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Diagnosis and treatment of nutritional deficiencies in alcoholic liver disease: Overview of available evidence and open issues

  • Roberta Elisa Rossi
    Correspondence
    Corresponding author at: Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milano, Italy. Tel.: +39 02 55033445; fax: +39 02 55033644.
    Affiliations
    Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Italy

    Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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  • Dario Conte
    Affiliations
    Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Italy

    Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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  • Sara Massironi
    Affiliations
    Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Italy
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Open AccessPublished:July 08, 2015DOI:https://doi.org/10.1016/j.dld.2015.05.021

      Abstract

      Malnutrition is common in alcoholic liver disease and is associated with high rates of complications and mortality. In this article, the current literature was reviewed to highlight the relevance of proper nutritional management providing levels of evidence, when available. A PubMed search was performed for English-language publications from 1980 through 2014 with the keywords: alcoholic liver disease, nutritional deficiencies, nutritional support, enteral nutrition, parenteral nutrition, and protein–energy malnutrition. Manuscripts focused on nutritional approach in patients with alcoholic liver disease were selected.
      Although nutritional support for malnourished patients improves the outcome of hospitalization, surgery, transplantation and reduces the complications of liver disease and the length of hospital stay, specific guidelines are scanty. Both enteral and parenteral nutrition appear to improve nutritional parameters and liver function; however data on survival is often conflicting. As micronutrient depletion is common in alcoholic liver disease and each deficiency produces specific sequelae, all cirrhotic patients should be screened at baseline for deficiencies of micronutrient and supplemented as needed.
      In summary, protein–energy malnutrition and micronutrient depletion are clinical concerns in alcoholic liver disease. Nutritional therapy, including enteral nutrition, parenteral nutrition and micronutrient supplementation should be part of the multidisciplinary management of these patients.

      Keywords

      1. Introduction

      Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Western countries and represents a negatively relevant co-factor in the progression of chronic liver injury of different aetiology [
      • Neff G.W.
      • Duncan C.W.
      • Schiff E.R.
      The current economic burden of cirrhosis.
      ,
      • Rehm J.
      • Mathers C.
      • Popova S.
      • et al.
      Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders.
      ].
      The term “ALD” includes a wide range of liver injury, including steatosis with or without fibrosis, alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma, and represents one of the most common indications for liver transplantation (LT) in Europe and the United States [
      • Mathurin P.
      • Hadengue A.
      • Bataller R.
      • et al.
      European Association for the Study of Liver, EASL clinical practical guidelines: management of alcoholic liver disease.
      ].
      Complete alcohol withdrawal represents the key treatment for ALD although possibly insufficient when facing with cirrhosis or severe AH [
      • Spengler E.K.
      • Dunkelberg J.
      • Schey R.
      Alcoholic hepatitis: current management.
      ]. Several medical approaches have been studied, but evidence about their effect on survival is still lacking [
      • Jaurigue M.M.
      • Cappell M.S.
      Therapy for alcoholic liver disease.
      ].
      Muscle wasting, weight loss, and nutritional deficiencies commonly occur in ALD, the underlying mechanisms including poor dietary intake (due to anorexia, altered sense of taste and smell, and nausea and vomiting), maldigestion and malabsorption (related to concomitant pancreatic insufficiency and bile acid deficiency, respectively), bacterial overgrowth due to reduced motility, loss of proteins secondary to portal hypertension, hypermetabolic state, insulin resistance, and impaired protein synthesis due to cytokine-induced inflammatory responses [
      • McClain C.J.
      • Barve S.S.
      • Barve A.
      • et al.
      Alcoholic liver disease and malnutrition.
      ,
      • Koretz R.L.
      • Avenell A.
      • Lipman T.O.
      Nutritional support for liver disease.
      ,
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ]. As malnutrition correlates with both higher rates of complications (variceal bleeding, ascites, encephalopathy, infections, and hepato-renal syndrome) and mortality, its finding in ALD may identify those patients at higher risk of hepatic decompensation and/or liver-related death [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ], as clearly demonstrated by a recent study on 363 AH patients, reporting a one year mortality of 14% and 76% in those with mild or severe malnutrition, respectively [
      • Spengler E.K.
      • Dunkelberg J.
      • Schey R.
      Alcoholic hepatitis: current management.
      ]. Furthermore, malnutrition has also been associated with a longer stay in intensive care units, longer length of hospital stay, and higher mortality after LT [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ].
      Although no difference in the prevalence and severity of malnutrition has been observed between ALD and viral-related liver disease in one series [
      • Caregaro L.
      • Alberino F.
      • Amodio P.
      • et al.
      Malnutrition in alcoholic and virus related cirrhosis.
      ]. Caly et al. reported a poorer nutritional status in patients with alcoholic cirrhosis compared to those with hepatitis C-related cirrhosis [
      • Caly W.R.
      • Strauss E.
      • Carrilho F.J.
      • et al.
      Different degrees of malnutrition and immunological alterations according to aetiology of cirrhosis: a prospective and sequential study.
      ].
      Nutrition plays an important role as supportive therapy, and the American Association for the Study of Liver Disease guidelines recommend that all ALD patients be screened for both protein–calorie deficiency and any specific micronutrient deficiencies (i.e. vitamin and mineral deficiency) [
      • Spengler E.K.
      • Dunkelberg J.
      • Schey R.
      Alcoholic hepatitis: current management.
      ].
      Based on the above findings, the present review is aimed at addressing both the main patterns of malnutrition in ALD and the role of nutritional support in this specific setting, reporting the clinical recommendations with pertinent evidence-based strength (Centre for Evidence Based Medicine. Levels of Evidence. http://www.cebm.net/index.aspx?o¼1025, Table 1).
      Table 1Grades of clinical recommendations based on literature studies strength.
      Grade of recommendationEvidence derived from
      AMeta-analysis of randomized controlled trials
      BAt least one randomized controlled trial, one controlled study without randomization or one other type of quasi-experimental study
      CComparative, correlation studies, or case-control studies
      DExpert committee reports or opinions or clinical experience of respected authorities, or both

      2. Methods

      An extensive bibliographical search was performed in PubMed using the following keywords: alcoholic liver disease, nutritional deficiencies, nutritional support, enteral nutrition, parenteral nutrition and protein–energy malnutrition, in order to identify all the pertinent articles published between 1980 and 2014. The reference lists from the selected studies were manually examined to identify further relevant reports. Non-English language papers were excluded. The quality and strength levels of the results were considered and when available meta-analyses and systematic reviews, large epidemiological studies and randomized control trials represented the main source of data.

      3. Results

      A total of 82 articles with the strongest level of evidence specific to the scope of this review were identified.

      3.1 Nutritional assessment

      Nutritional assessment in ALD is based on detailed history and physical examination [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ]. Of the several clinical markers of malnutrition of which none exclusive, the body mass index (BMI, kg/m2) and the degree of weight loss are the most relevant ones, in spite of their potential unreliability in presence of fluid retention [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ]. A more comprehensive assessment includes anthropometry and scoring systems such as the Nutrition Risk Screening, which considers the amount and duration of weight loss; the BMI for adults; percentile charts for children; the degree of appetite and the ability to eat and retain food (i.e. food intake) and ‘stress factors’, i.e. the effects of health status on nutritional requirements [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ]. A further widely used tool, whose details are given in Table 2, is the Subjective Global Assessment (SGA), based on a standardized questionnaire aimed at assessing any changes in dietary intake, recent changes in body weight, gastrointestinal symptoms, functional capacity, and physical signs of malnutrition represented by loss of subcutaneous fat or muscle mass, oedema, ascites [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ]. In addition, as listed in Table 3, several biochemical markers can help to better define malnutrition, even though albumin, prealbumin, and transferrin may lack accuracy as they are synthesized by the liver; a further critical point is the lack of correlation between these proteins and both the BMI and the lean body mass [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ]. Moreover, the widespread use of albumin supplementation in cirrhotic patients can mask actual plasma albumin levels. The total lymphocyte count (TLC) has also been proposed as a useful indicator of nutritional status and outcome, even if its use in patients with hepatic disorders needs further evaluation as few pertinent studies are currently available [
      • Purnak T.
      • Yilmaz Y.
      Liver disease and malnutrition.
      ]. Low insulin-like growth factor 1 levels may also be a marker of malnutrition [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ], whilst serum creatinine may not accurately reflect the loss of muscle mass in patients with concomitant renal insufficiency. Noteworthy, in patients with chronic illnesses, including cirrhosis, muscle wasting can be assessed by measuring psoas muscle thickness by computed tomography (CT) scanning, a novel accurate, objective marker of nutritional status [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ].
      Table 2Features of the subjective global assessment
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      .
      History
       Weight change
       Dietary intake change (relative to normal)
       Gastrointestinal symptoms (that persisted for >2 weeks), including nausea, vomiting, diarrhoea, anorexia.
       Functional capacity: full capacity, dysfunction (working suboptimally, ambulatory, bedridden).
       Disease and its relation to nutritional requirements
       Primary diagnosis (specify)
       Metabolic demand (stress)
      Physical (0 = normal, 1+ = mild, 2+ = moderate, 3+ = severe)
       Loss of subcutaneous fat (triceps, chest)
       Muscle wasting (quadriceps, deltoids)
       Ankle oedema
       Sacral oedema
       Ascites
      SGA rating
       A: Well nourished
       B: Moderately (or suspected of being) malnourished
       C: Severely malnourished
      SGA, subjective global assessment.
      Table 3Parameters aimed at assessing the presence and degree of malnutrition.
      ParametersDegree of malnutrition
      MildModerateSevere
      Albumin (g/dL)3.5–3.02.9–2.5<2.5
      Transferrin (mg/dL)200–150149–100<100
      Pre-albumin (mg/dL)22–2817–10<10
      Retinol binding protein (mg/dL)2.9–2.52.4–2.1<2.1
      Lymphocytes/mm31500–12001199–800<800
      Summary: As per current guidelines, the European Society for Clinical Nutrition and Metabolism (ESPEN) recommends the bedside nutritional assessment using SGA and anthropometric measurements [
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      ].
      Grade of recommendation: C.

      3.2 Protein–energy malnutrition

      Malnutrition, characterized by an altered functional and structural development of an organism, results in an imbalance between the need, intake and utilization of nutrients and is usually associated with poor clinical outcomes.
      Patients with chronic liver disease (CLD) are particularly prone to develop malnutrition due to the altered regulation by the affected liver of both the nutritional status and the energy balance. Moreover, the presence of CLD may also decrease the appetite, thus negatively influencing nutrient intake. As no difference in malnutrition has been reported between alcoholic and non-alcohol-related liver diseases [
      • Caregaro L.
      • Alberino F.
      • Amodio P.
      • et al.
      Malnutrition in alcoholic and virus related cirrhosis.
      ], the severity of liver damage per se is crucial in promoting nutritional disorders [
      • McClain C.J.
      • Barve S.S.
      • Barve A.
      • et al.
      Alcoholic liver disease and malnutrition.
      ].
      The prevalence of protein–calorie malnutrition in patients with ALD ranges from 20% to 60% in outpatients with alcoholic cirrhosis to the almost 100% in hospitalized patients with AH [
      • McClain C.J.
      • Barve S.S.
      • Barve A.
      • et al.
      Alcoholic liver disease and malnutrition.
      ,
      • Mendenhall C.L.
      • Moritz T.E.
      • Roselle G.A.
      • et al.
      Protein energy malnutrition in severe alcoholic hepatitis: diagnosis and response to treatment. The VA Cooperative Study Group #275.
      ,
      • Cheung K.
      • Lee S.S.
      • Raman M.
      Prevalence and mechanisms of malnutrition in patients with advanced liver disease, and nutrition management strategies.
      ]. ALD represents a strong predictor of malnutrition due to the several risk factors associated with chronic alcohol abuse [
      • Purnak T.
      • Yilmaz Y.
      Liver disease and malnutrition.
      ] and protein–calorie malnutrition may in turn promote complications, e.g. encephalopathy and/or bacterial infections in ALD patients [
      • Gao B.
      • Bataller R.
      Alcoholic liver disease: pathogenesis and new therapeutic targets.
      ]. Moreover, malnutrition may itself have a negative impact on liver integrity as reported several decades ago in malnourished children with kwashiorkor [
      • Hughes W.
      Fatty liver and malignant malnutrition.
      ]. The current lack of strong clinical practice guidelines aimed at assessing and grading ALD-related malnutrition accounts for the poor recognition, diagnosis and treatment of this condition. Accordingly, physicians should be trained to this specific field as nutritional supplementation can be effective in improving liver function and is also positively affecting survival as suggested by short-term follow-up studies [
      • Cabre E.
      • Rodriguez-Iglesias P.
      • Caballeria J.
      • et al.
      Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.
      ,
      • Foody W.
      • Heuman D.D.
      • Mihas A.A.
      • et al.
      Nutritional therapy for alcoholic hepatitis: new life for an old idea.
      ,
      • Stickel F.
      • Hoehn B.
      • Schuppan D.
      • et al.
      Review article: nutritional therapy in alcoholic liver disease.
      ]. Conversely, a recent Cochrane meta-analysis failed to confirm a clear-cut benefit on morbidity or mortality from the oral, enteral or parenteral nutritional support even when specific nutrient deficiencies have been identified and corrected [
      • Koretz R.L.
      • Avenell A.
      • Lipman T.O.
      Nutritional support for liver disease.
      ].
      Summary: Although several studies have recommended nutritional supplementation for ALD malnourished patients, the available results are often inconclusive and further studies are needed to clearly define the role of nutritional support.
      Grade of recommendation: C.

      3.3 Micronutrient depletion

      The depletion of fat-soluble and water-soluble vitamins or various minerals is common in patients with ALD, each deficiency producing specific symptoms, signs, and complications [
      • McClain C.J.
      • Barve S.S.
      • Barve A.
      • et al.
      Alcoholic liver disease and malnutrition.
      ,
      • Manne V.
      • Saab S.
      Impact of nutrition and obesity on chronic liver disease.
      ]. The ESPEN suggests a baseline screening of all cirrhotics for possible deficiency of serum zinc, calcium and vitamins leading to their supplementation whenever needed [
      • Teiusanu A.
      • Andrei M.
      • Arbanas T.
      • et al.
      Nutritional status in cirrhotic patients.
      ] and an annual check-up once stable levels are achieved.
      The mechanisms underlying micronutrient deficiency include dietary restrictions, frequent paracentesis, diuretic regimens and lactulose therapy. Advanced liver disease associated with cholestasis, bacterial overgrowth and/or malabsorption, causes severe deficiencies of fat-soluble vitamins and other nutrients [
      • O’Brien A.
      • Williams R.
      Nutrition in end-stage liver disease: principles and practice.
      ].
      Summary: Baseline screening for micronutrient depletion and an appropriate correction when necessary are recommended.
      Grade of recommendation: D.

      3.3.1 Folate deficiency

      Folate deficiency typically characterizes ALD due to reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary excretion [
      • Medici V.
      • Halsted C.H.
      Folate, alcohol, and liver disease.
      ]. Herbert et al. originally reported that 80% of the 70 chronic alcoholics admitted to a large US urban hospital showed low serum folate levels, with severe deficiency in 44% of them [
      • Herbert V.
      • Zalusky R.
      • Davidson C.S.
      Correlation of folate deficiency with alcoholism and associated macrocytosis, anemia, and liver disease.
      ].
      Both dietary and endogenous folate are involved in the hepatic methionine metabolism, which regulates homocysteine levels, antioxidant defences, DNA assembly, lipid export, and all epigenetic methylation reactions contributing to the gene expression regulation [
      • Medici V.
      • Halsted C.H.
      Folate, alcohol, and liver disease.
      ]. Dietary folates are metabolized in the liver and other tissues and the final metabolite is S-adenosylmethionine (SAM), which acts as a methyl donor for all the methylation reactions involving DNA, histones, and proteins [
      • Medici V.
      • Halsted C.H.
      Folate, alcohol, and liver disease.
      ].
      The methionine metabolic pathways are deeply influenced by alcohol consumption and folate deficiency may promote liver disease resulting in defective DNA synthesis and stability, both associated with an increased risk for hepatocellular carcinoma [
      • Halsted C.H.
      • Villanueva J.
      • Chandler C.J.
      • et al.
      Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation.
      ] and reduced methylation capacity on the expression of genes related to liver injury [
      • Halsted C.H.
      • Villanueva J.A.
      • Devlin A.M.
      • et al.
      Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig.
      ].
      The beneficial effect of both methyl donor SAM and betaine as protective against the development of experimental ALD in animal models has been clearly shown [
      • Chen Y.L.
      • Yang S.S.
      • Peng H.C.
      • et al.
      Folate and vitamin B12 improved alcohol-induced hyper homocysteinemia in rats.
      ,
      • Esfandiari F.
      • You M.
      • Villanueva J.A.
      • et al.
      S-adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet.
      ], whilst inconclusive results have been achieved in the clinical trials focused on the efficacy of SAM in established ALD [
      • Vendemiale G.
      • Altomare E.
      • Trizio T.
      • et al.
      Effects of oral S-adenosyl-l-methionine on hepatic glutathione in patients with liver disease.
      ,
      • Mato J.M.
      • Camara J.
      • Fernandez de Paz J.
      • et al.
      S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.
      ,
      • Medici V.
      • Virata M.C.
      • Peerson J.M.
      • et al.
      S-adenosyl-l-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial.
      ].
      Summary: Even though folate should be properly supplemented in ALD patients, inconclusive results are available regarding the therapeutic effect of its final metabolite (SAM).
      Grade of recommendation: C.

      3.3.2 Water-soluble vitamin deficiency

      Due to the hepatic activation and transport of vitamins B1, B6 and others, water-soluble vitamin deficiency commonly occurs in liver disease.
      Thiamine (vitamin B1) deficiency is a well-recognized complication of ALD leading to Wernicke's encephalopathy and Korsakoff's syndrome [
      • Manne V.
      • Saab S.
      Impact of nutrition and obesity on chronic liver disease.
      ].
      As cyanocobalamin (B12) deficiency has been reported in CLD, serum cobalamin levels determination has been suggested; however, falsely elevated B12 levels have been reported in ALD due to the inclusion of endogenous metabolically inactive forms of cobalamin. Accordingly, holotranscobalamin, i.e. the active form of cobalamin, has been reported to be more reliable as an early marker of vitamin B12 deficit in alcoholics [
      • Fragasso A.
      • Mannarella C.
      • Ciancio A.
      • et al.
      Holotranscobalamin is a useful marker of vitamin B12 deficiency in alcoholics.
      ].
      Summary: Vitamin B1 and/or B12 deficiency should be promptly treated to avoid complications (i.e. Wernicke's encephalopathy, Korsakoff's syndrome, megaloblastic anaemia, neuropathies).
      Grade of recommendation: C.

      3.3.3 Fat-soluble vitamin deficiency

      Decreased bile acid production, decreased oral intake, derangement in hepatic synthesis of carrier proteins, and other mechanisms can all account for the deficiency of fat-soluble vitamins (i.e., A, D, E, and K) in CLD patients [
      • Manne V.
      • Saab S.
      Impact of nutrition and obesity on chronic liver disease.
      ].
      Vitamin A deficit with loss of night vision, nyctalopia and more rarely xerophtalmia, has been reported in alcoholics [
      • Lieber C.S.
      Relationships between nutrition, alcohol use, and liver disease.
      ]. Alcohol intake has a profound impact on the whole body's retinoid homeostasis, but the effects of chronic alcohol consumption are tissue specific; in other words, alcohol consumption is associated with a decrease in the hepatic retinoid content, while extra-hepatic retinoid levels are elevated [
      • Clugston R.D.
      • Blaner W.S.
      The adverse effects of alcohol on vitamin A metabolism.
      ]. Noteworthy, caution in replacing vitamin A levels is mandatory as continuous alcohol intake stimulates cytochrome P450 with the conversion of retinoids into toxic metabolites [
      • Stickel F.
      • Kessebohm K.
      • Weimann R.
      • et al.
      Review of liver injury associated with dietary supplements.
      ].
      Vitamin D deficiency has already been reported in ALD, especially in the presence of established cirrhosis [
      • Fisher L.
      • Fisher A.
      Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease.
      ]. In a recent European study on 324 ALD patients, low 25(OH) vitamin D levels were associated with increased liver damage and mortality, suggesting that vitamin D might be both a biomarker of severity and a potential therapeutic target in ALD [
      • Trépo E.
      • Ouziel R.
      • Pradat P.
      • et al.
      Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease.
      ]. Notably, a recent Danish study suggested that a single oral mega-dose (300,000 IU) of cholecalciferol was more effective than ergocalciferol in the treatment of vitamin D deficiency [
      • Malham M.
      • Peter Jørgensen S.
      • Lauridsen A.L.
      • et al.
      The effect of a single oral megadose of vitamin D provided as either ergocalciferol (D2) or cholecalciferol (D3) in alcoholic liver cirrhosis.
      ], although these results need to be reproduced in larger cohorts of ALD patients.
      Vitamin E exerts definite antioxidant effects. However, whilst several studies have suggested a link between vitamin E deficiency and progression from NAFLD to non-alcoholic steato-hepatitis (NASH) [
      • Cankutaran M.
      • Kav T.
      • Yavuz B.
      • et al.
      Serum vitamin E levels and its relation to clinical features in nonalcoholic fatty liver disease with elevated ALT levels.
      ], comparable data in ALD are still scanty.
      Vitamin K is a known co-factor for the carboxylation of multiple proteins, including blood coagulation factors and its deficiency, common in advanced liver disease, is usually responsible for bleeding. Despite the lack of specific studies addressing the vitamin K status in ALD patients, those with impaired prothrombin time and/or international normalized ratio (INR) should receive vitamin K supplementation [
      • Manne V.
      • Saab S.
      Impact of nutrition and obesity on chronic liver disease.
      ].
      Summary: Supplementation with fat-soluble vitamins is not routinely recommended for ALD patients, except for vitamin D deficiency, which should be corrected in all patients with advanced CLD [
      • Fisher L.
      • Fisher A.
      Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease.
      ].
      Grade of recommendation: B.

      3.3.4 Other nutritional deficiencies

      A deficit of other micronutrients including ascorbic acid, magnesium and zinc, has also been observed in ALD patients, but the need for their supplementation remains a matter of debate.
      Although full-blown vitamin C deficiency is currently uncommon in Western countries, sporadic cases of scurvy have been described in malnourished patients including alcoholics [
      • Léger D.
      Scurvy: reemergence of nutritional deficiencies.
      ,
      • Maltos A.L.
      • Portari G.V.
      • Saldanha J.C.
      • et al.
      Scurvy in an alcoholic malnourished cirrhotic man with spontaneous bacterial peritonitis.
      ]. That prompts for careful skin examination and ascorbic acid measurements when available in this setting [
      • Maltos A.L.
      • Portari G.V.
      • Saldanha J.C.
      • et al.
      Scurvy in an alcoholic malnourished cirrhotic man with spontaneous bacterial peritonitis.
      ].
      Zinc or magnesium deficiency can provoke dysgeusia or altered taste sensation, partially explaining the decreased dietary intake reported in most CLD patients [
      • Manne V.
      • Saab S.
      Impact of nutrition and obesity on chronic liver disease.
      ]. Zinc deficiency, common in liver disease especially in ALD, may be partially due to decreased intake, increased losses secondary to malabsorption, increased dietary requirement and, possibly, a diuretic regimen [
      • O’Brien A.
      • Williams R.
      Nutrition in end-stage liver disease: principles and practice.
      ,
      • Johnson T.M.
      • Overgard E.B.
      • Cohen A.E.
      • et al.
      Nutrition assessment and management in advanced liver disease.
      ]. The complications of zinc deficiency include skin lesions, impaired night vision, altered taste and smell, immune dysfunction, hypogonadism, encephalopathy, altered protein metabolism and retarded wound healing [
      • Johnson T.M.
      • Overgard E.B.
      • Cohen A.E.
      • et al.
      Nutrition assessment and management in advanced liver disease.
      ]. The severity of zinc deficiency parallels the extent of liver damage as suggested by lower serum zinc levels in alcoholic cirrhotics vs. non-cirrhotics, both groups showing a significant decrease of serum zinc levels when compared to healthy controls [
      • Rodriguez-Moreno F.
      • Gonzalez-Reimers E.
      • Santolaria-Fernandez F.
      • et al.
      Zinc, copper, manganese, and iron in chronic alcoholic liver disease.
      ]. According to some studies, zinc supplementation can revert the known manifestations of zinc deficiency in ALD [
      • McClain C.J.
      • Antonow D.R.
      • Cohen D.A.
      • et al.
      Zinc metabolism in alcoholic liver disease.
      ], even if the results remain inconclusive. In the series by Zarski et al. zinc sulfate was given at a dosage of 600 mg/daily for 10 days to ALD patients and for 10, 30, and 60 days to alcoholic cirrhotics; both groups normalized serum zinc levels without adverse reactions, although some cirrhotics maintained persistently low levels [
      • Zarski J.P.
      • Arnaud J.
      • Labadie H.
      • et al.
      Serum and tissue concentrations of zinc after oral supplementation in chronic alcoholics with or without cirrhosis.
      ]. Bianchi and colleagues administered a long-term oral zinc supplementation (200 mg tid for 2–3 months) to cirrhotic patients, including alcoholics, with beneficial effects on both the liver metabolic function and nutrition parameters [
      • Bianchi G.P.
      • Marchesini G.
      • Brizi M.
      • et al.
      Nutritional effects of oral zinc supplementation in cirrhosis.
      ]. Since nutritional parameters remained below lower limits of normal, further studies are needed on both the interaction between zinc and ALD and the long-term outcome of oral zinc supplementation, to define the optimal duration and overall dose.
      Magnesium deficiency affects patient's appetite, and its levels have been shown to be an independent predictor of muscle strength [
      • Aargaard N.K.
      • Andersen H.
      • Vilstrup H.
      • et al.
      Magnesium supplementation and muscle function in patients with alcoholic liver disease: a randomised placebo-controlled trial.
      ]. The mechanisms underlying magnesium deficiency are still far from being fully understood as its deficit may be due to cirrhosis or heavy alcohol intake as well. Additionally, the need for magnesium supplementation is still controversial [
      • Aargaard N.K.
      • Andersen H.
      • Vilstrup H.
      • et al.
      Magnesium supplementation and muscle function in patients with alcoholic liver disease: a randomised placebo-controlled trial.
      ].
      Other minerals, such as selenium, may decrease with liver disease but the effects are poorly known in cirrhotic patients [
      • Manne V.
      • Saab S.
      Impact of nutrition and obesity on chronic liver disease.
      ].
      Summary: Guidelines for assessing micronutrient deficiency in ALD patients are scanty and evidence supporting their supplementation is still inconclusive. Moreover, the potential benefits and the possible harmful effects of any dietary supplementation should be considered.
      Grade of recommendation: D.

      3.4 Nutritional therapeutic approaches

      3.4.1 Dietary interventions

      Dietary interventions represent a relevant step in the management of patients with ALD to reduce the length of hospital stay, to improve the outcome of surgery and transplantation and to reduce the rate of complications [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ].
      Nutritional management should firstly be addressed to cover basal needs and then to provide additional sources for the hypermetabolic state. Caloric need estimation for ALD patients, based on the Harris-Benedict equation, may be inaccurate owing to an underestimate of the caloric needs by even 15–18% when compared with the measurement using indirect calorimetry [
      • Singal A.K.
      • Charlton M.R.
      Nutrition in alcoholic liver disease.
      ]. General nutritional guidelines for patients with cirrhosis as released by the ESPEN are listed in Table 4 [
      • Plauth M.
      • Cabre E.
      • Campillo B.
      • et al.
      ESPEN guidelines on parenteral nutrition: hepatology.
      ]. Unnecessary dietary restrictions should be avoided in order to reduce the risk of malnutrition or micronutrient deficiency and a low-sodium diet should be only recommended in decompensated cirrhosis with ascites and oedema. Due to the limited reserves and inability of the liver to handle prolonged starvation due to reduced gluconeogenesis, patients with cirrhosis are recommended to assume frequent meals, including nighttime snacks [
      • Plank L.D.
      • Gane E.J.
      • Peng S.
      • et al.
      Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomised 12-month trial.
      ]. In this context, a randomized controlled trial (RCT) reported an increase of the total body protein stores, with a sustained gain of 2 kg over a 12-month period, in patients receiving a nighttime snack when compared with patients receiving an equicaloric diet but lacking the late evening meal [
      • Plank L.D.
      • Gane E.J.
      • Peng S.
      • et al.
      Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomised 12-month trial.
      ]. Additionally, cirrhotic patients fasting for more than 12 hours should receive intravenous glucose at the rate of endogenous hepatic glucose production (2–3 mg/kg/d). Protein restriction should be limited to patients with acute hepatic failure, whilst such restriction is not required in the medium or long-term management of patients with liver disease as this limitation may be responsible for an increased incidence of complications related to malnutrition [
      • Mullen K.D.
      • Dasarathy S.
      Protein restriction in hepatic encephalopathy: necessary evil or illogical dogma?.
      ]. In a recent RCT 30 cirrhotic patients hospitalized for an episode of encephalopathy received a 14-day low-protein regimen with progressive increments or a normal protein diet, in addition to the standard measures to treat hepatic encephalopathy. Overall, the protein intake of 1.2 g/kg/day prevented muscle catabolism without the concomitant precipitation of hepatic encephalopathy [
      • Cordoba J.
      • Lopez-Hellin J.
      • Planas M.
      • et al.
      Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.
      ]. The ESPEN consensus guidelines recommend that the daily protein intake in patients with liver disease should possibly be from 1.0 to 1.5 g/kg depending on the degree of hepatic decompensation [
      • Morgan T.R.
      • Moritz T.E.
      • Mendenhall C.L.
      • et al.
      Protein consumption and hepatic encephalopathy in alcoholic hepatitis. VA Cooperative Study Group #275.
      ,
      • Plauth M.
      • Merli M.
      • Kondrup J.
      • et al.
      ESPEN Consensus Group, ESPEN guidelines for nutrition in liver disease and transplantation.
      ].
      Table 4Summary of general nutrition guidelines for patients with cirrhosis, released by the European Society for Clinical Nutrition and Metabolism.
      Intervention
      Overall provision 30–35 kcal/kg dry body weight
      Calories distribution (%):
       – Carbohydrates 50–60
       – Proteins 25–30 (1–1.5 g/kg body weight)
       – Fats 15–20
      Avoidance of unnecessary dietary restriction
      A low-sodium diet (<2 g/day) should be recommended only if ascites or oedema is present
      Frequent (4–6) small meals including night-time snacks: to be encouraged
      Screen for deficiency of serum zinc, calcium and vitamins A, D, E and K and supplement as needed
      Protein restriction for acute hepatic encephalopathy
      In case of protein intolerance: vegetable or dairy and branched chain amino acids
      Cholesterol intake should be limited, as high cholesterol levels have been reported to increase the degree of liver fibrosis [
      • Teratani T.
      • Tomita K.
      • Suzuki T.
      • et al.
      A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells.
      ], the risk of cirrhosis and liver cancer [
      • Ioannou G.N.
      • Morrow O.B.
      • Connole M.L.
      • et al.
      Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the United States population.
      ] and to suppress the immune function [
      • Battistella F.D.
      • Widergren J.T.
      • Anderson J.T.
      • et al.
      A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition.
      ]. The use of statins should be encouraged in cirrhotic patients with hypercholesterolemia [
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
      • et al.
      Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
      ].
      Branched-chain amino acids (BCAAs) have nutritional and/or metabolic effects on the liver, muscles, and brain, but their levels are reduced in cirrhosis. There is evidence that long-term oral BCAA supplementation (about 0.25 g/kg) both exerts nutritional benefits and reduces the recurrence rates or symptoms of hepatic encephalopathy in patients with cirrhosis [
      • Horst D.
      • Grace N.D.
      • Conn H.O.
      • et al.
      Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portalsystemic encephalopathy: a randomized controlled trial.
      ]. However, the currently available studies are often controversial [
      • Plauth M.
      • Schuetz T.
      • Working Group for developing the guidelines for parenteral nutrition of The German Association for Nutritional Medicine
      Hepatology – guidelines on parenteral nutrition, chapter 16.
      ]: an initial RCT including 37 cirrhotic patients reported that BCAA supplementation was superior to conventional protein supplements in improving hepatic encephalopathy [
      • Horst D.
      • Grace N.D.
      • Conn H.O.
      • et al.
      Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portalsystemic encephalopathy: a randomized controlled trial.
      ], whilst two other RCTs failed to confirm these findings [
      • Christie M.L.
      • Sack D.M.
      • Pomposelli J.
      • et al.
      Enriched branched-chain amino acid formula versus a casein-based supplement in the treatment of cirrhosis.
      ,
      • McGhee A.
      • Henderson J.M.
      • Millikan Jr., W.J.
      • et al.
      Comparison of the effects of Hepatic-Aid and a Casein modular diet on encephalopathy, plasma amino acids, and nitrogen balance in cirrhotic patients.
      ], even if they had a small sample size (eight and four patients only, respectively) and the BCAAs regimen was short-term (11–12 days). More recently, two RCTs including larger cohorts (174 and 646 patients, respectively) focused on the long-term use of BCAAs (1–2 years) among patients with alcoholic cirrhosis; both studies reported a decreased morbidity and mortality and an improved quality of life in the group receiving BCAAs [
      • Marchesini G.
      • Bianchi G.
      • Merli M.
      • et al.
      Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomised trial.
      ,
      • Muto Y.
      • Sato S.
      • Watanabe A.
      • et al.
      Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis.
      ]. According to available data, BCAA supplementation should be recommended in ALD patients with hepatic encephalopathy. BCAA-enriched formulae are available for patients with hepatic encephalopathy who require enteral nutrition (EN) by a nasogastric tube.
      Summary: ALD patients should avoid unnecessary dietary restrictions. Cirrhotic patients should receive a daily protein intake of approximately 1.0–1.5 g/kg and should have frequent meals including night-time snacks. Intravenous glucose should be administered to cirrhotic patients fasting for more than 12 hours; BCAA supplementation should be performed in ALD patients with hepatic encephalopathy.
      Grade of recommendation: B.

      3.4.2 Enteral nutrition (EN)

      In ALD patients unable to meet their caloric requirements through normal feeding, supplementary EN ensures the adequate energy and protein intake without the risk of complications including hepatic encephalopathy [
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      ].
      EN is largely preferred over parenteral nutrition (PN) due to the lower incidence of serious complications and far lower costs. Moreover, the presence of luminal nutrients represents an important trophic factor for intestinal mucosa, which may prevent bacterial translocation and maintain gastrointestinal functions.
      Whole protein formulae are generally recommended and more concentrated high-energy formulae are preferable in patients with ascites to avoid fluid unbalance. BCAA-enriched formulae should be administered to patients with encephalopathy [
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      ]. The oral route is preferable; however, in the case of inadequate oral intake due to the disease severity, tube feeding is recommended, even in patients with oesophageal varices who can safely undergo the procedure without any risk of variceal haemorrhage [
      • de Ledinghen V.
      • Beau P.
      • Mannant P.R.
      • et al.
      Early feeding or enteral nutrition in patients with cirrhosis after bleeding from esophageal varices?. A randomized controlled study.
      ]. On the other hand, percutaneous endoscopic gastrostomy (PEG) should be avoided in the presence of ascites and coagulopathy [
      • Baltz J.G.
      • Argo C.K.
      • Al-Osaimi A.M.
      • et al.
      Mortality after percutaneous endoscopic gastrostomy in patients with cirrhosis: a case series.
      ].
      Five RCTs have shown an improvement both in nutritional status and liver function with EN in patients with AH [
      • Cabre E.
      • Rodriguez-Iglesias P.
      • Caballeria J.
      • et al.
      Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.
      ,
      • Calvey H.
      • Davis M.
      • Williams R.
      Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis.
      ,
      • Mendenhall C.
      • Bongiovanni G.
      • Goldberg S.
      • et al.
      VA Cooperative Study on Alcoholic Hepatitis, III: changes in protein–calorie malnutrition associated with 30 days of hospitalization with and without enteral nutritional therapy.
      ,
      • Mendenhall C.L.
      • Moritz T.E.
      • Roselle G.A.
      • et al.
      A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: results of a Department of Veterans Affairs cooperative study.
      ,
      • Moreno C.
      • Langlet P.
      • Hittelet A.
      • et al.
      Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial.
      ], but data on the long-term survival are often inconclusive as limited to a small samples or derived from a short-term follow-up. Noteworthy, Cabré et al. enrolled 71 patients with severe AH randomized to receive 40 mg/day prednisolone (n = 36) or enteral tube feeding (2000 kcal/day) for 28 days (n = 35) and followed for one year or until death. Eventually, EN was comparable to steroids in the short-term, although death occurred earlier with EN. Steroid therapy however was associated with a higher mortality rate in the immediate weeks after treatment, mainly because of infections [
      • Cabre E.
      • Rodriguez-Iglesias P.
      • Caballeria J.
      • et al.
      Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.
      ]. Similar results have been reported in a series including 273 male patients and comparing oxandrolone plus enteral feeding vs. placebo in severe AH. Combined treatment obtained a lower mortality at six months in the subset of patients with moderate malnutrition [
      • Mendenhall C.L.
      • Moritz T.E.
      • Roselle G.A.
      • et al.
      A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: results of a Department of Veterans Affairs cooperative study.
      ], supporting the preference for early EN to be maintained for a sufficient period.
      Four RCTs comparing EN with a standard diet in alcoholic cirrhotics have shown the improvement in nutritional parameters and liver function with EN; however, the data on survival was conflicting, due to the heterogeneity in both the sample size and the inclusion/exclusion criteria [
      • Bunout D.
      • Aicardi V.
      • Hirsch S.
      • et al.
      Nutritional support in hospitalized patients with alcoholic liver disease.
      ,
      • Cabre E.
      • Gonzalez-Huix F.
      • Abad-Lacruz A.
      • et al.
      Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. A randomized controlled trial.
      ,
      • Hirsch S.
      • Bunout D.
      • de la Maza P.
      • et al.
      Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis.
      ,
      • Kearns P.J.
      • Young H.
      • Garcia G.
      • et al.
      Accelerated improvement of alcoholic liver disease with enteral nutrition.
      ]. In particular, in the trials by Cabré et al. and Kearns et al. [
      • Cabre E.
      • Gonzalez-Huix F.
      • Abad-Lacruz A.
      • et al.
      Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. A randomized controlled trial.
      ,
      • Kearns P.J.
      • Young H.
      • Garcia G.
      • et al.
      Accelerated improvement of alcoholic liver disease with enteral nutrition.
      ] the results are difficult to interpret due to the large number of patients with AH, which is known to benefit from EN [
      • Cabre E.
      • Rodriguez-Iglesias P.
      • Caballeria J.
      • et al.
      Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.
      ] and the low number of patients included in the first series [
      • Cabre E.
      • Gonzalez-Huix F.
      • Abad-Lacruz A.
      • et al.
      Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. A randomized controlled trial.
      ].
      In a recent multicentre prospective RCT including 99 alcoholic cirrhotics with jaundice but without AH, patients were randomized to receive either conventional symptomatic treatment alone (n = 55) or in association with EN with a supply of 35 kcal/kg/day for four weeks, followed by an oral nutritional support alone lasting two months (n = 44) [
      • Dupont B.
      • Dao T.
      • Joubert C.
      • et al.
      Randomised clinical trial: enteral nutrition does not improve the long-term outcome of alcoholic cirrhotic patients with jaundice.
      ]. Disappointingly, EN failed to improve survival and hepatic or nutritional parameters, even if results could have been partially influenced by the inclusion of Child–Pugh C cirrhotic patients with ascites, suggesting the use of EN in earlier stages of ALD.
      Summary: EN is preferable over PN whenever feasible and is associated with improvement in nutritional status and liver function in ALD patients, even if data on long-term survival are often inconclusive.
      Grade of recommendation: A.

      3.4.3 Parenteral nutrition (PN)

      EN has been reported to be as effective as PN, though with lower costs and fewer side effects, therefore the current indication for PN support is restricted to a small group of ALD patients for whom enteral feeding has failed or is contraindicated, or when patients need to stay fasting for 72 h or more [
      • Plauth M.
      • Cabre E.
      • Campillo B.
      • et al.
      ESPEN guidelines on parenteral nutrition: hepatology.
      ].
      PN should be started early in ALD patients with moderate or severe malnutrition, who cannot be sufficiently fed either orally or enterally [
      • Plauth M.
      • Cabre E.
      • Campillo B.
      • et al.
      ESPEN guidelines on parenteral nutrition: hepatology.
      ]. PN should be administered via a central catheter, carefully considering the increased risk of several complications such as sepsis, venous thrombosis, pneumothorax, and lymphatic duct damage. In patients with long-lasting and severe malnutrition, an extremely cautious introduction of PN and careful patient monitoring for the risk of re-feeding syndrome are of paramount relevance.
      In 1980 a RCT by Nasrallah et al. [
      • Nasrallah S.M.
      • Galambos J.T.
      Aminoacid therapy of alcoholic hepatitis.
      ] reported an improved survival in 18 AH patients receiving parenteral supplementation of 70–85 g of amino acids in addition to a standard diet (3000 kcal/day and protein 100 g/day) when compared to 17 similar cases on standard diet alone. Unfortunately, six further studies failed to confirm the above promising results [
      • Diehl A.M.
      • Boitnott J.K.
      • Herlong H.F.
      • et al.
      Effect of parenteral amino acid supplementation in alcoholic hepatitis.
      ,
      • Naveau S.
      • Pelletier G.
      • Poynard T.
      • et al.
      A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients.
      ,
      • Achord J.L.
      A prospective randomized clinical trial of peripheral amino acid glucose supplementation in acute alcoholic hepatitis.
      ,
      • Simon D.
      • Galambos J.T.
      A randomized controlled study of peripheral parenteral nutrition in moderate and severe alcoholic hepatitis.
      ,
      • Mezey E.
      • Caballeria J.
      • Mitchell M.C.
      • et al.
      Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: a randomized controlled trial.
      ,
      • Charlton M.
      Branched-chain amino acid-enriched supplements as therapy for liver disease: Rasputin lives.
      ], probably due to the different inclusion criteria, as the study by Nasrallah et al. included mild to moderate AH. Notably, an improvement in nutritional status and nitrogen balance was reported in all these studies. In particular, in a RCT from Simon et al., 12 patients with moderate and 22 with severe AH were randomized for a four-week regimen of peripheral PN or standard therapy; comparable results were found in moderate AH, but with a more rapid improvement in liver tests, particularly bilirubin levels in severe alcoholic hepatitis, without deleterious effects on encephalopathy or ascites [
      • Simon D.
      • Galambos J.T.
      A randomized controlled study of peripheral parenteral nutrition in moderate and severe alcoholic hepatitis.
      ].
      The role of PN in alcoholic cirrhotics has been reported in only one series in which 40 in-patients with total serum bilirubin greater than or equal to 5 mg/dl were randomized to receive an oral diet containing 40 kcal per kg per day alone or in combination with parenteral supplementation (40 kcal/kg/day and 200 mg nitrogen/kg/day using a central catheter). Despite an improvement in bilirubin and nutritional status in the PN subset, overall survival did not improve and was comparable in both groups (5%) [
      • Naveau S.
      • Pelletier G.
      • Poynard T.
      • et al.
      A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients.
      ].
      Summary: PN should be limited to a small group of ALD patients for whom enteral feeding has failed or is contraindicated or when patients need to stay fasting for at least 72 hours. PN showed promising results in terms of improvement in the nutritional status of ALD patients, however data on survival are inconclusive.
      Grade of recommendation: A.

      4. Conclusion

      Patients with ALD are at high risk for malnutrition, which in turn carries a high risk of developing complications, negatively affecting clinical outcome and increasing healthcare costs. Thus, physicians should detect, diagnose and treat nutritional deficiencies early in this subset of patients. The baseline evaluation of a patient's nutritional status by SGA and anthropometric measurements is recommended by the ESPEN. Nutritional support for malnourished ALD patients is aimed at improving the outcome of hospitalization, surgical procedures, and transplantation and at reducing the length of hospital stay and the rate of complications. Nevertheless, there is still no approved therapy for this common and often devastating disease. Both EN, the first choice whenever possible, and PN seem to improve nutritional parameters and liver function in ALD patients, but fail in increasing overall survival. Micronutrient depletion is common in ALD patients and each deficiency produces specific sequelae. According to the ESPEN guidelines, all cirrhotic patients should be screened at baseline for deficiencies of micronutrients and then properly supplemented. Summary of current evidence on nutritional supplementation in ALD patients is reported in Table 5.
      Table 5Summary of current evidence about nutritional supplementation in alcoholic liver disease patients.
      Key points
      Alcoholic liver disease patients are at high risk for malnutrition and when malnourished can develop complications negatively affecting both the clinical outcome and healthcare costs.
      The European Society for Clinical Nutrition and Metabolism recommends the bedside nutritional assessment using Subjective Global Assessment and anthropometric measurements.
      Further studies are needed to clearly define the role of nutrient supplementation in alcoholic liver disease patients.
      Alcoholic liver disease patients should be screened at baseline for micronutrient depletion and properly supplemented when necessary.
      Folate, vitamin B1 and B12 deficiency should be promptly treated to avoid complications. Inconclusive results are currently available regarding the therapeutic effect of folate's final metabolite.
      Vitamin D deficiency should be treated and corrected.
      The actual need for supplementation of micronutrients including ascorbic acid, zinc, selenium and magnesium in alcoholic liver disease patients remains to be determined.
      Unnecessary dietary restrictions should be avoided and appropriate dietary intake should be given according to European Society for Clinical Nutrition and Metabolism recommendations.
      Both enteral (first choice whenever possible), and parenteral nutrition seem to improve the nutritional parameters and liver function. However, their effect on survival remains to be proven.
      A complete nutritional assessment, evaluation for EN, PN and micronutrient supplementation supports the need for a multi-disciplinary management of ALD patients.

      Conflict of interest

      None declared.

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