      Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation.
      Body mass assessment can also be performed by simple bedside anthropometric methods
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • Assis-Camilo M.
      • Pirlich M.
      • Kondrup J.
      • et al.
      ESPenteral nutrition guidelines on enteral nutrition: liver disease.
      including mid-arm muscle circumference (MAMC, defined as mid-arm circumference minus [triceps skinfold (TSF) × 0.314]),
      • Tandon P.
      • Low G.
      • Mourtzakis M.
      • Zenith L.
      • Myers R.P.
      • Abraldes J.G.
      • et al.
      A model to identify sarcopenia in patients with cirrhosis.
      mid-arm muscular area [MAMA = (MAMC)2/4 × 0.314] and TSF, which are simple to perform, rapid, low cost, and not affected by the presence of fluid retention. Both MAMC and TSF have a demonstrated prognostic value for mortality among cirrhotic patients, with MAMC having a higher prognostic power than TSF.
      • Alberino F.
      • Gatta A.
      • Amodio P.
      • Merkel C.
      • Di Pascoli L.
      • Boffo G.
      • et al.
      Nutrition and survival in patients with liver cirrhosis.
      If performed by trained personnel, these measurements have good intra and inter-observer agreement (intra-class correlation of 0.8 and 0.9 for TSF and MAMC, respectively).
      • Morgan M.Y.
      • Madden A.M.
      • Soulsby C.T.
      • Morris R.W.
      Derivation and validation of a new global method for assessing nutritional status in patients with cirrhosis.
      Compared to the diagnosis of sarcopenia by cross-sectional imaging (by CT or magnetic resonance), the predictive value of MAMC was shown to be good, with an area under the receiver operating characteristic curve (AUROC) of 0.75 for men and 0.84 for women.
      • Tandon P.
      • Low G.
      • Mourtzakis M.
      • Zenith L.
      • Myers R.P.
      • Abraldes J.G.
      • et al.
      A model to identify sarcopenia in patients with cirrhosis.
      In a small sample study, a significant but moderate correlation was observed between CT measurement and MAMC in cirrhotic men (r = 0.48, p <0.001), but not in women.
      • Alberino F.
      • Gatta A.
      • Amodio P.
      • Merkel C.
      • Di Pascoli L.
      • Boffo G.
      • et al.
      Nutrition and survival in patients with liver cirrhosis.
      In addition, low MAMC was found to be an independent predictor of mortality after liver transplant,
      • Giusto M.
      • Lattanzi B.
      • Albanese C.
      • Galtieri A.
      • Farcomeni A.
      • Giannelli V.
      • et al.
      Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry.
      and in a large sample of the general population, but only among men.
      • Wu L.W.
      • Lin Y.Y.
      • Kao T.W.
      • Lin C.M.
      • Liaw F.Y.
      • Wang C.C.
      • et al.
      Mid-arm muscle circumference as a significant predictor of all-cause mortality in male individuals.
      Whole body dual-energy X-ray absorptiometry (DEXA) allows measurement of bone mineral density, fat mass and fat-free mass. However, fat-free mass is not only skeletal muscle mass. Radiation exposure, cost and logistics are additional limitations, while water retention may limit the validity of the formula applied to assess body composition. The ability to quantify limb muscle mass, which could be more reliable and has corresponding cut-offs in the healthy population, is an advantage and may overcome the confounding effect of overhydration.
      Tetrapolar bioelectrical impedance analysis (BIA) uses the two-compartment model, and segmental BIA measurements allow limb non-fat mass quantification. Low cost, portable equipment and ease of use are advantages of BIA. However, the validity of these methods also depends on stable hydration status, which may be altered in patients with cirrhosis.
      • Morgan M.Y.
      • Madden A.M.
      • Jennings G.
      • Elia M.
      • Fuller N.J.
      Two-component models are of limited value for the assessment of body composition in patients with cirrhosis.
      Skeletal muscle contractile function is not a direct measure of muscle mass but has been used as a measure of sarcopenia. Handgrip strength is a simple, inexpensive, and effective method to detect malnutrition in cirrhotic patients; predicting incidence of major complications and mortality.
      • Alvares-da-Silva M.R.
      • Reverbel da Silveira T.
      Comparison between handgrip strength, subjective global assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in cirrhotic outpatients.
      • Tandon P.
      • Tangri N.
      • Thomas L.
      • Zenith L.
      • Shaikh T.
      • Carbonneau M.
      • et al.
      A rapid bedside screen to predict unplanned hospitalization and death in outpatients with cirrhosis: a prospective evaluation of the clinical frailty scale.
      • Wang C.W.
      • Feng S.
      • Covinsky K.E.
      • Hayssen H.
      • Zhou L.Q.
      • Yeh B.M.
      • et al.
      A comparison of muscle function, mass, and quality in liver transplant candidates: results from the functional assessment in liver transplantation study.
      Measures of frailty, defined as patient's vulnerability to stress, decreased physiologic reserve and functional status deficits
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • Newman A.B.
      • Hirsch C.
      • Gottdiener J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      • Lai J.C.
      • Feng S.
      • Terrault N.A.
      • Lizaola B.
      • Hayssen H.
      • Covinsky K.
      Frailty predicts waitlist mortality in liver transplant candidates.
      can also be used in the assessment of cirrhotic patients. There are several measures of frailty that are used in geriatrics and were also demonstrated to have predictive value in cirrhotic patients. The Fried frailty phenotype is characterised by five domains: unintentional weight loss, self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • Newman A.B.
      • Hirsch C.
      • Gottdiener J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      An increase in the Fried frailty score was demonstrated to be associated with increased risk of liver transplant waitlist mortality, even when adjusting for MELD.
      • Lai J.C.
      • Feng S.
      • Terrault N.A.
      • Lizaola B.
      • Hayssen H.
      • Covinsky K.
      Frailty predicts waitlist mortality in liver transplant candidates.
      The short physical performance battery (SPPB) consists of timed repeated chair stands, balance testing, and a timed 13-ft walk and takes 2–3 mins to complete. Although the SPPB does not correlate with CT-based muscle mass in men or women,
      • Wang C.W.
      • Feng S.
      • Covinsky K.E.
      • Hayssen H.
      • Zhou L.Q.
      • Yeh B.M.
      • et al.
      A comparison of muscle function, mass, and quality in liver transplant candidates: results from the functional assessment in liver transplantation study.
      it predicts liver transplant waitlist mortality.
      • Wang C.W.
      • Feng S.
      • Covinsky K.E.
      • Hayssen H.
      • Zhou L.Q.
      • Yeh B.M.
      • et al.
      A comparison of muscle function, mass, and quality in liver transplant candidates: results from the functional assessment in liver transplantation study.
      • Lai J.C.
      • Feng S.
      • Terrault N.A.
      • Lizaola B.
      • Hayssen H.
      • Covinsky K.
      Frailty predicts waitlist mortality in liver transplant candidates.
      At present, there are no standardised or universally accepted criteria to diagnose frailty in cirrhosis.

      Global assessment tools in cirrhosis

      The technique of subjective global assessment (SGA) uses data collected during clinical evaluation to determine nutritional status without recourse to objective measurements.
      • Morgan M.Y.
      • Madden A.M.
      • Soulsby C.T.
      • Morris R.W.
      Derivation and validation of a new global method for assessing nutritional status in patients with cirrhosis.
      Overall, SGA has fair to good inter-observer reproducibility
      • Hasse J.
      • Strong S.
      • Gorman M.A.
      • Liepa G.
      Subjective global assessment: alternative nutrition-assessment technique for liver-transplant candidates.
      and is associated with various clinical and prognostic variables of liver transplantation.
      • Bakshi N.
      • Singh K.
      Nutrition assessment and its effect on various clinical variables among patients undergoing liver transplant.
      However, agreement of SGA with other methods of assessment of nutritional status (total lymphocyte count, MAMC, MAMA, TSF, subscapular skinfold thickness, BMI and handgrip measurement) is low (K <0.26).
      • Ferreira L.G.
      • Anastacio L.R.
      • Lima A.S.
      • Correia M.I.
      Assessment of nutritional status of patients waiting for liver transplantation.
      Furthermore, SGA underestimates the prevalence of muscle loss in liver disease patients, compared with other objective measures.
      • Alvares-da-Silva M.R.
      • Reverbel da Silveira T.
      Comparison between handgrip strength, subjective global assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in cirrhotic outpatients.
      • Figueiredo F.A.
      • Dickson E.R.
      • Pasha T.M.
      • Porayko M.K.
      • Therneau T.M.
      • Malinchoc M.
      • et al.
      Utility of standard nutritional parameters in detecting body cell mass depletion in patients with end-stage liver disease.
      • Fernandes S.A.
      • Bassani L.
      • Nunes F.F.
      • Aydos M.E.
      • Alves A.V.
      • Marroni C.A.
      Nutritional assessment in patients with cirrhosis.
      • Figueiredo F.A.
      • Perez R.M.
      • Freitas M.M.
      • Kondo M.
      Comparison of three methods of nutritional assessment in liver cirrhosis: subjective global assessment, traditional nutritional parameters, and body composition analysis.
      • Naveau S.
      • Belda E.
      • Borotto E.
      • Genuist F.
      • Chaput J.C.
      Comparison of clinical judgment and anthropometric parameters for evaluating nutritional status in patients with alcoholic liver disease.
      The Royal Free Hospital-global assessment (RFH-GA),
      • Morgan M.Y.
      • Madden A.M.
      • Soulsby C.T.
      • Morris R.W.
      Derivation and validation of a new global method for assessing nutritional status in patients with cirrhosis.
      for determining nutritional status in patients with cirrhosis is reproducible, correlates with other measures of body composition and predicts survival and post-transplant complications.
      • Morgan M.Y.
      • Madden A.M.
      • Soulsby C.T.
      • Morris R.W.
      Derivation and validation of a new global method for assessing nutritional status in patients with cirrhosis.
      • Sasidharan M.
      • Nistala S.
      • Narendhran R.T.
      • Murugesh M.
      • Bhatia S.J.
      • Rathi P.M.
      Nutritional status and prognosis in cirrhotic patients.
      • Kalafateli M.
      • Mantzoukis K.
      • Choi Yau Y.
      • Mohammad A.O.
      • Arora S.
      • Rodrigues S.
      • et al.
      Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease score.
      Patients are stratified into one of three categories based on their dry weight-based BMI and their MAMC: adequately nourished, moderately malnourished (or suspected to be), or severely malnourished. The limitations of this tool include the time required, and the need for trained personnel for consistent results.

      Reported dietary intake

      Dietary interviews provide practical information for nutritional interventions by identifying what and how much the patient is willing and capable of eating and determining specific nutrient deficiencies that need to be corrected. A detailed assessment of dietary intake is suggested to include: food, fluids, supplements, number of meals and their timing throughout the day (e.g. interval between meals, breakfast and late-night meals as recommended), as well as calories and quality and quantity of protein intake. It should also include barriers to eating: nausea, vomiting, aversion to certain foods, taste, low-sodium diet, early satiety, gastrointestinal pain and diarrhoea or constipation. The symptoms section of the abridged scored patient-generated subjective global assessment (abPG-SGA) can be used to construct the questions.
      • Gabrielson D.K.
      • Scaffidi D.
      • Leung E.
      • Stoyanoff L.
      • Robinson J.
      • Nisenbaum R.
      • et al.
      Use of an abridged scored Patient-Generated Subjective Global Assessment (abPG-SGA) as a nutritional screening tool for cancer patients in an outpatient setting.
      Evaluation of dietary intake is time consuming, requires skilled personnel and relies on patient recall and cooperation. The best method that relies the least on patient recall is a three-day food diary. However, it requires patients to cooperate and follow detailed instructions, which may make it difficult to implement in those with advanced disease. Therefore, repeated 24 h dietary recalls are also optional.
      • De Keyzer W.
      • Huybrechts I.
      • De Vriendt V.
      • Vandevijvere S.
      • Slimani N.
      • Van Oyen H.
      • et al.
      Repeated 24-hour recalls versus dietary records for estimating nutrient intakes in a national food consumption survey.
      The 24 h recall technique requires short-term recall, is less burdensome, less likely to alter eating behaviour than food diary, and can be used across diverse populations because it does not require a high level of literacy.
      • Ahluwalia N.
      • Dwyer J.
      • Terry A.
      • Moshfegh A.
      • Johnson C.
      Update on NHANES dietary data: focus on collection, release, analytical considerations, and uses to inform public policy.
      At a minimum, patients should be asked if their relative food intake has changed and, if so, by how much (by half etc.) and over what period of time (for example, as indicated in the SGA – nutritional assessment tool).
      • Detsky A.S.
      • McLaughlin J.R.
      • Baker J.P.
      • Johnston N.
      • Whittaker S.
      • Mendelson R.A.
      • et al.
      What is subjective global assessment of nutritional status?.

      Obesity in cirrhosis: Assessment and interpretation

      With the increasing prevalence of obesity and NASH-related cirrhosis, attention needs to be paid to obesity in patients with cirrhosis. Obesity does not rule out malnutrition. The combination of loss of skeletal muscle and gain of adipose tissue is termed sarcopenic obesity and is observed in a significant number of patients with cirrhosis.
      • Montano-Loza A.J.
      • Angulo P.
      • Meza-Junco J.
      • Prado C.M.
      • Sawyer M.B.
      • Beaumont C.
      • et al.
      Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis.
      • Carias S.
      • Castellanos A.L.
      • Vilchez V.
      • Nair R.
      • Dela Cruz A.C.
      • Watkins J.
      • et al.
      Nonalcoholic steatohepatitis is strongly associated with sarcopenic obesity in patients with cirrhosis undergoing liver transplant evaluation.
      • Choudhary N.S.
      • Saigal S.
      • Saraf N.
      • Mohanka R.
      • Rastogi A.
      • Goja S.
      • et al.
      Sarcopenic obesity with metabolic syndrome: a newly recognized entity following living donor liver transplantation.
      Moreover, post-transplant obesity and metabolic syndrome are common and weight gain after transplantation is considered to be primarily due to an increase in the adipose tissue, with concomitant loss in skeletal muscle.
      • Choudhary N.S.
      • Saigal S.
      • Saraf N.
      • Mohanka R.
      • Rastogi A.
      • Goja S.
      • et al.
      Sarcopenic obesity with metabolic syndrome: a newly recognized entity following living donor liver transplantation.
      • Dasarathy S.
      Posttransplant sarcopenia: an underrecognized early consequence of liver transplantation.
      Therefore, malnutrition needs to be estimated routinely and treated in the obese cirrhotic patient. In clinical practice, BMI is adequate to recognise obesity (defined as BMI equal or greater than 30 kg/m2) in cirrhotic patients, in the absence of fluid retention. In the case of fluid retention, BW needs to be corrected by evaluating the patient’s dry weight, commonly estimated by post-paracentesis BW or weight recorded before fluid retention if available, or by subtracting a percentage of weight based upon the severity of ascites (mild 5%; moderate 10%; severe 15%), with an additional 5% subtracted if bilateral pedal oedema is present, as performed in several studies.
      • Tandon P.
      • Ney M.
      • Irwin I.
      • Ma M.M.
      • Gramlich L.
      • Bain V.G.
      • et al.
      Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value.
      • Tandon P.
      • Low G.
      • Mourtzakis M.
      • Zenith L.
      • Myers R.P.
      • Abraldes J.G.
      • et al.
      A model to identify sarcopenia in patients with cirrhosis.
      This is still not validated but excellent inter-observer agreement has been demonstrated. The dry-weight BMI is then calculated by dividing the patient’s estimated dry weight (kg) by the square of the patient’s height (m).
      The proposed process for nutritional screening and assessment in patients with chronic liver disease is summarised (Fig. 1).
      • Perform a rapid nutritional screen in all patients with cirrhosis and complete a detailed assessment in those at risk of malnutrition, to confirm the presence and severity of malnutrition. (Grade II-2, B1)
      • Assume risk for malnutrition to be high if BMI <18.5 kg/m2 or Child-Pugh C. Utilise nutritional screening tools to assess the risk of malnutrition in all other instances. (Grade II-2, B1)
      • In the diagnosis of obesity (BMI >30 kg/m2) always consider the confounding effect of fluid retention and estimate dry BW, even though the accuracy is low. (Grade II-2, B2)
      • Include an assessment of sarcopenia within the nutritional assessment. (Grade II-2, B1)
      • Whenever a CT scan has been performed, assess muscle mass on images by this method. Anthropometry, DEXA or BIA are possible alternatives, which also allow for serial measurements. (Grade II-2, B1)
      • Assess muscle function, in the clinical setting, with the most appropriate tool, such as handgrip strength and/or the short physical performance battery. (Grade II-2, B1)
      • Assess dietary intake by trained personnel (ideally a dietician with knowledge of managing patients with liver disease) working as part of a team with the hepatologist. Assessment should include: quality and quantity of food and supplements, fluids, sodium in diet, number and timing of meals during the day and barriers to eating. (Grade II-2, B1)
      Figure thumbnail gr1
      Fig. 1Nutritional screening and assessment in patients with cirrhosis. All patients should undergo a rapid screening of malnutrition using validated, accepted tools. A liver specific screening tool which takes into consideration fluid retention may be advisable (Royal Free Hospital Nutritional Prioritizing Tool (RFH-NPT). Patients found to be at high risk of malnutrition should undergo a detailed nutritional assessment, and based on the findings they should receive either supplementation or regular follow-up. In a case of fluid retention, body weight should be corrected by evaluating the patient’s dry weight by post-paracentesis body weight or weight recorded before fluid retention if available, or by subtracting a percentage of weight based upon severity of ascites (mild, 5%; moderate, 10%; severe, 15%), with an additional 5% subtracted if bilateral pedal oedema is present. BIA, bioelectrical impedance analysis; BMI, body mass index; CT, computed tomography; DEXA; dual-energy X-ray absorptiometry.

      Nutritional management principles in patients with liver cirrhosis

      Since malnutrition and sarcopenia are independent predictors of adverse clinical outcomes including survival
      • Merli M.
      • Giusto M.
      • Gentili F.
      • Novelli G.
      • Ferretti G.
      • Riggio O.
      • et al.
      Nutritional status: its influence on the outcome of patients undergoing liver transplantation.
      • Englesbe M.J.
      • Patel S.P.
      • He K.
      • Lynch R.J.
      • Schaubel D.E.
      • Harbaugh C.
      • et al.
      Sarcopenia and mortality after liver transplantation.
      • Ney M.
      • Vandermeer B.
      • Van Zanten S.
      • Ma M.
      • Gramlich L.
      • Tandon P.
      Meta-analysis: oral or enteral nutritional supplementation in cirrhosis.
      • Tandon P.
      • Raman M.
      • Mourtzakis M.
      • Merli M.
      A practical approach to nutritional screening and assessment in cirrhosis.
      • Merli M.
      • Riggio O.
      • Dally L.
      Does malnutrition affect survival in cirrhosis? PINC (Policentrica Italiana Nutrizione Cirrosi).
      any nutritional approach in cirrhotic patients needs to be guided by some general principles of nutritional management.

      Energy and protein requirements in cirrhosis

      Cirrhosis is a state of accelerated starvation demonstrated by a rapid post absorptive physiology which is characterised by a reduction in the respiratory quotient.
      • Glass C.
      • Hipskind P.
      • Tsien C.
      • Malin S.K.
      • Kasumov T.
      • Shah S.N.
      • et al.
      Sarcopenia and a physiologically low respiratory quotient in patients with cirrhosis: a prospective controlled study.
      • Glass C.
      • Hipskind P.
      • Cole D.
      • Lopez R.
      • Dasarathy S.
      Handheld calorimeter is a valid instrument to quantify resting energy expenditure in hospitalized cirrhotic patients: a prospective study.
      The reduction in the respiratory quotient is the manifestation of a metabolic switch in the primary fuel from glucose to fatty acids. During this state of accelerated starvation, protein synthesis is decreased and gluconeogenesis from amino acids is increased, necessitating proteolysis, which contributes to sarcopenia. Gluconeogenesis is an energy-expensive procedure which may further increase resting energy expenditure (REE) in these patients. Accelerated starvation is aggravated by reduced dietary intake due to a variety of factors including dysgeusia, anorexia of chronic disease, salt restricted food that is not tasty, portal hypertension that contributes to impaired gut motility, decreased nutrient absorption and protein losing enteropathy.
      • Dasarathy S.
      • Merli M.
      Sarcopenia from mechanism to diagnosis and treatment in liver disease.
      • Dasarathy S.
      Nutrition and alcoholic liver disease: effects of alcoholism on nutrition, effects of nutrition on alcoholic liver disease, and nutritional therapies for alcoholic liver disease.
      • Dasarathy S.
      Cause and management of muscle wasting in chronic liver disease.
      • Dasarathy J.
      • McCullough A.J.
      • Dasarathy S.
      Sarcopenia in alcoholic liver disease: clinical and molecular advances.
      Additional factors that result in decreased dietary intake include inappropriate dietary protein restriction, hospitalisation with periods of fasting for diagnostic and therapeutic procedures, encephalopathy and gastrointestinal bleeding.
      Energy supply needs to balance total energy expenditure (TEE), which includes REE, food-related thermogenesis and energy expenditure related to physical activity. TEE is measured ideally with doubly labelled water or in a respiratory chamber, but these methods are not feasible in the clinical setting. Physical activity is reduced in patients with decompensated cirrhosis and negligible when patients are hospitalised. In cirrhotic patients, TEE varies between 28 to 37.5 kcal/kg.BW/d.
      • Dasarathy S.
      • Merli M.
      Sarcopenia from mechanism to diagnosis and treatment in liver disease.
      • Greco A.V.
      • Mingrone G.
      • Benedetti G.
      • Capristo E.
      • Tataranni P.A.
      • Gasbarrini G.
      Daily energy and substrate metabolism in patients with cirrhosis.
      • Guglielmi F.W.
      • Panella C.
      • Buda A.
      • Budillon G.
      • Caregaro L.
      • Clerici C.
      • et al.
      Nutritional state and energy balance in cirrhotic patients with or without hypermetabolism. Multicentre prospective study by the ‘Nutritional Problems in Gastroenterology’ Section of the Italian Society of Gastroenterology (SIGE).
      • Riggio O.
      • Angeloni S.
      • Ciuffa L.
      • Nicolini G.
      • Attili A.F.
      • Albanese C.
      • et al.
      Malnutrition is not related to alterations in energy balance in patients with stable liver cirrhosis.
      • Nielsen K.
      • Kondrup J.
      • Martinsen L.
      • Dossing H.
      • Larsson B.
      • Stilling B.
      • et al.
      Long-term oral refeeding of patients with cirrhosis of the liver.
      Some studies evaluated whether decompensated liver cirrhosis affected REE. One small longitudinal study suggested that ascites increases REE.
      • Dolz C.
      • Raurich J.M.
      • Ibanez J.
      • Obrador A.
      • Marse P.
      • Gaya J.
      Ascites increases the resting energy expenditure in liver cirrhosis.
      However, a cross-sectional study found no difference in REE between patients with varying levels of liver disease severity and fluid retention.
      • Madden A.M.
      • Morgan M.Y.
      Resting energy expenditure should be measured in patients with cirrhosis, not predicted.
      • Tajika M.
      • Kato M.
      • Mohri H.
      • Miwa Y.
      • Kato T.
      • Ohnishi H.
      • et al.
      Prognostic value of energy metabolism in patients with viral liver cirrhosis.
      • Knudsen A.W.
      • Krag A.
      • Nordgaard-Lassen I.
      • Frandsen E.
      • Tofteng F.
      • Mortensen C.
      • et al.
      Effect of paracentesis on metabolic activity in patients with advanced cirrhosis and ascites.
      Measured REE may be higher than predicted, a situation termed hypermetabolism. However, hypermetabolism cannot be identified by clinical or laboratory parameters,
      • Muller M.J.
      • Bottcher J.
      • Selberg O.
      • Weselmann S.
      • Boker K.H.
      • Schwarze M.
      • et al.
      Hypermetabolism in clinically stable patients with liver cirrhosis.
      the severity and the aetiology of liver cirrhosis and the presence of ascites.
      • Peng S.
      • Plank L.D.
      • McCall J.L.
      • Gillanders L.K.
      • McIlroy K.
      • Gane E.J.
      Body composition, muscle function, and energy expenditure in patients with liver cirrhosis: a comprehensive study.
      REE may be estimated by predictive formulae but these are inaccurate in advanced cirrhotic patients, and thus measurement by indirect calorimetry is advisable whenever possible.
      • Glass C.
      • Hipskind P.
      • Tsien C.
      • Malin S.K.
      • Kasumov T.
      • Shah S.N.
      • et al.
      Sarcopenia and a physiologically low respiratory quotient in patients with cirrhosis: a prospective controlled study.
      • Glass C.
      • Hipskind P.
      • Cole D.
      • Lopez R.
      • Dasarathy S.
      Handheld calorimeter is a valid instrument to quantify resting energy expenditure in hospitalized cirrhotic patients: a prospective study.
      The availability of the hand held calorimeter at the bedside is a possible alternative to determine a patient’s daily caloric needs.
      • Hipskind P.
      • Glass C.
      • Charlton D.
      • Nowak D.
      • Dasarathy S.
      Do handheld calorimeters have a role in assessment of nutrition needs in hospitalized patients? A systematic review of literature.
      The approach of most nutritional intervention studies in liver cirrhosis is to supply at least 35 kcal/kg.BW/d. The use of actual BW, corrected for ascites (see previous section), is considered safe. This can be achieved primarily by tailoring the oral dietary intake, even though this goal is frequently difficult to accomplish. The role of a nutrition support team has recently been underlined by a retrospective study showing that nutritional intervention, led by a multidisciplinary team, and in which cirrhotic patients participated in teaching sessions about the relevance of appropriate nutrition in chronic liver disease, was able to improve survival rates and quality of life.
      • Iwasa M.
      • Iwata K.
      • Hara N.
      • Hattori A.
      • Ishidome M.
      • Sekoguchi-Fujikawa N.
      • et al.
      Nutrition therapy using a multidisciplinary team improves survival rates in patients with liver cirrhosis.
      Whether frequent feeding can help prevent accelerated starvation and the related proteolysis has also been extensively evaluated. Since the longest inter-meal duration is at night, strategies to shorten nocturnal fasting with a late evening snack have been explored, achieving an improvement in metabolic profile and quality of life, although muscle mass did not show consistent improvement.
      • Tsien C.D.
      • McCullough A.J.
      • Dasarathy S.
      Late evening snack: exploiting a period of anabolic opportunity in cirrhosis.
      The adoption of a breakfast containing some proteins
      • Vaisman N.
      • Katzman H.
      • Carmiel-Haggai M.
      • Lusthaus M.
      • Niv E.
      Breakfast improves cognitive function in cirrhotic patients with cognitive impairment.
      and a late evening snack
      • Plank L.D.
      • Gane E.J.
      • Peng S.
      • Muthu C.
      • Mathur S.
      • Gillanders L.
      • et al.
      Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial.
      to shorten the period of fasting are therefore recommended in cirrhotic patients.
      Protein needs are based on the minimum protein intake required to maintain nitrogen balance. In alcoholic cirrhosis, nitrogen balance was achieved with intakes of 0.8 g/kg.BW/d.
      • Nielsen K.
      • Kondrup J.
      • Martinsen L.
      • Stilling B.
      • Wikman B.
      Nutritional assessment and adequacy of dietary intake in hospitalized patients with alcoholic liver cirrhosis.
      This cut-off was confirmed in studies wherein cirrhotic patients received diets with increasing protein content.
      • Nielsen K.
      • Kondrup J.
      • Martinsen L.
      • Dossing H.
      • Larsson B.
      • Stilling B.
      • et al.
      Long-term oral refeeding of patients with cirrhosis of the liver.
      • Swart G.R.
      • van den Berg J.W.
      • van Vuure J.K.
      • Rietveld T.
      • Wattimena D.L.
      • Frenkel M.
      Minimum protein requirements in liver cirrhosis determined by nitrogen balance measurements at three levels of protein intake.
      These studies also showed that cirrhotic patients are able to utilise up to 1.8 g/kg.BW/d of protein.
      • Nielsen K.
      • Kondrup J.
      • Martinsen L.
      • Dossing H.
      • Larsson B.
      • Stilling B.
      • et al.
      Long-term oral refeeding of patients with cirrhosis of the liver.
      In the past, there has been controversy about whether patients suffering from HE should undergo a transient restriction in protein intake, in order to limit the synthesis of ammonium and the deamination of protein to aromatic amino acids. However, normal to high protein intake does not precipitate HE
      • Fenton J.C.
      • Knight E.J.
      • Humpherson P.L.
      Milk-and-cheese diet in portal-systemic encephalopathy.
      • Bianchi G.P.
      • Marchesini G.
      • Fabbri A.
      • Rondelli A.
      • Bugianesi E.
      • Zoli M.
      • et al.
      Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison.
      and may even improve mental status
      • Gheorghe L.
      • Iacob R.
      • Vadan R.
      • Iacob S.
      • Gheorghe C.
      Improvement of hepatic encephalopathy using a modified high-calorie high-protein diet.
      • Cordoba J.
      • Lopez-Hellin J.
      • Planas M.
      • Sabin P.
      • Sanpedro F.
      • Castro F.
      • et al.
      Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.
      (see paragraph on hepatic encephalopathy).
      The recommended protein intake in patients with a diagnosis of liver cirrhosis is 1.2–1.5 g/kg.BW/d to prevent loss of muscle mass and reverse muscle loss in those who are sarcopenic. Indeed, sarcopenia, as previously stated, contributes to worse clinical outcomes, independent of the severity of liver disease.
      • Carey E.J.
      • Lai J.C.
      • Wang C.W.
      • Dasarathy S.
      • Lobach I.
      • Montano-Loza A.J.
      • et al.
      A multicenter study to define sarcopenia in patients with end-stage liver disease.
      • Dasarathy S.
      • Merli M.
      Sarcopenia from mechanism to diagnosis and treatment in liver disease.
      Options for the treatment of sarcopenia will be discussed in the next section.
      Short dietary advice for use when treating a cirrhotic patient at bedside or during an outpatient visit is provided (Box 2).
      Figure thumbnail gr5
      Box 2Short, practical dietary advice for bedside or outpatient clinic use.

      Approach to sarcopenia in patients with liver cirrhosis

      Factors related with sarcopenia in patients with cirrhosis

      Skeletal muscle mass is the largest protein store in the body. A balance between skeletal muscle protein synthesis and breakdown is responsible for protein homeostasis (or proteostasis) that maintains skeletal muscle mass.
      • Dasarathy J.
      • McCullough A.J.
      • Dasarathy S.
      Sarcopenia in alcoholic liver disease: clinical and molecular advances.
      • Rennie M.J.
      • Tipton K.D.
      Protein and amino acid metabolism during and after exercise and the effects of nutrition.
      • Periyalwar P.
      • Dasarathy S.
      Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses.
      In the past, whole body protein turnover studies have yielded conflicting results with unaltered, increased or decreased protein synthesis and breakdown in cirrhosis.
      • Dasarathy S.
      Consilience in sarcopenia of cirrhosis.
      • Tessari P.
      Protein metabolism in liver cirrhosis: from albumin to muscle myofibrils.
      Skeletal muscle mass depends on a number of physiological factors including age, gender and ethnicity. The severity and aetiology of liver disease also affects muscle mass, with cholestatic and alcoholic liver disease leading to the most severe muscle loss independently of the severity of the underlying liver disease, although data on alcoholic liver disease are not consistent.
      • Dasarathy J.
      • McCullough A.J.
      • Dasarathy S.
      Sarcopenia in alcoholic liver disease: clinical and molecular advances.
      • DiCecco S.R.
      • Wieners E.J.
      • Wiesner R.H.
      • Southorn P.A.
      • Plevak D.J.
      • Krom R.A.
      Assessment of nutritional status of patients with end-stage liver disease undergoing liver transplantation.
      Hepatocellular dysfunction and portosystemic shunting also result in biochemical and hormonal perturbations in cirrhosis that contribute to sarcopenia.
      Increased skeletal muscle ammonia, reduction in testosterone and growth hormone, endotoxemia, as well as decreased dietary nutrient intake contribute to sarcopenia.
      • Tessari P.
      Protein metabolism in liver cirrhosis: from albumin to muscle myofibrils.
      • Sinclair M.
      • Grossmann M.
      • Hoermann R.
      • Angus P.W.
      • Gow P.J.
      Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial.
      • Assy N.
      • Hochberg Z.
      • Amit T.
      • Shen-Orr Z.
      • Enat R.
      • Baruch Y.
      Growth hormone-stimulated insulin-like growth factor (IGF) I and IGF-binding protein-3 in liver cirrhosis.
      • Chen H.W.
      • Dunn M.A.
      Muscle at risk: the multiple impacts of ammonia on sarcopenia and frailty in cirrhosis.
      In addition, amino acid perturbations, specifically reduction in the branched chain amino acid, l-leucine, and consequent impaired global protein synthesis has also been reported to contribute to sarcopenia in cirrhosis.
      • Dasarathy S.
      Consilience in sarcopenia of cirrhosis.
      • Dam G.
      • Ott P.
      • Aagaard N.K.
      • Vilstrup H.
      Branched-chain amino acids and muscle ammonia detoxification in cirrhosis.
      • Tsien C.
      • Davuluri G.
      • Singh D.
      • Allawy A.
      • Ten Have G.A.
      • Thapaliya S.
      • et al.
      Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis.
      • Nishikawa H.
      • Enomoto H.
      • Ishii A.
      • Iwata Y.
      • Miyamoto Y.
      • Ishii N.
      • et al.
      Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis.
      • Holecek M.
      Branched-chain amino acid supplementation in treatment of liver cirrhosis: Updated views on how to attenuate their harmful effects on cataplerosis and ammonia formation.
      To better understand how to correct the progressive depletion of muscle mass in cirrhotic patients, molecular mechanisms of muscle wasting have recently been investigated (Fig. 2). Molecular pathways that regulate skeletal muscle mass include myostatin, a TGFβ superfamily member that inhibits protein synthesis and potentially increases proteolysis.
      • Periyalwar P.
      • Dasarathy S.
      Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses.
      Data in animal models, humans and cellular systems have consistently shown that myostatin expression is increased in cirrhosis.
      • Tsien C.
      • Davuluri G.
      • Singh D.
      • Allawy A.
      • Ten Have G.A.
      • Thapaliya S.
      • et al.
      Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis.
      • Dasarathy S.
      • McCullough A.J.
      • Muc S.
      • Schneyer A.
      • Bennett C.D.
      • Dodig M.
      • et al.
      Sarcopenia associated with portosystemic shunting is reversed by follistatin.
      • Qiu J.
      • Thapaliya S.
      • Runkana A.
      • Yang Y.
      • Tsien C.
      • Mohan M.L.
      • et al.
      Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-kappaB-mediated mechanism.
      In addition to impaired protein synthesis, proteolysis is also required for loss of muscle mass.
      • Dasarathy S.
      • Merli M.
      Sarcopenia from mechanism to diagnosis and treatment in liver disease.
      • Dasarathy J.
      • McCullough A.J.
      • Dasarathy S.
      Sarcopenia in alcoholic liver disease: clinical and molecular advances.
      The ubiquitin proteasome pathway and autophagy are currently believed to be the dominant mechanisms of skeletal muscle proteolysis.
      • Dasarathy S.
      • Merli M.
      Sarcopenia from mechanism to diagnosis and treatment in liver disease.
      • Qiu J.
      • Tsien C.
      • Thapalaya S.
      • Narayanan A.
      • Weihl C.C.
      • Ching J.K.
      • et al.
      Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis.
      Human skeletal muscle from patients with cirrhosis and preclinical models of hyperammonaemia show increased autophagy with impaired or unaltered proteasome-mediated proteolysis.
      • Tsien C.
      • Davuluri G.
      • Singh D.
      • Allawy A.
      • Ten Have G.A.
      • Thapaliya S.
      • et al.
      Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis.
      • Qiu J.
      • Tsien C.
      • Thapalaya S.
      • Narayanan A.
      • Weihl C.C.
      • Ching J.K.
      • et al.
      Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis.
      • Thapaliya S.
      • Runkana A.
      • McMullen M.R.
      • Nagy L.E.
      • McDonald C.
      • Naga Prasad S.V.
      • et al.
      Alcohol-induced autophagy contributes to loss in skeletal muscle mass.
      A more extensive view of molecular mechanisms of muscle wasting in patients with liver cirrhosis is reviewed in Refs.
      • Dasarathy S.
      • Merli M.
      Sarcopenia from mechanism to diagnosis and treatment in liver disease.
      ,
      • Dasarathy S.
      Cause and management of muscle wasting in chronic liver disease.
      .
      Figure thumbnail gr2
      Fig. 2Mechanisms and potential targets for anabolic resistance and dysregulated proteostasis resulting in sarcopenia and/or failure to respond to standard supplementation. Adapted from Dasarathy S. et al. 2016.65 BCAA, branched chain amino acid; ROS, reactive oxygen species; Tx, treatment.

      Strategies to improve muscle mass in cirrhosis

      A number of potential therapeutic strategies to improve muscle mass in patients with cirrhosis have been evaluated. These include dietary manipulations, increased physical activity and exercise,
      • Dasarathy S.
      Consilience in sarcopenia of cirrhosis.
      • Zenith L.
      • Meena N.
      • Ramadi A.
      • Yavari M.
      • Harvey A.
      • Carbonneau M.
      • et al.
      Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis.
      • Berzigotti A.
      • Saran U.
      • Dufour J.F.
      Physical activity and liver diseases.
      • Berzigotti A.
      • Albillos A.
      • Villanueva C.
      • Genesca J.
      • Ardevol A.
      • Augustin S.
      • et al.
      Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study.
      hormone replacement therapies,
      • Nagasue N.
      • Yukaya H.
      • Chang Y.C.
      • Ogawa Y.
      • Kohno H.
      • Ito A.
      Active uptake of testosterone by androgen receptors of hepatocellular carcinoma in humans.
      ammonia-lowering strategies and targeting the underlying liver disease.
      • Gorostiaga E.M.
      • Navarro-Amezqueta I.
      • Calbet J.A.
      • Sanchez-Medina L.
      • Cusso R.
      • Guerrero M.
      • et al.
      Blood ammonia and lactate as markers of muscle metabolites during leg press exercise.
      • Takeda K.
      • Takemasa T.
      Expression of ammonia transporters Rhbg and Rhcg in mouse skeletal muscle and the effect of 6-week training on these proteins.
      • McDaniel J.
      • Davuluri G.
      • Hill E.A.
      • Moyer M.
      • Runkana A.
      • Prayson R.
      • et al.
      Hyperammonemia results in reduced muscle function independent of muscle mass.
      • Kumar A.
      • Davuluri G.
      • Silva R.N.E.
      • Engelen M.
      • Ten Have G.A.M.
      • Prayson R.
      • et al.
      Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis.

      Nutritional supplementation

      It is advised that any nutritional interventions follow the general recommendations reported as “energy and protein requirements in cirrhotic patients” (previous paragraph). However, an adequate calorie and protein intake is difficult to achieve in malnourished sarcopenic patients with advanced liver disease. Oral nutritional supplement and branched chain amino acid (BCAA) supplements have been utilised in clinical trials to overcome this issue
      • Nakaya Y.
      • Harada N.
      • Kakui S.
      • Okada K.
      • Takahashi A.
      • Inoi J.
      • et al.
      Severe catabolic state after prolonged fasting in cirrhotic patients: effect of oral branched-chain amino-acid-enriched nutrient mixture.
      • Yoshida T.
      • Muto Y.
      • Moriwaki H.
      • Yamato M.
      Effect of long-term oral supplementation with branched-chain amino acid granules on the prognosis of liver cirrhosis.
      showing some benefits.
      In patients with malnutrition and cirrhosis, who are unable to achieve adequate dietary intake with the oral diet (even with oral supplements), short-term enteral or parenteral nutrition should be used to overcome the phase of underfeeding. Nutritional guidelines proposed by international medical societies for enteral and parenteral nutrition in patients with chronic liver disease are reported (Table S1).
      Enteral feeding has been utilised in malnourished cirrhotic patients admitted to hospital, but despite promising individual studies, systematic meta-analyses have not shown significant benefits in terms of survival.
      • Fialla A.D.
      • Israelsen M.
      • Hamberg O.
      • Krag A.
      • Gluud L.L.
      Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis.
      • Koretz R.L.
      • Avenell A.
      • Lipman T.O.
      Nutritional support for liver disease.
      • Antar R.
      • Wong P.
      • Ghali P.
      A meta-analysis of nutritional supplementation for management of hospitalized alcoholic hepatitis.
      There are also conflicting data on the benefits of parenteral nutritional supplementation in patients with cirrhosis, but this is likely to have a beneficial role during prolonged periods of poor oral intake including encephalopathy, gastrointestinal bleeding and impaired gut motility or ileus.
      • Plauth M.
      • Cabre E.
      • Campillo B.
      • Kondrup J.
      • Marchesini G.
      • Schutz T.
      • et al.
      ESPenteral nutrition Guidelines on Parenteral Nutrition: hepatology.
      The use of enteral and parenteral nutrition in the perioperative setting is dealt with in a dedicated section.
      There is limited but consistent data that supplemental nutrition improves quality of life if it results in an increase in lean body mass, even though direct studies on sarcopenia are currently unavailable.
      • Maharshi S.
      • Sharma B.C.
      • Sachdeva S.
      • Srivastava S.
      • Sharma P.
      Efficacy of nutritional therapy for patients with cirrhosis and minimal hepatic encephalopathy in a randomized trial.

      Exercise and physical activity

      In addition to nutritional supplementation, increased physical activity and exercise are also anabolic stimuli that can improve muscle mass and function. However, consistent long-term data in cirrhosis are lacking.
      • Rennie M.J.
      • Tipton K.D.
      Protein and amino acid metabolism during and after exercise and the effects of nutrition.
      • Liao C.D.
      • Tsauo J.Y.
      • Wu Y.T.
      • Cheng C.P.
      • Chen H.C.
      • Huang Y.C.
      • et al.
      Effects of protein supplementation combined with resistance exercise on body composition and physical function in older adults: a systematic review and meta-analysis.
      Endurance or aerobic exercise improves skeletal muscle functional capacity but not necessarily muscle mass.
      • Baar K.
      Training for endurance and strength: lessons from cell signaling.
      Resistance exercise promotes an increase in skeletal muscle mass.
      • Baar K.
      Training for endurance and strength: lessons from cell signaling.
      However, exercise also increases muscle ammonia generation and portal pressure,
      • Dietrich R.
      • Bachmann C.
      • Lauterburg B.H.
      Exercise-induced hyperammonemia in patients with compensated chronic liver disease.
      • Garcia-Pagan J.C.
      • Santos C.
      • Barbera J.A.
      • Luca A.
      • Roca J.
      • Rodriguez-Roisin R.
      • et al.
      Physical exercise increases portal pressure in patients with cirrhosis and portal hypertension.
      both of which can have adverse effects in cirrhotic patients. Despite these potential adverse responses, beneficial effects have been reported.
      • Berzigotti A.
      • Saran U.
      • Dufour J.F.
      Physical activity and liver diseases.
      • Berzigotti A.
      • Albillos A.
      • Villanueva C.
      • Genesca J.
      • Ardevol A.
      • Augustin S.
      • et al.
      Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study.
      Since both muscle loss and impaired contractile function are components of sarcopenia in cirrhosis, a combination of resistance and endurance exercise would probably be appropriate and beneficial, as confirmed by emerging data indicating the benefit of a moderate intensity exercise regimen in cirrhosis.
      • Berzigotti A.
      • Albillos A.
      • Villanueva C.
      • Genesca J.
      • Ardevol A.
      • Augustin S.
      • et al.
      Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study.
      Nutrient supplementation following physical activity is beneficial in physiological states, but whether such an intervention is beneficial in cirrhosis is currently unknown.
      • Schoenfeld B.J.
      • Aragon A.A.
      • Krieger J.W.
      The effect of protein timing on muscle strength and hypertrophy: a meta-analysis.
      • Beale D.J.
      • et al.
      Evidence inconclusive – comment on article by Schoenfeld.
      Continued impaired functional capacity and reduced peak oxygen consumption are associated with decreased survival and poor post-transplant outcomes.
      • Jones J.C.
      • Coombes J.S.
      • Macdonald G.A.
      Exercise capacity and muscle strength in patients with cirrhosis.
      • Dharancy S.
      • Lemyze M.
      • Boleslawski E.
      • Neviere R.
      • Declerck N.
      • Canva V.
      • et al.
      Impact of impaired aerobic capacity on liver transplant candidates.
      Hence measures to increase functional capacity are likely to improve long-term clinical outcomes in cirrhosis.
      • Zenith L.
      • Meena N.
      • Ramadi A.
      • Yavari M.
      • Harvey A.
      • Carbonneau M.
      • et al.
      Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis.

      Other strategies

      Hormone replacement therapy utilising growth hormone or testosterone has been proposed but has not been consistently effective.
      • Sinclair M.
      • Grossmann M.
      • Hoermann R.
      • Angus P.W.
      • Gow P.J.
      Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial.
      • Assy N.
      • Hochberg Z.
      • Amit T.
      • Shen-Orr Z.
      • Enat R.
      • Baruch Y.
      Growth hormone-stimulated insulin-like growth factor (IGF) I and IGF-binding protein-3 in liver cirrhosis.
      • Matsumoto R.
      • Fukuoka H.
      • Iguchi G.
      • Nishizawa H.
      • Bando H.
      • Suda K.
      • et al.
      Long-term effects of growth hormone replacement therapy on liver function in adult patients with growth hormone deficiency.
      • Sinclair M.
      • Gow P.J.
      • Grossmann M.
      • Angus P.W.
      Review article: sarcopenia in cirrhosis–aetiology, implications and potential therapeutic interventions.
      Furthermore caution is needed when using testosterone because of the possibility of increasing the risk of hepatocellular carcinoma.
      • Nagasue N.
      • Yukaya H.
      • Chang Y.C.
      • Ogawa Y.
      • Kohno H.
      • Ito A.
      Active uptake of testosterone by androgen receptors of hepatocellular carcinoma in humans.
      A number of reports in preclinical models have shown that hyperammonaemia results in impaired protein synthesis and increased autophagy, both of which result in loss of muscle mass.
      • Qiu J.
      • Thapaliya S.
      • Runkana A.
      • Yang Y.
      • Tsien C.
      • Mohan M.L.
      • et al.
      Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-kappaB-mediated mechanism.
      • Qiu J.
      • Tsien C.
      • Thapalaya S.
      • Narayanan A.
      • Weihl C.C.
      • Ching J.K.
      • et al.
      Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis.
      Long-term ammonia-lowering strategies may result in increased muscle mass and contractile strength but the data are derived from preclinical studies and require validation in human studies.
      • Kumar A.
      • Davuluri G.
      • Silva R.N.E.
      • Engelen M.
      • Ten Have G.A.M.
      • Prayson R.
      • et al.
      Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis.

      Nutritional approach and management of obesity in patients with liver cirrhosis

      Two studies have shown that obesity is at least as frequent in compensated cirrhosis as it is in the general population, ranging from 20 to 35%,
      • Berzigotti A.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Morillas R.
      • et al.
      Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis.
      • Everhart J.E.
      • Lok A.S.
      • Kim H.Y.
      • Morgan T.R.
      • Lindsay K.L.
      • Chung R.T.
      • et al.
      Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial.
      regardless of the origin of liver disease. In NASH-related cirrhosis obesity is present in most cases. Moreover, a sedentary lifestyle is highly prevalent in patients with cirrhosis and might be seen as a cofactor, leading to an increase in BW in this population. In the HALT-C trial
      • Everhart J.E.
      • Lok A.S.
      • Kim H.Y.
      • Morgan T.R.
      • Lindsay K.L.
      • Chung R.T.
      • et al.
      Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial.
      the risk of histological progression or decompensation increased by 14% for each increase in BMI quartile, and the risk of progression increased by 35% in patients whose BW increased by >5% at one year.
      In a randomised controlled trial comparing the use of timolol or placebo to prevent the onset of gastroesophageal varices, BMI was associated with clinical decompensation, independently of portal hypertension and albumin, in patients with no varices and an hepatic venous pressure gradient ≥6 mmHg.
      • Berzigotti A.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Morillas R.
      • et al.
      Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis.
      Data from different studies suggest that a reduction in BW improves outcomes in obese patients with compensated cirrhosis.
      • Zenith L.
      • Meena N.
      • Ramadi A.
      • Yavari M.
      • Harvey A.
      • Carbonneau M.
      • et al.
      Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis.
      • Everhart J.E.
      • Lok A.S.
      • Kim H.Y.
      • Morgan T.R.
      • Lindsay K.L.
      • Chung R.T.
      • et al.
      Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial.
      • Macias-Rodriguez R.U.
      • Ilarraza-Lomeli H.
      • Ruiz-Margain A.
      • Ponce-de-Leon-Rosales S.
      • Vargas-Vorackova F.
      • Garcia-Flores O.
      • et al.
      Changes in hepatic venous pressure gradient induced by physical exercise in cirrhosis: results of a pilot randomized open clinical trial.
      This was achieved by a programme of lifestyle intervention including nutritional therapy and supervised moderate intensity physical exercise. A weight decrease ≥5–10% is considered an adequate goal, associated with a reduced rate of disease progression in patients included in the HALT-C trial.
      • Everhart J.E.
      • Lok A.S.
      • Kim H.Y.
      • Morgan T.R.
      • Lindsay K.L.
      • Chung R.T.
      • et al.
      Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial.
      Dietary intake is aimed to guarantee both moderate caloric restriction and adequate protein intake. Indeed, although good quality data are lacking, particular attention must be paid to the protein intake needed to maintain muscle mass, because of the potential risk of exacerbating sarcopenia during weight loss interventions.
      No clear-cut data is available regarding the best type of physical exercise (aerobic vs. anaerobic; endurance vs. resistance/strength training) and its duration in this population. In patients with portal hypertension, avoidance of abdominal pressure seems reasonable even though there is some data suggesting that resistance exercise is probably safe.
      • Macias-Rodriguez R.U.
      • Ilarraza-Lomeli H.
      • Ruiz-Margain A.
      • Ponce-de-Leon-Rosales S.
      • Vargas-Vorackova F.
      • Garcia-Flores O.
      • et al.
      Changes in hepatic venous pressure gradient induced by physical exercise in cirrhosis: results of a pilot randomized open clinical trial.
      Exercise needs to be tailored to the patient’s ability, beginning with moderate intensity and maintained for the long-term.
      • Nutritional counselling should be performed in cirrhotic patients with malnutrition, when possible by a multidisciplinary team, helping patients to achieve adequate caloric and protein intake. (Grade II-2, C2)
      • Optimal daily energy intake should not be lower than the recommended 35 kcal/kg. actual BW/d (in non-obese individuals). (Grade II-2, B1)
      • Optimal daily protein intake should not be lower than the recommended 1.2–1.5 g/kg. actual BW/d. (Grade II-2, B1)
      • Include late evening oral nutritional supplementation and breakfast in dietary regimen of malnourished decompensated cirrhotic patients. (Grade II-1, B1)
      • BCAA supplements and leucine enriched amino acid supplements should be considered in decompensated cirrhotic patients when adequate nitrogen intake is not achieved by oral diet. (Grade II-1, C1)
      • In patients with malnutrition and cirrhosis who are unable to achieve adequate dietary intake with the oral diet (even with oral supplements), a period of enteral nutrition is recommended. (Grade II-1, B1)
      • Patients with cirrhosis, whenever possible, can be encouraged to avoid hypomobility and to progressively increase physical activity to prevent and/or ameliorate sarcopenia. (Grade II-1, C2)
      • Implement a nutritional and lifestyle programme to achieve progressive weight loss (>5–10%) in obese cirrhotic patients (BMI >30 kg/m2 corrected for water retention). (Grade II-2, C1)
      • A tailored, moderately hypocaloric (-500–800 kcal/d) diet, including adequate protein intake (>1.5 g proteins/kg.ideal BW/d) can be adopted to achieve weight loss without compromising protein stores in obese cirrhotic patients. (Grade II-1, C2)
      New research should address the following topics
      • 1.
        Does the improvement in muscle mass and/or muscle function improve clinical outcomes (lower the risk of first decompensation, ascites, infection and encephalopathy, reduce hospital readmissions, decrease length of hospital stay, reduce risk of falls, improve survival)?
      • 2.
        Do ammonia-lowering strategies in decompensated cirrhosis reverse muscle loss and improve clinical outcomes?
      • 3.
        Does a gradual increase in physical activity delay or reverse muscle loss and contractile dysfunction? What type and duration of exercise are beneficial in cirrhotic patients?
      • 4.
        Is the addition of supplements (leucine, isoleucine or other nutrient supplements) needed to lower ammonia and increase mitochondrial intermediates during training?
      • 5.
        How can therapies targeting the muscle protein synthesis pathway or dysregulated muscle autophagy be implemented?
      • 6.
        How can anabolic resistance be overcome, or the underlying causes of anabolic resistance in cirrhotic patients be reversed?

      Micronutrients

      In general, vitamin deficiencies in liver disease are related to hepatic dysfunction, diminished reserves and, with increasing disease severity, inadequate dietary intake and malabsorption.
      Fat-soluble vitamin deficiencies are common. A retrospective study reported that the majority of liver disease patients being considered for transplantation presented with vitamin A and D deficiencies.
      • Venu M.
      • Martin E.
      • Saeian K.
      • Gawrieh S.
      High prevalence of vitamin A deficiency and vitamin D deficiency in patients evaluated for liver transplantation.
      The prevalence of vitamin D deficiency in the general population ranges from 20 to 100% when referring to serum 25-hydroxyvitamin D (25(OH)D) concentrations <20 ng/ml, and affects all age groups.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • Gordon C.M.
      • Hanley D.A.
      • Heaney R.P.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      In patients with chronic liver disease vitamin D (25(OH)D) levels below 20 ng/ml have been reported in between 64 and 92% of patients, predominantly in chronic cholestatic conditions, and usually inversely correlated with more advanced disease and Child-Pugh score.
      • Trautwein C.
      • Possienke M.
      • Schlitt H.J.
      • Boker K.H.
      • Horn R.
      • Raab R.
      • et al.
      Bone density and metabolism in patients with viral hepatitis and cholestatic liver diseases before and after liver transplantation.
      • Stokes C.S.
      • Volmer D.A.
      • Grunhage F.
      • Lammert F.
      Vitamin D in chronic liver disease.
      Although low vitamin D levels might, in part, be due to decreased plasma binding proteins in the presence of liver insufficiency, some evidence in pre-cirrhotic stages provide support for a true nutritional deficit. Recent data suggest a close correlation between vitamin D levels and response to treatment in patients with hepatitis C virus infection, non-alcoholic fatty liver disease and those who develop hepatocellular carcinoma.
      • Stokes C.S.
      • Volmer D.A.
      • Grunhage F.
      • Lammert F.
      Vitamin D in chronic liver disease.
      • Barchetta I.
      • Angelico F.
      • Del Ben M.
      • Baroni M.G.
      • Pozzilli P.
      • Morini S.
      • et al.
      Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes.
      • Petta S.
      • Camma C.
      • Scazzone C.
      • Tripodo C.
      • Di Marco V.
      • Bono A.
      • et al.
      Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.
      Based on these data, it is advisable to assess plasma vitamin D (25(OH)D) levels in all patients with chronic liver disease, particularly in those with advanced disease,
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • Gordon C.M.
      • Hanley D.A.
      • Heaney R.P.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      • Stokes C.S.
      • Volmer D.A.
      • Grunhage F.
      • Lammert F.
      Vitamin D in chronic liver disease.
      non-alcoholic fatty liver and cholestatic disorders.
      • European Association for the Study of the
      L. EASL Clinical Practice Guidelines: management of cholestatic liver diseases.
      Although there are no specific recommendations in patients with chronic liver disease except for those with chronic cholestasis, it seems reasonable to supplement all chronic liver disease patients with vitamin D levels below 20 ng/ml with oral vitamin D until reaching a serum vitamin D level above 30 ng/ml. Higher doses may be necessary in patients with non-alcoholic fatty liver disease.
      • Dasarathy J.
      • Varghese R.
      • Feldman A.
      • Khiyami A.
      • McCullough A.J.
      • Dasarathy S.
      Patients with nonalcoholic fatty liver disease have a low response rate to vitamin D supplementation.
      Vitamin K deficiency should always be considered in patients who are jaundiced or whose liver disease is cholestatic in origin, and parenteral supplementation might be needed.
      Patients with both alcohol and non-alcohol related cirrhosis are prone to deficiencies in water-soluble vitamins, particularly thiamine (B1). They often exhibit evidence at autopsy of Wernicke’s encephalopathy, even in the absence of a history/clinical signs during life.
      • Kril J.J.
      • Butterworth R.F.
      Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease.
      If Wernicke’s encephalopathy is suspected, generous parenteral thiamine supplementation is mandatory. Deficiencies in pyridoxine (B6), folate (B9) and cobalamin (B12) may also develop rapidly in chronic liver disease resulting from diminished hepatic storage.
      • Bemeur C.
      • Butterworth R.F.
      Nutrition in the management of cirrhosis and its neurological complications.
      However, good quality data on their prevalence and/or need for supplementation are scarce. As vitamin status is not easily assessed and multivitamin supplementation is cheap and substantially side effect free, a course of oral multivitamin supplementation could be justified in decompensated patients.
      Hyponatraemia is common in patients with cirrhosis and is more likely to occur when the intake of sodium is low, and that of water unchanged or increased.
      • Cosgray R.E.
      • Hanna V.
      • Davidhizar R.E.
      • Smith J.
      The water-intoxicated patient.
      Thus, careful monitoring of both sodium and water intake is required. If severe hyponatraemia is corrected, this needs to be done slowly, to avoid the risk of central pontine myelinolysis.
      • Kleinschmidt-DeMasters B.K.
      • Norenberg M.D.
      Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis.
      A reduction in dietary sodium intake is recommended in patients with ascites,
      European Association for the Study of the L
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      although evidence in this respect is limited and conflicting.
      • Gu X.B.
      • Yang X.J.
      • Zhu H.Y.
      • Xu B.Y.
      Effect of a diet with unrestricted sodium on ascites in patients with hepatic cirrhosis.
      Sodium intake should certainly not be reduced below 60 mmol/d, as this makes the diet unpalatable, potentially compromising energy and protein intake.
      • Morando F.
      • Rosi S.
      • Gola E.
      • Nardi M.
      • Piano S.
      • Fasolato S.
      • et al.
      Adherence to a moderate sodium restriction diet in outpatients with cirrhosis and ascites: a real-life cross-sectional study.
      Reductions in circulating levels of calcium, magnesium, and iron need to be considered and corrected.
      • Huskisson E.
      • Maggini S.
      • Ruf M.
      The influence of micronutrients on cognitive function and performance.
      Tissue zinc concentrations are reduced in patients with cirrhosis and zinc has been implicated in the pathogenesis of HE. However, data on the effects of zinc supplementation on mental performance have been conflicting.
      • Bresci G.
      • Parisi G.
      • Banti S.
      Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment.
      • Takuma Y.
      • Nouso K.
      • Makino Y.
      • Hayashi M.
      • Takahashi H.
      Clinical trial: oral zinc in hepatic encephalopathy.
      • Katayama K.
      • Saito M.
      • Kawaguchi T.
      • Endo R.
      • Sawara K.
      • Nishiguchi S.
      • et al.
      Effect of zinc on liver cirrhosis with hyperammonemia: a preliminary randomized, placebo-controlled double-blind trial.
      Selenium deficiency has been related to the severity of hepatic fibrosis in patients with hepatitis C and identified as one of the factors contributing to insulin resistance in these patients.
      • Himoto T.
      • Yoneyama H.
      • Kurokohchi K.
      • Inukai M.
      • Masugata H.
      • Goda F.
      • et al.
      Selenium deficiency is associated with insulin resistance in patients with hepatitis C virus-related chronic liver disease.
      Patients with cirrhosis have elevated total body manganese levels, which may result in selective manganese accumulation in the basal ganglia.
      • Inoue E.
      • Hori S.
      • Narumi Y.
      • Fujita M.
      • Kuriyama K.
      • Kadota T.
      • et al.
      Portal-systemic encephalopathy: presence of basal ganglia lesions with high signal intensity on MR images.
      While there is no clear relationship between such a phenomenon and HE, it is probably reasonable to avoid nutritional supplements containing manganese.
      Specific evidence about the beneficial effect of micronutrients and vitamin supplementation in cirrhotic patients is not available. However, confirmed or clinically suspected deficiency should be treated based on accepted general recommendations and common practice.
      • In cirrhotic patients, administer micronutrients and vitamins to treat confirmed or clinically suspected deficiency. (Grade II-1, C1)
      • Assess vitamin D levels in cirrhotic patients, as deficiency is highly prevalent and may adversely affect clinical outcomes. (Grade II-3, B1)
      • Supplement vitamin D orally in cirrhotic patients with vitamin D levels <20 ng/ml, to reach serum vitamin D (25(OH)D) >30 ng/ml. (Grade II-1, B1)
      • In cirrhotic patients with ascites under sodium restriction (recommended intake of sodium ∼80 mmol day = 2 g of sodium corresponding to 5 g of salt added daily to the diet according to EASL guidelines) take care to improve diet palatability as this regime may cause a reduction in caloric intake. (Grade II-2, B1)

      Nutritional treatment options for hepatic encephalopathy

      The relationship between malnutrition and HE has been known since the seminal observation that decreased energy intake determines weight loss and coma in Eck’s fistula dogs.
      • Thompson J.
      • Schafer D.
      • Haun J.
      • Schafer G.
      Adequate diet prevents hepatic coma in dogs with Eck fistulas.
      Human studies also support this association. HE occurs more frequently in malnourished patients with cirrhosis, and there is an inverse relationship between muscle mass and blood ammonia levels.
      • Kalaitzakis E.
      • Olsson R.
      • Henfridsson P.
      • Hugosson I.
      • Bengtsson M.
      • Jalan R.
      • et al.
      Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis.
      • Merli M.
      • Giusto M.
      • Lucidi C.
      • Giannelli V.
      • Pentassuglio I.
      • Di Gregorio V.
      • et al.
      Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study.
      Sarcopenia, as assessed by the skeletal muscle index, is an independent risk factor for the development of HE after transjugular intrahepatic portosystemic shunt placement.
      • Nardelli S.
      • Lattanzi B.
      • Torrisi S.
      • Greco F.
      • Farcomeni A.
      • Gioia S.
      • et al.
      Sarcopenia is risk factor for development of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt placement.
      Muscle plays an important role in ammonia removal
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • Redhead D.N.
      • Dejong C.H.
      • Hynd P.
      • et al.
      The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.
      by increasing glutamine synthesis, a reaction that is catalysed by the enzyme glutamine synthetase.
      • Chatauret N.
      • Desjardins P.
      • Zwingmann C.
      • Rose C.
      • Rao K.R.
      • Butterworth R.F.
      Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure.
      This has generally been thought of as a straightforward, benign process of ammonia disposal but evidence is accumulating that hyperammonaemia may impair muscle function and contribute to muscle loss,
      • McDaniel J.
      • Davuluri G.
      • Hill E.A.
      • Moyer M.
      • Runkana A.
      • Prayson R.
      • et al.
      Hyperammonemia results in reduced muscle function independent of muscle mass.
      thus establishing a vicious circle. There is also evidence that lowering ammonia levels can reverse sarcopenia in animal models.
      • Kumar A.
      • Davuluri G.
      • Engelen M.P.
      • Ten Have G.A.
      • Prayson R.
      • Deutz N.E.
      • et al.
      Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis.
      Recently a randomised clinical trial showed that nutritional intervention (30–35 kcal/kg.BW/d, 1.0–1.5 g vegetable protein/kg.BW/d for six months) was able to improve neuropsychiatric performance in patients with minimal HE, and decrease their risk of developing overt HE compared to no nutritional intervention.
      • Maharshi S.
      • Sharma B.C.
      • Sachdeva S.
      • Srivastava S.
      • Sharma P.
      Efficacy of nutritional therapy for patients with cirrhosis and minimal hepatic encephalopathy in a randomized trial.
      Energy requirements in patients with cirrhosis and HE are thought to be the same as those of patients with cirrhosis per se.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      Patients with HE need to avoid long periods of fasting, and should be encouraged to split their caloric and protein intake into small, frequent meals. It is advisable that breakfast
      • Vaisman N.
      • Katzman H.
      • Carmiel-Haggai M.
      • Lusthaus M.
      • Niv E.
      Breakfast improves cognitive function in cirrhotic patients with cognitive impairment.
      and a late evening snack
      • Plank L.D.
      • Gane E.J.
      • Peng S.
      • Muthu C.
      • Mathur S.
      • Gillanders L.
      • et al.
      Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial.
      also include some proteins (see also paragraph: Energy and protein requirements in patients with liver cirrhosis).
      Dysregulated nitrogen metabolism plays a major role in the development of HE and its modulation is key to HE management. Up until the middle of the 20th century, meat protein was administered to patients with cirrhosis to avoid catabolism.
      • Schwartz R.
      • Phillips G.B.
      • Seegmiller J.E.
      • Gabuzda Jr., G.J.
      • Davidson C.S.
      Dietary protein in the genesis of hepatic coma.
      Then, a few uncontrolled studies showed that decreased protein intake was associated with better mental status in patients with HE and porto-systemic shunts,
      • Summerskill W.
      • Wolfe S.J.
      • Davidson C.S.
      The management of hepatic coma in relation to protein withdrawal and certain specific measures.
      leading to a widespread practice of chronic protein restriction.
      • Soulsby C.T.
      • Morgan M.Y.
      Dietary management of hepatic encephalopathy in cirrhotic patients: survey of current practice in United Kingdom.
      Protein restriction is now considered detrimental, except perhaps, for very short periods of time, in patients with severe overt HE and gastrointestinal bleeding. There is sufficient evidence that, in general, patients with HE tolerate diets with a normal protein content,
      • Cordoba J.
      • Lopez-Hellin J.
      • Planas M.
      • Sabin P.
      • Sanpedro F.
      • Castro F.
      • et al.
      Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.
      and their nitrogen requirements are the same as those of patients with cirrhosis per se.
      • Campollo O.
      • Sprengers D.
      • Dam G.
      • Vilstrup H.
      • McIntyre N.
      Protein tolerance to standard and high protein meals in patients with liver cirrhosis.
      The type of protein ingested may be important. The original demonstration that Eck’s fistula dogs fed with fish/milk protein rather than meat developed fewer/no behavioural abnormalities
      • Condon R.E.
      Effect of dietary protein on symptoms and survival in dogs with an Eck fistula.
      led to the idea that patients with HE may benefit from the replacement of meat with dairy/vegetable protein. Subsequent uncontrolled, human studies showed that dairy protein is better tolerated than protein from mixed sources and that vegetable protein is better tolerated than meat protein.
      • Fenton J.C.
      • Knight E.J.
      • Humpherson P.L.
      Milk-and-cheese diet in portal-systemic encephalopathy.
      • Bessman A.N.
      • Mirick G.S.
      Blood ammonia levels following the ingestion of casein and whole blood.
      • Greenberger N.J.
      • Carley J.
      • Schenker S.
      • Bettinger I.
      • Stamnes C.
      • Beyer P.
      Effect of vegetable and animal protein diets in chronic hepatic encephalopathy.
      While there is a good pathophysiological basis for the use of dairy/vegetable diets in patients with HE, the results of the clinical studies undertaken remain unconvincing.
      • Amodio P.
      • Caregaro L.
      • Patteno E.
      • Marcon M.
      • Del Piccolo F.
      • Gatta A.
      Vegetarian diets in hepatic encephalopathy: facts or fantasies?.
      In addition, concerns have been raised in relation to tolerability/palatability, and thus potential negative effects on overall caloric intake.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      This is likely to depend on the features of the staple diet. Interestingly, a 14-day casein-vegetable, high-protein, high-calorie diet was shown to improve mental performance and to decrease ammonia levels in 150 patients with overt HE.
      • Gheorghe L.
      • Iacob R.
      • Vadan R.
      • Iacob S.
      • Gheorghe C.
      Improvement of hepatic encephalopathy using a modified high-calorie high-protein diet.
      One of the advantages of vegetable diets may be due to their fibre content rather than protein content, as fibre has both prebiotic and laxative properties. While increased dietary fibre may be of value in patients with HE, the available literature is limited,
      • Uribe M.
      • Dibildox M.
      • Malpica S.
      • Guillermo E.
      • Villallobos A.
      • Nieto L.
      • et al.
      Beneficial effect of vegetable protein diet supplemented with psyllium plantago in patients with hepatic encephalopathy and diabetes mellitus.
      and increasing fibre consumption is difficult even in the healthy population. Notably, support from a multidisciplinary nutrition team has been shown to be useful in patients with cirrhosis
      • Iwasa M.
      • Iwata K.
      • Hara N.
      • Hattori A.
      • Ishidome M.
      • Sekoguchi-Fujikawa N.
      • et al.
      Nutrition therapy using a multidisciplinary team improves survival rates in patients with liver cirrhosis.
      and should be considered in patients with HE.
      A decreased serum ratio of BCAA to aromatic amino acids has been associated with a poor prognosis,
      • Kawaguchi T.
      • Izumi N.
      • Charlton M.R.
      • Sata M.
      Branched-chain amino acids as pharmacological nutrients in chronic liver disease.
      but there is limited evidence that the original assumptions behind BCAA supplementation in HE are correct. However, BCAA supplements, in daily divided doses, may facilitate the provision of an adequate nitrogen intake in patients who are intolerant to meat protein.
      • Holecek M.
      Three targets of branched-chain amino acid supplementation in the treatment of liver disease.
      • Dam G.
      • Ott P.
      • Aagaard N.K.
      • Vilstrup H.
      Branched-chain amino acids and muscle ammonia detoxification in cirrhosis.
      The replacement of meat with dairy/vegetable protein plus BCAA supplements is likely to be preferable to a reduction in total protein intake. Long-term, oral BCAA supplementation may also have nutritional value.
      • Nakaya Y.
      • Harada N.
      • Kakui S.
      • Okada K.
      • Takahashi A.
      • Inoi J.
      • et al.
      Severe catabolic state after prolonged fasting in cirrhotic patients: effect of oral branched-chain amino-acid-enriched nutrient mixture.
      • Marchesini G.
      • Bianchi G.
      • Merli M.
      • Amodio P.
      • Panella C.
      • Loguercio C.
      • et al.
      Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial.
      Palatability has proven to be a significant issue. In addition, costs and the possibility to prescribe BCAA as a drug (vs. a food supplement) vary considerably between countries.
      It has also been shown that L-leucine alone can reverse the decrease in disturbed muscle protein homeostasis (proteostasis) due to hyperammonaemia.
      • Davuluri G.
      • Krokowski D.
      • Guan B.J.
      • Kumar A.
      • Thapaliya S.
      • Singh D.
      • et al.
      Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis.
      A Cochrane meta-analysis included 16 randomised clinical trials, comparing oral or intravenous BCAA supplementation vs. a control intervention in 827 patients with HE.
      • Gluud L.L.
      • Dam G.
      • Les I.
      • Cordoba J.
      • Marchesini G.
      • Borre M.
      • et al.
      Branched-chain amino acids for people with hepatic encephalopathy.
      Oral BCAA had a positive impact on HE. However, oral or intravenous BCAA did not influence mortality, quality of life or nutritional status. No firm conclusions could be reached on their nutritional effects and on how they compare with non-absorbable disaccharides/antibiotics.
      • Gluud L.L.
      • Dam G.
      • Les I.
      • Marchesini G.
      • Borre M.
      • Aagaard N.K.
      • et al.
      Branched-chain amino acids for people with hepatic encephalopathy.
      Their use intravenously for episodic overt HE is not supported by the available evidence.
      In patients with HE grade III-IV, as oral dietary intake is unfeasible or impossible, in keeping with common practice in patients with neurologic coma, nutrition should be provided by nasogastric tube or parenterally.
      • Nutritional status and the presence of sarcopenia should be evaluated in patients with HE. (Grade II-3, B1)
      • Avoid protein restriction in patients with HE. (Grade II-1, A1)
      • Optimal daily protein and energy intake should not be lower than the general recommendations for cirrhotic patients (recommendations 14 and 15). (Grade II-1, A1)
      • Encourage the consumption of vegetables and dairy protein. (Grade II-3, B1)
      • BCAA supplementation should be considered to improve neuropsychiatric performance and to reach the recommended nitrogen intake. (Grade I-1, A1)
      • Oral dietary intake is preferred in patients who can tolerate it. In patients with grade III-IV encephalopathy, who are unable to eat, provide nutrition by nasogastric tube (in patients with protected airways) or parenterally. (Grade II-1, B1)

      Nutritional treatment options in cirrhotic patients with bone diseases

      ‘Hepatic osteodystrophy’, including osteoporosis and osteomalacia, has been used for years to describe the bone disease of patients with liver damage. Osteoporosis, characterised by loss of bone mass and quality that leads to fragility fractures, is common in patients with chronic liver disease.
      • Guanabens N.
      • Pares A.
      Liver and bone.
      Osteomalacia resulting from poor bone mineralisation is uncommon and only present when associated with persistent vitamin D deficiency in individuals with severe and long-lasting cholestasis and intestinal malabsorption.
      • Compston J.E.
      Hepatic osteodystrophy: vitamin D metabolism in patients with liver disease.
      Nutritional, hormonal, metabolic, genetic, and inflammatory factors play a significant role in the pathogenesis of osteoporosis in patients with chronic liver disease, mainly because of decreased bone formation.
      The diagnosis of osteoporosis is based on bone mineral density (BMD) that is generally measured by DEXA. According to World Health Organization, osteoporosis is considered when BMD is 2.5 standard deviations below the young average value (T-score ≤2.5) and osteopenia when the T-score is between −1 and −2.5, and severe or ‘established’ osteoporosis refers to individuals who meet densitometric criteria and have one or more fragility fractures.
      Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group.
      Prevalence of osteoporosis in patients with chronic liver disease depends mostly on patient selection and diagnostic criteria. In summary, about 30% of patients have osteoporosis, with higher prevalence in patients with cholestasis including primary biliary cholangitis (PBC) and primary sclerosing cholangitis.
      • Menon K.V.
      • Angulo P.
      • Weston S.
      • Dickson E.R.
      • Lindor K.D.
      Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.
      • Pares A.
      • Guanabens N.
      • Alvarez L.
      • De Osaba M.J.
      • Oriola J.
      • Pons F.
      • et al.
      Collagen type Ialpha1 and vitamin D receptor gene polymorphisms and bone mass in primary biliary cirrhosis.
      • Guanabens N.
      • Pares A.
      • Ros I.
      • Caballeria L.
      • Pons F.
      • Vidal S.
      • et al.
      Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis.
      • Guichelaar M.M.
      • Kendall R.
      • Malinchoc M.
      • Hay J.E.
      Bone mineral density before and after OLT: long-term follow-up and predictive factors.
      • Guanabens N.
      • Cerda D.
      • Monegal A.
      • Pons F.
      • Caballeria L.
      • Peris P.
      • et al.
      Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis.
      • Angulo P.
      • Grandison G.A.
      • Fong D.G.
      • Keach J.C.
      • Lindor K.D.
      • Bjornsson E.
      • et al.
      Bone disease in patients with primary sclerosing cholangitis.
      • Diamond T.
      • Stiel D.
      • Lunzer M.
      • Wilkinson M.
      • Roche J.
      • Posen S.
      Osteoporosis and skeletal fractures in chronic liver disease.
      • Chen C.C.
      • Wang S.S.
      • Jeng F.S.
      • Lee S.D.
      Metabolic bone disease of liver cirrhosis: is it parallel to the clinical severity of cirrhosis?.
      • Monegal A.
      • Navasa M.
      • Guanabens N.
      • Peris P.
      • Pons F.
      • Martinez de Osaba M.J.
      • et al.
      Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation.
      • Ninkovic M.
      • Skingle S.J.
      • Bearcroft P.W.
      • Bishop N.
      • Alexander G.J.
      • Compston J.E.
      Incidence of vertebral fractures in the first three months after orthotopic liver transplantation.
      • Carey E.J.
      • Balan V.
      • Kremers W.K.
      • Hay J.E.
      Osteopenia and osteoporosis in patients with end-stage liver disease caused by hepatitis C and alcoholic liver disease: not just a cholestatic problem.
      • Gonzalez-Calvin J.L.
      • Mundi J.L.
      • Casado-Caballero F.J.
      • Abadia A.C.
      • Martin-Ibanez J.J.
      Bone mineral density and serum levels of soluble tumor necrosis factors, estradiol, and osteoprotegerin in postmenopausal women with cirrhosis after viral hepatitis.
      • Monegal A.
      • Navasa M.
      • Peris P.
      • Colmenero J.
      • Cuervo A.
      • Muxi A.
      • et al.
      Bone disease in patients awaiting liver transplantation. Has the situation improved in the last two decades?.
      In patients eligible for liver transplantation the prevalence of osteoporosis is 30%.
      • Monegal A.
      • Navasa M.
      • Peris P.
      • Colmenero J.
      • Cuervo A.
      • Muxi A.
      • et al.
      Bone disease in patients awaiting liver transplantation. Has the situation improved in the last two decades?.
      • Sinigaglia L.
      • Fargion S.
      • Fracanzani A.L.
      • Binelli L.
      • Battafarano N.
      • Varenna M.
      • et al.
      Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload.
      • Guggenbuhl P.
      • Deugnier Y.
      • Boisdet J.F.
      • Rolland Y.
      • Perdriger A.
      • Pawlotsky Y.
      • et al.
      Bone mineral density in men with genetic hemochromatosis and HFE gene mutation.
      • Valenti L.
      • Varenna M.
      • Fracanzani A.L.
      • Rossi V.
      • Fargion S.
      • Sinigaglia L.
      Association between iron overload and osteoporosis in patients with hereditary hemochromatosis.
      Fracture prevalence ranges between 7% and 35%,
      • Menon K.V.
      • Angulo P.
      • Weston S.
      • Dickson E.R.
      • Lindor K.D.
      Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.
      • Pares A.
      • Guanabens N.
      • Alvarez L.
      • De Osaba M.J.
      • Oriola J.
      • Pons F.
      • et al.
      Collagen type Ialpha1 and vitamin D receptor gene polymorphisms and bone mass in primary biliary cirrhosis.
      • Guanabens N.
      • Pares A.
      • Ros I.
      • Caballeria L.
      • Pons F.
      • Vidal S.
      • et al.
      Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis.
      • Guichelaar M.M.
      • Kendall R.
      • Malinchoc M.
      • Hay J.E.
      Bone mineral density before and after OLT: long-term follow-up and predictive factors.
      • Guanabens N.
      • Cerda D.
      • Monegal A.
      • Pons F.
      • Caballeria L.
      • Peris P.
      • et al.
      Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis.
      • Angulo P.
      • Grandison G.A.
      • Fong D.G.
      • Keach J.C.
      • Lindor K.D.
      • Bjornsson E.
      • et al.
      Bone disease in patients with primary sclerosing cholangitis.
      • Diamond T.
      • Stiel D.
      • Lunzer M.
      • Wilkinson M.
      • Roche J.
      • Posen S.
      Osteoporosis and skeletal fractures in chronic liver disease.
      • Chen C.C.
      • Wang S.S.
      • Jeng F.S.
      • Lee S.D.
      Metabolic bone disease of liver cirrhosis: is it parallel to the clinical severity of cirrhosis?.
      • Monegal A.
      • Navasa M.
      • Guanabens N.
      • Peris P.
      • Pons F.
      • Martinez de Osaba M.J.
      • et al.
      Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation.
      • Ninkovic M.
      • Skingle S.J.
      • Bearcroft P.W.
      • Bishop N.
      • Alexander G.J.
      • Compston J.E.
      Incidence of vertebral fractures in the first three months after orthotopic liver transplantation.
      • Carey E.J.
      • Balan V.
      • Kremers W.K.
      • Hay J.E.
      Osteopenia and osteoporosis in patients with end-stage liver disease caused by hepatitis C and alcoholic liver disease: not just a cholestatic problem.
      • Gonzalez-Calvin J.L.
      • Mundi J.L.
      • Casado-Caballero F.J.
      • Abadia A.C.
      • Martin-Ibanez J.J.
      Bone mineral density and serum levels of soluble tumor necrosis factors, estradiol, and osteoprotegerin in postmenopausal women with cirrhosis after viral hepatitis.
      • Monegal A.
      • Navasa M.
      • Peris P.
      • Colmenero J.
      • Cuervo A.
      • Muxi A.
      • et al.
      Bone disease in patients awaiting liver transplantation. Has the situation improved in the last two decades?.
      • Guanabens N.
      • Pares A.
      • Navasa M.
      • Martinez de Osaba M.J.
      • Hernandez M.E.
      • Munoz J.
      • et al.
      Cyclosporin A increases the biochemical markers of bone remodeling in primary biliary cirrhosis.
      • Springer J.E.
      • Cole D.E.
      • Rubin L.A.
      • Cauch-Dudek K.
      • Harewood L.
      • Evrovski J.
      • et al.
      Vitamin D-receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis.
      • Newton J.
      • Francis R.
      • Prince M.
      • James O.
      • Bassendine M.
      • Rawlings D.
      • et al.
      Osteoporosis in primary biliary cirrhosis revisited.
      • Solerio E.
      • Isaia G.
      • Innarella R.
      • Di Stefano M.
      • Farina M.
      • Borghesio E.
      • et al.
      Osteoporosis: still a typical complication of primary biliary cirrhosis?.
      • Bonkovsky H.L.
      • Hawkins M.
      • Steinberg K.
      • Hersh T.
      • Galambos J.T.
      • Henderson J.M.
      • et al.
      Prevalence and prediction of osteopenia in chronic liver disease.
      • Ninkovic M.
      • Love S.A.
      • Tom B.
      • Alexander G.J.
      • Compston J.E.
      High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation.
      • Sokhi R.P.
      • Anantharaju A.
      • Kondaveeti R.
      • Creech S.D.
      • Islam K.K.
      • Van Thiel D.H.
      Bone mineral density among cirrhotic patients awaiting liver transplantation.
      being more frequent in postmenopausal women than in young women and men,
      • Diamond T.
      • Stiel D.
      • Lunzer M.
      • Wilkinson M.
      • Roche J.
      • Posen S.
      Osteoporosis and skeletal fractures in chronic liver disease.
      and in patients receiving corticosteroid therapy.
      • Olsson R.
      • Johansson C.
      • Lindstedt G.
      • Mellstrom D.
      Risk factors for bone loss in chronic active hepatitis and primary biliary cirrhosis.
      Vertebral fractures are associated with osteoporosis and osteopenia with a T-score lower than −1.5 in patients with PBC and primary sclerosing cholangitis.
      • Guanabens N.
      • Cerda D.
      • Monegal A.
      • Pons F.
      • Caballeria L.
      • Peris P.
      • et al.
      Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis.
      . Patients with a T-score below −1.5 have a high risk of hip and vertebral fractures, supporting this T-score as a practical guide for starting specific therapy.
      Osteoporosis is frequently observed in transplanted patients,
      • Monegal A.
      • Navasa M.
      • Guanabens N.
      • Peris P.
      • Pons F.
      • Martinez de Osaba M.J.
      • et al.
      Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics.
      and associated with a high incidence of fractures (25 to 35%) within the first year after liver transplantation.
      • Leidig-Bruckner G.
      • Hosch S.
      • Dodidou P.
      • Ritschel D.
      • Conradt C.
      • Klose C.
      • et al.
      Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study.
      • Navasa M.
      • Monegal A.
      • Guanabens N.
      • Peris P.
      • Rimola A.
      • Munoz-Gomez J.
      • et al.
      Bone fractures in liver transplant patients.
      Improvements in the management of bone health in transplanted patients have reduced the incidence of fractures.
      • Compston J.E.
      Osteoporosis after liver transplantation.
      According to the WHO, bone densitometry of the lumbar spine and hip is the gold standard procedure for the diagnosis of osteoporosis and osteopenia. Lateral X-rays of dorsal and lumbar spine should also be performed to disclose vertebral fractures.
      • Pares A.
      • Guanabens N.
      Treatment of bone disorders in liver disease.
      Laboratory measurements to identify abnormal calcium and vitamin D metabolism are also appropriate. The biochemical markers of bone turnover can be determined, but they are most helpful for monitoring the response to therapy. Undecalcified transiliac bone biopsy is recommended only in the exceptional cases with presumed osteomalacia.
      The diagnosis and management of bone disease in patients with chronic liver disease is summarised in (Fig. 3). Bone densitometry should be evaluated in patients with previous fragility fractures and those treated with corticosteroids and before liver transplantation.
      • Guanabens N.
      • Cerda D.
      • Monegal A.
      • Pons F.
      • Caballeria L.
      • Peris P.
      • et al.
      Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis.
      • Pares A.
      • Guanabens N.
      Treatment of bone disorders in liver disease.
      Bone densitometry needs to be assessed in patients with cholestatic diseases or if any of the described risk factors are found, and in cirrhotics. In patients within normal BMD, it is advisable to repeat DEXA after two to three years, as is suggested in the non-cirrhotic population. In conditions associated with rapid bone loss, such as in cholestatic patients with more than one risk factor for osteoporosis, and in those in whom high-dose corticosteroid therapy has recently been initiated, DEXA can be repeated in a shorter interval of approximately one year. This schedule is also recommended for patients with advanced cirrhosis, particularly in those eligible for transplantation. Inaccuracies in BMD and bone marker measurements in patients with cirrhosis or chronic cholestasis need to be taken into consideration.
      • Guanabens N.
      • Pares A.
      • Alvarez L.
      • Martinez de Osaba M.J.
      • Monegal A.
      • Peris P.
      • et al.
      Collagen-related markers of bone turnover reflect the severity of liver fibrosis in patients with primary biliary cirrhosis.
      • Guanabens N.
      • Monegal A.
      • Muxi A.
      • Martinez-Ferrer A.
      • Reyes R.
      • Caballeria J.
      • et al.
      Patients with cirrhosis and ascites have false values of bone density: implications for the diagnosis of osteoporosis.
      Recognition of the risk factors for bone loss including those for osteoporosis and fractures in patients with chronic liver disease is recommended, as in general population and in postmenopausal women (Table 2).
      • Pares A.
      • Guanabens N.
      Treatment of bone disorders in liver disease.
      Figure thumbnail gr3
      Fig. 3Diagnosis and management of bone disease in patients with chronic liver disease. *Calcium (1,000–1,500 mg/d) and 25(OH)D (400–800 IU/d or 260 µg every two weeks) to preserve normal levels. **According to the severity of liver disease and cholestasis, and in patients taking corticosteroids. ***Depending on additional risk factors. 25(OH)D, 25-hydroxyvitamin D. DEXA; dual-energy X-ray absorptiometry.
      Table 2Risk factors for the development of osteoporosis in chronic liver disease.
      Alcohol abuse
      Smoking
      Body mass index lower than 19 kg/m2
      Male hypogonadism
      Early menopause
      Secondary amenorrhea of more than 6 months
      Family history of osteoporotic fracture
      Treatment with corticosteroids (5 mg/d or more of prednisone for 3 months or longer)
      Advanced age
      A balanced diet is recommended because patients with chronic liver disease are often malnourished. Supplements of calcium (1,000–1,500 mg/d) and 25(OH)D (400–800 IU/d or 260 µg every two weeks) or the dose required to preserve normal levels should be provided. However, there is no definite data confirming the efficacy of these supplements in preventing bone loss in patients with liver disease.
      • Dasarathy J.
      • Varghese R.
      • Feldman A.
      • Khiyami A.
      • McCullough A.J.
      • Dasarathy S.
      Patients with nonalcoholic fatty liver disease have a low response rate to vitamin D supplementation.
      Physical activity is recommended, in particular with exercises designed to improve the mechanics of the spine. Factors that contribute to bone loss need to be reduced to a minimum, including alcohol and tobacco use. Corticosteroids ought to be minimised whenever possible.
      Different pharmacological therapies have been proposed for improving bone mass in patients with chronic liver disease, but most studies have included small numbers of patients, and therefore it is difficult to reach any definite conclusions. Furthermore, no clear anti-fracture effect has been demonstrated, and except for osteoporosis in PBC and after liver transplantation, no systematic studies have been reported.
      There is no general agreement concerning the appropriate time to start treatment, but patients with established osteoporosis, and therefore with fragility fractures, should be treated to reduce the risk of further fractures. Since patients with PBC with a lumbar or a proximal femur T-score lower than <−1.5 have a high risk of vertebral fracture, it seems reasonable to consider specific therapy in these patients,
      • Guanabens N.
      • Cerda D.
      • Monegal A.
      • Pons F.
      • Caballeria L.
      • Peris P.
      • et al.
      Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis.
      and in all patients with osteoporosis before transplantation.
      Bisphosphonates are anti-catabolic drugs which increase bone mass and reduce the incidence of fractures in postmenopausal osteoporosis. Their effects in chronic liver disease are not entirely defined, mostly because of the very limited number of studies and small numbers of patients.
      • Guanabens N.
      • Pares A.
      • Monegal A.
      • Peris P.
      • Pons F.
      • Alvarez L.
      • et al.
      Etidronate versus fluoride for treatment of osteopenia in primary biliary cirrhosis: preliminary results after 2 years.
      • Guanabens N.
      • Pares A.
      • Ros I.
      • Alvarez L.
      • Pons F.
      • Caballeria L.
      • et al.
      Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis.
      • Lindor K.D.
      • Jorgensen R.A.
      • Tiegs R.D.
      • Khosla S.
      • Dickson E.R.
      Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial.
      • Wolfhagen F.H.
      • van Buuren H.R.
      • den Ouden J.W.
      • Hop W.C.
      • van Leeuwen J.P.
      • Schalm S.W.
      • et al.
      Cyclical etidronate in the prevention of bone loss in corticosteroid-treated primary biliary cirrhosis. A prospective, controlled pilot study.