EASL Clinical Practice Guidelines on nutrition in chronic liver disease

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(1). 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(2)(1).

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 (3), are associated with a higher rate of complications (4) such as susceptibility to infections (5), hepatic encephalopathy (HE) (6) and ascites (4), as well as being independent predictors of lower survival in cirrhosis (7, 8) and in patients undergoing liver transplantation (9). Given these observations, malnutrition and sarcopenia should be recognised as a complication of cirrhosis, which in turn worsens 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, avoiding those limitations and restrictions that are not evidence based, amelioration of the nutritional status and muscle mass is not always achievable (10–12).

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 (13–15)(3).

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.

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 reference from papers identified. 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 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 (16). 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 C. The recommendations were peer-reviewed by external expert reviewers and approved by the EASL Governing Board.

Evidence quality according to the GRADE scoring system.

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).

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 (17–19), in order to actively manage this complication.

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 metre]2) Open in a separate windowFigure 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 edema is present.

Since malnutrition and sarcopenia are independent predictors of adverse clinical outcomes including survival (57),(58, 59), (17) (60) any nutritional approach in cirrhotic patients needs to follow some general principles of nutritional management.

Cirrhosis is a state of accelerated starvation demonstrated by a rapid post absorptive physiology which is characterised by a reduction in the respiratory quotient(61, 62). 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 (63–66). 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. (63, 67–70). Some studies evaluated whether decompensated liver cirrhosis affected REE. One small longitudinal study suggested that ascites increases REE (71). However, a cross-sectional study found no difference in REE between patients with varying levels of liver disease severity and fluid retention (72–74). Measured REE may be higher than predicted, a situation termed hypermetabolism. However, hypermetabolism cannot be identified by clinical or laboratory parameters (75), the severity and the aetiology of liver cirrhosis and the presence of ascites (25). 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 (61, 62). The availability of the hand held calorimeter at the bedside is a possible alternative to determine a patient’s daily caloric needs (76).

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(77).

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(78). The adoption of a breakfast containing some proteins (79) and a late evening snack (80) 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 (81). This cut-off was confirmed in studies wherein cirrhotic patients received diets with increasing protein content (70, 82). These studies also showed that cirrhotic patients are able to utilise up to 1.8 g/kg.BW/d of protein (70). 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 (83),(84) and may even improve mental status (85), (86) (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 (27, 63). 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 (Table 2).

Short, practical dietary advice for bedside or outpatient clinic use.

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(66, 87, 88). In the past, whole body protein turnover studies have yielded conflicting results with unaltered, increased or decreased protein synthesis and breakdown in cirrhosis (3, 89). Skeletal muscle mass depends on a number of factors including age, gender and ethnicity in physiological states. 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 (66, 90). 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(89, 91–93). 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(3, 94–97). To better understand 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 (88). Data in animal models, humans and cellular systems have consistently shown that myostatin expression is increased in cirrhosis (95, 98, 99). In addition to impaired protein synthesis, proteolysis is also required for loss of muscle mass (63, 66). The ubiquitin proteasome pathway and autophagy are currently believed to be the dominant mechanisms of skeletal muscle proteolysis (63, 100). Human skeletal muscle from patients with cirrhosis and preclinical models of hyperammonaemia show increased autophagy with impaired or unaltered proteasome-mediated proteolysis (95, 100, 101). A more extensive view of molecular mechanisms of muscle wasting in patients with liver cirrhosis is reviewed in reference 19 (18).

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 (3, 102–104), hormone replacement therapies, (105) ammonia-lowering strategies and targeting the underlying liver disease. (106–109)

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(110, 111) 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 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(11, 12, 112). 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 (113). 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 (114).

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 (87, 115). Endurance or aerobic exercise improves skeletal muscle functional capacity but not necessarily muscle mass (116). Resistance exercise promotes an increase in skeletal muscle mass(116). However, exercise also increases muscle ammonia generation and portal pressure (117, 118), both of which can have adverse effects in cirrhotic patients. Despite these potential adverse responses, beneficial effects have been reported (103, 104). 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 (104).

Nutrient supplementation following physical activity is beneficial in physiological states, but whether such an intervention is beneficial in cirrhosis is currently unknown (119, 120). Continued impaired functional capacity and reduced peak oxygen consumption are associated with decreased survival and poor post-transplant outcomes(121, 122). Hence measures to increase functional capacity are likely to improve long-term clinical outcomes in cirrhosis(102).

Hormone replacement therapy utilising growth hormone or testosterone has been proposed but has not been consistently effective(91, 92, 123, 124). Furthermore caution is needed when using testosterone because of the possibility of increasing the risk of hepatocellular carcinoma(105).

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(99, 100).

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 (109).

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% (13, 125), 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 (125) 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 (13).

Data from different studies suggest that a reduction in BW improves outcomes in obese patients with compensated cirrhosis (102, 125, 126). 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 (125). 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 (126). Exercise needs to be tailored to the patient’s ability, beginning with moderate intensity and maintained for the long-term.

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 (127).

The prevalence of vitamin D deficiency in the general population ranges from 20 to 100% when referring to serum 25(OH)D concentrations Open in a separate windowFigure 3Diagnosis and management of bone disease in patients with chronic liver disease.Table 3.

Risk factors for the development of osteoporosis in chronic liver disease.

A balanced diet is recommended because chronic liver disease patients often are malnourished. Supplements of calcium (1,000–1,500 mg/d) and 25-hydroxy-vitamin D (400–800 IU/d or 260 µg every 2 weeks) or the dose required to preserve normal levels should be provided.- There is however no definite data confirming the efficacy of these supplements in preventing bone loss in patients with liver disease (134). Physical activity is recommended, in particular with exercises designed to improve the mechanics of the spine. Factors contributing to bone loss need to be reduced to a minimum, including discontinuation of alcohol and tobacco use. Corticosteroids ought to be minimized 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 40 kg· m−2) prior to liver transplantation are associated with increased mortality and morbidity (226–229). Severe obesity prior to liver transplantation is associated with a higher prevalence of comorbidities (diabetes, hypertension), cryptogenic cirrhosis and increased mortality from infectious complications, cardiovascular disease and cancer (228, 229). Some investigators found that severe obesity was associated with increased morbidity and mortality even when patients were classified according to “dry BMI” (229) while others have reported that the amount of ascites and not BMI contributes to the increase mortality risk (230).

Numerous descriptive studies have shown higher morbidity and mortality in cirrhotic patients with protein malnutrition when such patients undergo liver transplantation (57, 231–233). Recently, sarcopenia and frailty have been shown to carry an increased risk of morbidity and mortality on the waiting list and after transplantation (58, 234–243). Patients on the wait are at risk due to an inadequate food or caloric intake (244) and those consuming a low protein diet (

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Clinical Practice Guideline Panel: Chair: Manuela Merli; Panel members: Shira Zelber-Sagi, Srinivasan Dasarathy, Sara Montagnese, Laurence Genton, Mathias Plauth, Albert Parés; EASL Governing Board representative: Annalisa Berzigotti

Supplementary Table 1. Nutritional guidelines for patients with chronic liver disease proposed by different medical societies in different settings.

European Association for the Study of the Liver :