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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2016; 22(4): 1513-1522
Published online Jan 28, 2016. doi: 10.3748/wjg.v22.i4.1513
Nutrition therapy: Integral part of liver transplant care
Lucilene Rezende Anastácio, Maria Isabel Toulson Davisson Correia
Lucilene Rezende Anastácio, Nutrition Department, Universidade Federal do Triângulo Mineiro, Uberaba 38025-440, Brazil
Maria Isabel Toulson Davisson Correia, Department of Surgery, Faculdade de Medicina, Universidade Federal de Minas Gerais, Minas Gerais 31270-901, Brazil
Author contributions: Anastácio LR and Davisson Correia MIT wrote and review this article.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Maria Isabel Toulson Davisson Correia, MD, PhD, Department of Surgery, Medical School, Universidade Federal de Minas Gerais, 110 Alfredo Balena Avenue, Santa Efigênia, Belo Horizonte, Minas Gerais 31270-901, Brazil. isabel_correia@uol.com.br
Telephone: +55-31-34094186 Fax: + 55-31-34094188
Received: April 28, 2015
Peer-review started: May 6, 2015
First decision: June 2, 2015
Revised: July 8, 2015
Accepted: November 19, 2015
Article in press: November 19, 2015
Published online: January 28, 2016

Abstract

Managing malnutrition before liver transplantation (LTx) while on the waiting list and, excessive weight gain/metabolic disturbances in post-surgery are still a challenge in LTx care. The aim of this review is to support an interdisciplinary nutrition approach of these patients. Cirrhotic patients are frequently malnourished before LTx and this is associated with a poor prognosis. Although the relation between nutritional status versus survival, successful operation and recovery after LTx is well established, prevalence of malnutrition before the operation is still very high. Emerging research has also demonstrated that sarcopenia pre and post-transplant is highly prevalent, despite the weight gain in the postoperative period. The diagnosis of the nutritional status is the first step to address the adequate nutritional therapy. Nutritional recommendations and therapy to manage the nutritional status of LTx patients are discussed in this review, regarding counseling on adequate diets and findings of the latest research on using certain immunonutrients in these patients (branched chain amino-acids, pre and probiotics). Nutrition associated complications observed after transplantation is also described. They are commonly related to the adverse effects of immunosuppressive drugs, leading to hyperkalemia, hyperglycemia and weight gain. Excessive weight gain and post-transplant metabolic disorders have long been described in post-LTx and should be addressed in order to reduce associated morbidity and mortality.

Key Words: Nutritional status, Malnutrition, Obesity, Metabolic syndrome, Nutrition therapy, Liver transplantation

Core tip: Cirrhotic patients are frequently malnourished before liver transplantation (LTx) and this is associated with a poor prognosis. Emerging research has also demonstrated that sarcopenia pre and post-transplant is highly prevalent, despite the weight gain in the postoperative period. The diagnosis of the nutritional status is the first step to address the adequate nutritional therapy. Nutritional recommendations and therapy to manage the nutritional status of LTx patients are discussed in this review. Nutrition associated complications observed after transplantation is also described. Excessive weight gain and post-transplant metabolic disorders have long been described in post-LTx and should be addressed to reduce associated morbidity/mortality.



INTRODUCTION

Nutritional therapy is an integral part of liver transplant care. Although many nutritional aspects of liver transplantation patients have previously been addressed, it is still a challenge to manage malnutrition[1] in the pre-transplant phase and, excessive weight gain/metabolic disturbances[2,3] postoperatively. Recent reports still show that little has changed in the last years with increased prevalence of both entities[4,5].

Interdisciplinary teams should definitely prioritize nutritional therapy as an integral part of liver transplant care in order to change this reality. The aim of this article is to review the nutritional status of liver transplant patients as well as the recommendations and therapy before and after liver transplantation.

NUTRITIONAL STATUS

Malnutrition is still highly prevalent in cirrhotic patients, despite the medical advances in liver transplantation care[1]. Causes of malnutrition in these patients are well described and, essentially, include the effects of a catabolic chronic illness accompanied by reduced food intake[6,7] leading to negative energy balance[8] (Table 1). Many reasons are cited to explain decreased diet intake in cirrhotic patients such as: anorexia caused by zinc deficiency, hyperglycemia and, increased inflammatory cytokine productions (e.g., TNF-α and IL-6) and leptin[7,9,10]; frequent fasting periods for medical examsand procedures as well as iatrogenic diet counseling, usually indicating the avoidance of protein sources, especially for those patients at higher risk of encephalopathy[11] and/or low-salt unpalatable diets. Furthermore, autonomic neuropathy observed in liver cirrhosis causes altered gustatory sensation, gastroparesis and delayed bowel transit time, which together with bacterial overgrowth and tense ascites, cause nausea and early satiety[7,12]. Protein losses due to gastrointestinal bleeding and frequent parecentesis also contribute to malnutrition, which may further be worsened by protein-losing enteropathy, contributing to the development of hypoalbuminemia[13]. Adequate nutrient utilization may be impaired because digestion, absorption and metabolism seem also to be affected in cirrhotic patients. When there is associated excessive alcohol intake or diseases affecting the biliary system, malabsorption is impaired[14,15]. The latter is also influenced by the use osmotic laxatives, as lactulose. Also, liver impairment negatively impacts the capacity of macronutrient metabolism, specially the reduction of protein synthesis, the decrease in glycogen storage and glycogenolysis[7]. Patients with end-stage liver disease may have impaired synthesis of polyunsaturated fatty acids from essential fatty acids precursors, with increases in the levels of n-6 and n-9 and decreases in n-3 fatty acids in plasma and adipose tissue[16]. Also, some authors have reported increased resting energy expenditure in cirrhotic patients[17,18].

Table 1 Factors associated with malnutrition in patients on the waiting list for liver transplantation.
Factors
Anorexia
Ascites
Altered taste perception
Metabolic and inflammatory derangements
Inadequate diet restrictions
Decreased social status
Polypharmacy
Multiple paracentesis
Variceal bleeding
Long fasting periods for labs and diagnostic procedures

As a consequence, nowadays, the prevalence of malnutrition is still very high[1] and seems not to have decreased from what was reported more than twenty years ago[4,19]. Thus, malnutrition may currently affect almost all cirrhotic patients. This could be justified by the fact that patients undergoing transplantation today are generally sicker than those who underwent it before the use of the model of end-stage liver disease (MELD) score. Therefore, it could be hypothesized that nutrition could play a more significant role today than in the past, placing patients at additional nutrition challenges for post-operative recovery[20].

Malnutrition related outcomes have been well recognized with many studies showing the negative impact after transplantation, which is associated to longer hospital andintensive care unit stay, infections, graft impairment and mortality[21-24]. Nevertheless, a recent metanalysis of randomized clinical trials has failed to demonstrate that nutritional therapy improves clinical outcomes[25]. Some reviews, however, reported beneficial effects of oral supplements, enteral and parenteral nutrition[26-28] in reducing complications and mortality of cirrhotic patients.

One fact that may have influenced the previous study results is related to the diagnosis of malnutrition in cirrhotic patients as well as the surrogate outcome measures used to assess nutrition interventions. Due to the hepatic disease, some common nutritional parameters are generally altered, such as the weight - if the patient presents with fluid overload and, also albumin - since it can be lower because of impaired hepatic protein synthesis. Other anthropometric measurements, as triceps skinfold and mid-arm muscle circumference, which assess subcutaneous fat and muscle mass, can also be affected by fluid retention[29,30]. The adapted subjective global assessment, an essential clinical assessment tool has been suggested as probably the best reliable tool (Table 2)[31]. Also, functional instruments such as handgrip strength and the six minute walk test have been advocated as potential good parameters not only to asses but also to follow up nutritional interventions[1,2,32].

Table 2 Subjective Global Assessment for patients on waiting list for transplantation[31] performance.
Subjective Global Assessment
I. History
A. Weight
Height_______ Current weight______
Pre-illness weight _____
Weight in past 6 months: High_____ Low______
Overall change in past 6 months:_________
B. Appetite
Dietary intake change relative to normal
Appetite in past two weeks: ____good ____fair ____poor
Early satiety: _____none _____1-2 weeks _____ > 2 weeks
Taste changes: _____none _____1-2 weeks _____ > 2 weeks
C. Current intake per recall
Calories____ Protein______
Calories needs _____ Protein needs______
D. Persistent gastrointestinal symptoms
Nausea: _____none _____1-2 weeks _____ > 2 weeks
Vomiting: _____none _____1-2 weeks _____ > 2 weeks
Diarrhea (loose stools, > 3/day)
Number of stools per day_____/Consistency______
_____none _____1 weeks _____ > 1 weeks
Constipation: _____none _____1-2 weeks _____ > 2 weeks
Difficulty chewing: _____none _____1-2 weeks _____ > 2 weeks
Difficulty swallowing: _____none _____1-2 weeks _____ > 2 weeks
E. Functional capacity
_____ No dysfunction ____Dysfunction
_____ weeks
_____ working suboptimally
_____ ambulatory
_____ bedridden
II. Physical exam
A. Status of subcutaneous fat (triceps, chest)
_____ good stores _____ fair stores _____poor stores
B. Muscle wasting (quadriceps, deltoids, shoulders)
_____none _____mild to moderate _____ severe
C. Edema and ascites
_____none _____ mild to moderate _____ severe
III. Existing conditions
A.Encephalopathy
_____ none _____ stage I-II _____stage III _____ stage IV
B.Chronic or recurrent infection
_____ none _____ 1 week _____> 1 week
C.Kidney function
_____good/_____decreased (no dialysis)/_____decreased (with dialysis)
D.Varices
_____none/_____ varices (no bleeds)/_____ varices (with bleeds)
IV. Subjective Global Assessment Rating (based on sections I, II, III)
A._____ Well nourished
B._____ Moderately malnourished (or suspected of being malnourished)
C.______ Severely malnourished

Therefore, despite the vast knowledge from research in the fields of metabolism, clinical nutrition and intervention, there is no generally accepted or standardized approach for the diagnosis and classification of malnutrition in these patients[33]. However, we suggest that because all cirrhotic patients are at high risk of malnutrition, it is strongly recommended that nutritional assessment be performed in every liver transplant candidate as an integral part of the evaluation protocol[1,6,32].

Recently, many researches have focused on sarcopenia, a condition defined as severe muscle wasting, and the related outcomes before and after liver transplantation have been reported[34-38]. The diagnosis can be done using dual energy X-ray absorptiometry, computed tomography and, bioelectrical impedance with sex-specific cutoffs for sarcopenia diagnosis[39,40]. Bioelectrical impedance testing is an easy, fast, a low cost tool that can be applied in nutritional transplant care to diagnose sarcopenia[41]. Prevalence of sarcopenia before transplantation is pointed in more than a half of cirrhotic patients[37,42]. It’s absolutely important to stress that muscle wasting is a consequence od inadequate nutritional status - malnutrition -, thus, the relationship of sarcopenia and outcomes should be the same as that of malnutrition. After surgery, the prevalence of sarcopenia does not seem to decrease[43] although patients gain weight, sarcopenic obesity co-exists[44-48]. Greater food intake and physical inactivity are responsible for the positive energy balance, which is observed in up to 88% of patients after liver transplant[49]. This is a risk factor for metabolic syndrome, described in half of patients after liver transplant[50].

NUTRITIONAL RECOMMENDATIONS
Pre liver transplantation

Guidelines for nutritional therapy in cirrhosis have been proposed and updated in the last decades[33,51-53]. Recommendations to avoid malnutrition include a dietetic plan contemplating a caloric intake of 35-40 kcal/kg and a protein intake of 1.2-1.5 g/kg (Table 2). If patients present with water overload, the latter should be considered and discounted for dry weight estimation and nutritional requirement calculation. Obviously, this is absolutely a subjective decision and, that’s why a probably better approach would be to estimate the ideal weight according to body height[54]. Indirectly calorimetry, if available, should be performed[30] as energy needs might be better estimated by this test, in liver transplant candidates[55].

A high protein intake may classically been known as a cause for encephalopathy. Nonetheless, there should be less fear in the prescription of higher amounts of protein, once modulation of nitrogen metabolism in not only due to the nutritional issue[56] and, on the other hand, protein restriction is no doubt one of the causes of malnutrition. For more than a decade, Cordoba et al[57] showed that diets containing 1.2 g/kg of protein can safely administered to patients with liver cirrhosis suffering from episodic encephalopathy. The authors also showed that protein restriction does not confer any benefit during an episode of encephalopathy. Besides, insufficient protein intake (< 0.8 g/kg) has been independently associated with malnutrition and mortality in a large cohort with 630 cirrhotic patients[22]. It is suggested that diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the diet[56].

Considering other nutritional aspects of encephalopathy, a meta-analysis of randomized controlled trials pointed out that oral branched chain amino-acid (BCAA - valine, isoleucine and leucine) supplements have beneficial effects on manifestations of hepatic encephalopathy compared with control supplements, by improving the grade of encephalopathy, but not for the resolution or worsening of this condition[58]. Some reviews have addressed that BCAA supplementation appears to be associated with decreased frequency of complications of cirrhosis and improved nutritional status when prescribed as maintenance therapy[59,60]. BCAA supplementation is suggested to allow recommended nitrogen intakes to be attained/maintained in patients who are intolerant of dietary protein[56]. However, these observations are not universal[61]. A recent prospective study showed that an oral BCAA supplement enriched with leucine reverted the impaired mTOR1 signaling and increased autophagy in skeletal muscle of patients with alcoholic cirrhosis, and could be a promise in the treatment of sarcopenia[62]. Cost and palatability may limit the potential applicability of this treatment modality.

Caloric intake should be guaranteed by 50%-70% of carbohydrates[30,51]. It must be acknowledged that patients with liver failure are at a high risk of hypoglycemia, due to the limitation in storage of glycogen and, liver neoglucogenesis[53]. Reach caloric intake both with carbohydrates and less fats (to avoid slower gastric emptying) is important to prevent the utilization of amino acids for glucose production, and consequent depletion of protein tissue and production of ammonia[63]. Patients should be advised to avoid fasting for longer than 3-6 h during daytime and, should be encouraged to take small, frequent meals distributed throughout the day[56]. A late-evening snack of 50 g of complex carbohydrates is suggested to reverse aberrant substrate utilization and improve nitrogen retention. This has been described to improve quality of life, survival and, reduce the frequency and severity of hepatic encephalopathy episodes[64]. Regarding the consumption of non-digestible carbohydrate (prebiotics), patients should be encouraged to ingest approximately 25-45 g a day[56]. These can either be supplemented as prebiotic formula, or those present in a rich fiber diet, whose fermentation seems to have a beneficial effect on neuropsychiatric performance. On the other hand, probiotic (beneficial bacteria) and symbiotic (prebiotic + probiotic) supplementation should be discouraged in the treatment of hepatic encephalopathy[65,66], but, they may be an option for the prevention[67] and treatment of minimal cases of this condition[65]. Future researches are needed in this population for a consistent recommendation[56].

Fat is important in order to reach caloric recommendations (not more than 30%)[30], thus dietary fat should not be restricted, unless true fat malabsorption has been diagnosed using a fecal fat test or slower gastric emptying is reported[7]. Medium chain triglycerides are an alternative form of fat not requiring bile salts for absorption and can be used both in oral, enteral or parenteral nutrition formulations[68,69]. Essential fatty acids and their derivates should be provided, as patients with end stage liver disease may have impaired synthesis of them[7]. Supplementation of n-3 fatty acids have been suggested as a strategy to delay disease progression in liver cirrhosis and, in post-transplant, it reduces injury of the transplanted liver as well as it has been reported to decrease the incidence of infectious morbidities[70,71].

Oral supplements can be useful to help meet nutritional recommendations and some studies have shown that cirrhotic patients receiving daily supplements plus adequate oral nutrition had better outcomes compared with controls[72-75]. However, one randomized, controlled trial demonstrated that regular dietary counseling is as effective in increasing energy intake as providing a nutritional supplement, since patients who receive a nutritional supplement might decrease the amount of food intake[76]. Nonetheless, this is definitely a matter of adequate counseling, which should encompass various strategies to guarantee compliance, such as different supplement preparations/options (the use of healthy gastronomy). Another strategic action should be the use of supplements in modest quantities (e.g., 50 mL) every time the patient as to take any medication. This ensures increased nutrition intake with probably low impact on satiety, however, diet-drug interactions must be addressed.

In relation to micronutrients, chronic liver disease generally courses with nutrient deficiencies, thus dietary counseling and planning should consider Dietary Reference Intakes[30].Thiamine, folate and magnesium, specially, when there is alcohol abuse[75], and deficiency of fat-soluble vitamins in advanced liver disease, especially in those with cholestatic liver disease[76] are very common. Also, vitamin D deficiency in cirrhotic liver patients is universal[77,78] not only due to the malabsorption but also as a consequence of inadequate dietary intake and decreased UV light exposure. There is also impairment in hepatic activation of this vitamin in cirrhosis[79,80]. This condition leads to calcium deficiency, and eventually osteomalacia or osteoporosis, contributing to fractures seen in 40% of patients with chronic liver disease[81]. Vitamin D (800-1000 IU) and calcium (1.000 mg) supplementation should be implemented in deficiency and in the case of corticosteroid use[82]. Calcium supplementation should be 1.200 to 1.500 mg for those patients with osteopenia and osteoporosis[29,30].

Cirrhotic patients usually have salt retention, which leads to hypernatraemia demanding treatment with diuretics. Depletion of potassium, magnesium, phosphate, zinc and other intracellular minerals are, then, usually observed. However, cirrhotic patients seem to have decreased serum zinc, magnesium and selenium levels with the progression of liver disease and, it is suggest that micronutrient supplementation could play a role in preventing progression of liver disease and its complications[83]. Nonetheless, no routine recommendation on the requirement of micronutrients can be made on the basis of controlled studies and, administration of micronutrients has no proven therapeutic effect apart from the prevention or correction of deficiency states[51]. Sodium restriction to 2 g/d is recommended for those patients with ascites/edema[30]. But patients should be encouraged to use alternative seasonings, as herbs and spices,in order to avoid reducing food intake due to unpalatable diets.

PER AND EARLY POST LIVER TRANSPLANTATION

Per and postoperative nutrition recommendations are similar to those for other postoperative situations. It is specially important to stress that preoperative fasting from midnight and interruption of nutritional intake after surgery is unnecessary and even contra-indicated in most patients[84]. Because in deceased donor transplantation, no one can predict when a patient will receive a transplant[20], aggressive early post-operative nutrition support (by enteral route if possible) should be allocated to those patients with highest MELD scores, especially when they are undernourished and, if it is anticipated that patients will be unable to eat within for more than two days. Also, this approach should be considered when patients cannot maintain oral intake above 60% of the recommended intake for more than 10 d[84]. For those undergoing transplantation from living donors, new opportunities for nutrition therapy, as the transplant operation may be scheduled, preoperative nutrition interventions should be considered for recipients and donors when applicable based on the previous addressed discussion[20].

After the liver transplant operation, energy and protein requirements are still increased for weeks. Metabolism in liver recipients only improves at 4 wk after LTx, especially considering the non-protein respiratory quotient, serum non esterified fatty acids and nitrogen balance[85]. In the immediate phase after the operation, protein catabolism is markedly increased and patients should receive about 1.5-2.0 g/kg of protein (Table 3). Non-protein energy requirements, in this period, vary according to the metabolic and inflammatory status, with unstable patients demanding lower intakes while the others more. When indirect calorimetry is not available, estimates between 25 to 30 kcal/kg per day maybe used[30,51]. Electrolyte abnormalities, thereby, serum potassium, phosphorus, and magnesium levels should be monitored, due to routine diuretic use, abdominal drains and fluid overload. Also, refeeding syndrome should be taken as a risk factor for these disorders[30].

Table 3 Nutritional recommendations in pre and peri liver transplant.
Nutrients/DietRecommendationsObservations
Pre-transplant
Calories35-40 kcal/kgAvoid fasting for longer than 3-6 h during daytime; encouraged to take small, frequent meals distributed throughout the day
Protein1.2-1.5 g/kgIt is suggested diets rich in vegetables and dairy protein
Carbohydrates50%-70%A late-evening snack of 50 g of complex carbohydrates is suggested to reverse aberrant substrate utilization and improve nitrogen retention
Fat30%It should not be restricted, unless true fat malabsorption has been diagnosed using a fecal fat test or slower gastric emptying is reported
Fiber25-45 g/dPrebiotics fermentation seems to have a beneficial effect on neuropsychiatric performance
Vitamin and mineraisDietary Reference IntakesOr pharmacological doses in case of deficiency
Peri-transplant
Calories25-30 kcal/kgUse indirect calorimetry if it is available
Proteins1.5-2.0 g/kgIn the immediate phase after the operation, protein catabolism is markedly increased
Food/enteral nutritionEarly normal food or enteral nutrition (12 h) after liver transplant is advisable as long as the patient is hemodynamically stable and has no nausea or vomiting

In summary, early normal food or enteral nutrition (12 h) after liver transplant is advisable as long as the patient is hemodynamically stable and has no nausea or vomiting[20,33,53]. A whole polymeric enteral formula is recommended and the use of immunonutrition (n-3 fatty acids, arginine, BCAA, nucleotides) in this period is still controversial[20,86].

After liver transplant, patients will have to take immunosuppressant medication to the end of their lives. Although modern drugs with less side effects are available, increased survival rates and decreased overall complications have led to many nutrition status implications associated with the use of cyclosporine, tacrolimus and corticosteroids. New onset diabetes or glucose impairment is common initially after the operation as the consequence of immunosuppressant regiment[87,88]. Diabetic dietary advice is usual required, and if necessary, the use of oral hypoglycemic or insulin regimens should be tethered according to the progression of diet. If hyperglycemia persists, it should be managed by reducing glucoseintake, since higher insulin might hamper increasedglucose oxidation in this period. Also, the diabetogenic potential of the immunosuppressant tacrolimus may be lowered by reducing its dose, without undue risk of rejection[51].

Many patients may concomitantly present with high potassium levels shortly after the operation. This usually results from the nephrotoxicity of the prescribed immunosuppressant medication. Thus, in the early post-transplant periods, it might be important to control potassium food sources as well as, it the recommendation of the use of dietary techniques which are able to reduce its content in nutrients[89]. In the long term, this is not indicated, as this condition mostly disappears. Hypomagnesemia also rises as a consequence of immunosuppression and, patients generally receive magnesium supplementation, however, some progress with diarrhea. The intake of magnesium rich food sources should be encouraged, such as dark cocoa, whole grains, nuts, legumes, fruits and green vegetables. Important to point that the consumption of this kind of food should not be restricted, even considering the immunocompromised host as a result of anti-graft rejection drugs. Patients should receive food safety advice to prevent food borne infections, which can be achieved with the correct handling of fruits and vegetables[90].

In the long-term after liver transplantation, weight gain is mostly observed. It is important to recover the nutritional status, since the patients lose an average of 9.1 kg during the course of liver disease[45]. Greatest relative weight gain occurs in the first six months after the operation[47] and, recovery of all weight loss happens in the first post-transplant year[45]. However, unfortunately, patients do not stop gaining weight in the subsequent years[44], resulting in the alarming prevalence of overweight and obesity[3]. During the first 12 mo, the fat mass progressively increases in those patients who had previously depleted overall body mass, but muscle mass recovery is subtle and non-significant by the end of the first year[91]. So, despite the weight gain, the high prevalence of sarcopenia does not change after transplantation and, new cases of this statusare incident leading to increased risk of morbidity and mortality[36].

LONG-TERM POST LIVER TRANSPLANTATION

Several metabolic complications related to weight gain and the immunosuppression are developed in long-term post-transplant. The risk of arterial hypertension, dyslipidemia and diabetes mellitus incidence increase after surgery and, impact outcomes as well as survival[92]. This set of metabolic disorders yield an increased risk of metabolic syndrome, described in approximately half of liver transplant recipients[2,50].

Every effort should be encouraged to avoid excessive weight gain and its consequences in the long-term after liver transplantation. There is, once again, the need for interdisciplinary, early, and close weight monitoring of all the patients, who certainly could benefit from counseling regarding weight gain and its consequences after surgery[44]. Beyond nutritional intervention, exercise counselingis essential to improve body composition (essentially sarcopenia),overall muscle function and metabolic parameters[32,91]. Specific nutritional and exercise guidelines are available and should be followed[93-98].

CONCLUSION

In summary, patients with terminal liver disease suffer from nutritional and metabolic disorders that are mostly associated to the disease per se, impacting morbidity, mortality and quality of life throughout their life spam either while on the waiting list for liver transplantation and thereafter. These derangements maybe prevented or decreased if adequate interdisciplinary approach is adopted, by providing adequate nutritional counseling and intervention, when necessary. These attitudes positively impact on overall outcomes in the perioperative period and in the long run after transplantation, avoiding future associated morbidity and mortality, such as metabolic syndrome.

Footnotes

P- Reviewer: Tao R S- Editor: Qi Y L- Editor: A E- Editor: Zhang DN

References
1.  Ferreira LG, Anastácio LR, Lima AS, Correia MI. Assessment of nutritional status of patients waiting for liver transplantation. Clin Transplant. 2011;25:248-254.  [PubMed]  [DOI]
2.  Anastácio LR, Diniz KG, Ribeiro HS, Ferreira LG, Lima AS, Correia MI, Vilela EG. Prospective evaluation of metabolic syndrome and its components among long-term liver recipients. Liver Int. 2014;34:1094-1101.  [PubMed]  [DOI]
3.  Anastácio LR, Ferreira LG, de Sena Ribeiro H, Lima AS, Vilela EG, Toulson Davisson Correia MI. Body composition and overweight of liver transplant recipients. Transplantation. 2011;92:947-951.  [PubMed]  [DOI]
4.  DiCecco SR, Wieners EJ, Wiesner RH, Southorn PA, Plevak DJ, Krom RA. Assessment of nutritional status of patients with end-stage liver disease undergoing liver transplantation. Mayo Clin Proc. 1989;64:95-102.  [PubMed]  [DOI]
5.  Everhart JE, Lombardero M, Lake JR, Wiesner RH, Zetterman RK, Hoofnagle JH. Weight change and obesity after liver transplantation: incidence and risk factors. Liver Transpl Surg. 1998;4:285-296.  [PubMed]  [DOI]
6.  Martin P, DiMartini A, Feng S, Brown R, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014;59:1144-1165.  [PubMed]  [DOI]
7.  Hammad A, Kaido T, Uemoto S. Perioperative nutritional therapy in liver transplantation. Surg Today. 2015;45:271-283.  [PubMed]  [DOI]
8.  Ferreira LG, Ferreira Martins AI, Cunha CE, Anastácio LR, Lima AS, Correia MI. Negative energy balance secondary to inadequate dietary intake of patients on the waiting list for liver transplantation. Nutrition. 2013;29:1252-1258.  [PubMed]  [DOI]
9.  Aranda-Michel J. Nutrition in hepatic failure and liver transplantation. Curr Gastroenterol Rep. 2001;3:362-370.  [PubMed]  [DOI]
10.  Madden AM, Bradbury W, Morgan MY. Taste perception in cirrhosis: its relationship to circulating micronutrients and food preferences. Hepatology. 1997;26:40-48.  [PubMed]  [DOI]
11.  Heyman JK, Whitfield CJ, Brock KE, McCaughan GW, Donaghy AJ. Dietary protein intakes in patients with hepatic encephalopathy and cirrhosis: current practice in NSW and ACT. Med J Aust. 2006;185:542-543.  [PubMed]  [DOI]
12.  Thuluvath PJ, Triger DR. Autonomic neuropathy and chronic liver disease. Q J Med. 1989;72:737-747.  [PubMed]  [DOI]
13.  Stanley AJ, Gilmour HM, Ghosh S, Ferguson A, McGilchrist AJ. Transjugular intrahepatic portosystemic shunt as a treatment for protein-losing enteropathy caused by portal hypertension. Gastroenterology. 1996;111:1679-1682.  [PubMed]  [DOI]
14.  Mezey E, Jow E, Slavin RE, Tobon F. Pancreatic function and intestinal absorption in chronic alcoholism. Gastroenterology. 1970;59:657-664.  [PubMed]  [DOI]
15.  Weber A, Roy CC. The malabsorption associated with chronic liver disease in children. Pediatrics. 1972;50:73-83.  [PubMed]  [DOI]
16.  Thomas EL, Taylor-Robinson SD, Barnard ML, Frost G, Sargentoni J, Davidson BR, Cunnane SC, Bell JD. Changes in adipose tissue composition in malnourished patients before and after liver transplantation: a carbon-13 magnetic resonance spectroscopy and gas-liquid chromatography study. Hepatology. 1997;25:178-183.  [PubMed]  [DOI]
17.  Müller MJ, Böttcher J, Selberg O, Weselmann S, Böker KH, Schwarze M, von zur Mühlen A, Manns MP. Hypermetabolism in clinically stable patients with liver cirrhosis. Am J Clin Nutr. 1999;69:1194-1201.  [PubMed]  [DOI]
18.  Ferreira LG, Santos LF, Silva TR, Anastácio LR, Lima AS, Correia MI. Hyper- and hypometabolism are not related to nutritional status of patients on the waiting list for liver transplantation. Clin Nutr. 2014;33:754-760.  [PubMed]  [DOI]
19.  Lautz HU, Selberg O, Körber J, Bürger M, Müller MJ. Protein-calorie malnutrition in liver cirrhosis. Clin Investig. 1992;70:478-486.  [PubMed]  [DOI]
20.  Hasse JM. Early postoperative tube feeding in liver transplantation. Nutr Clin Pract. 2014;29:222-228.  [PubMed]  [DOI]
21.  DiMartini A, Cruz RJ, Dew MA, Myaskovsky L, Goodpaster B, Fox K, Kim KH, Fontes P. Muscle mass predicts outcomes following liver transplantation. Liver Transpl. 2013;19:1172-1180.  [PubMed]  [DOI]
22.  Ney M, Abraldes JG, Ma M, Belland D, Harvey A, Robbins S, Den Heyer V, Tandon P. Insufficient Protein Intake Is Associated With Increased Mortality in 630 Patients With Cirrhosis Awaiting Liver Transplantation. Nutr Clin Pract. 2015;30:530-536.  [PubMed]  [DOI]
23.  Merli M, Giusto M, Gentili F, Novelli G, Ferretti G, Riggio O, Corradini SG, Siciliano M, Farcomeni A, Attili AF. Nutritional status: its influence on the outcome of patients undergoing liver transplantation. Liver Int. 2010;30:208-214.  [PubMed]  [DOI]
24.  Ferreira LG, Anastácio LR, Lima AS, Touslon Davisson Correia MI. Predictors of mortality in patients on the waiting list for liver transplantation. Nutr Hosp. 2013;28:914-919.  [PubMed]  [DOI]
25.  Koretz RL, Avenell A, Lipman TO. Nutritional support for liver disease. Cochrane Database Syst Rev. 2012;5:CD008344.  [PubMed]  [DOI]
26.  Ney M, Vandermeer B, van Zanten SJ, Ma MM, Gramlich L, Tandon P. Meta-analysis: oral or enteral nutritional supplementation in cirrhosis. Aliment Pharmacol Ther. 2013;37:672-679.  [PubMed]  [DOI]
27.  Koretz RL, Avenell A, Lipman TO, Braunschweig CL, Milne AC. Does enteral nutrition affect clinical outcome? A systematic review of the randomized trials. Am J Gastroenterol. 2007;102:412-429; quiz 468.  [PubMed]  [DOI]
28.  Fialla AD, Israelsen M, Hamberg O, Krag A, Gluud LL. Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis. Liver Int. 2015;35:2072-2078.  [PubMed]  [DOI]
29.  Naveau S, Belda E, Borotto E, Genuist F, Chaput JC. Comparison of clinical judgment and anthropometric parameters for evaluating nutritional status in patients with alcoholic liver disease. J Hepatol. 1995;23:234-235.  [PubMed]  [DOI]
30.  Sanchez AJ, Aranda-Michel J. Nutrition for the liver transplant patient. Liver Transpl. 2006;12:1310-1316.  [PubMed]  [DOI]
31.  Hasse J, Strong S, Gorman MA, Liepa G. Subjective global assessment: alternative nutrition-assessment technique for liver-transplant candidates. Nutrition. 1993;9:339-343.  [PubMed]  [DOI]
32.  Garcia AM, Veneroso CE, Soares DD, Lima AS, Correia MI. Effect of a physical exercise program on the functional capacity of liver transplant patients. Transplant Proc. 2014;46:1807-1808.  [PubMed]  [DOI]
33.  Plauth M, Cabré E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, Ferenci P, Holm E, Vom Dahl S, Müller MJ. ESPEN Guidelines on Enteral Nutrition: Liver disease. Clin Nutr. 2006;25:285-294.  [PubMed]  [DOI]
34.  Valero V, Amini N, Spolverato G, Weiss MJ, Hirose K, Dagher NN, Wolfgang CL, Cameron AA, Philosophe B, Kamel IR. Sarcopenia adversely impacts postoperative complications following resection or transplantation in patients with primary liver tumors. J Gastrointest Surg. 2015;19:272-281.  [PubMed]  [DOI]
35.  Clark K, Cross T. Sarcopenia and survival after liver transplantation. Liver Transpl. 2014;20:1423.  [PubMed]  [DOI]
36.  Tsien C, Garber A, Narayanan A, Shah SN, Barnes D, Eghtesad B, Fung J, McCullough AJ, Dasarathy S. Post-liver transplantation sarcopenia in cirrhosis: a prospective evaluation. J Gastroenterol Hepatol. 2014;29:1250-1257.  [PubMed]  [DOI]
37.  Masuda T, Shirabe K, Ikegami T, Harimoto N, Yoshizumi T, Soejima Y, Uchiyama H, Ikeda T, Baba H, Maehara Y. Sarcopenia is a prognostic factor in living donor liver transplantation. Liver Transpl. 2014;20:401-407.  [PubMed]  [DOI]
38.  Dasarathy S. Posttransplant sarcopenia: an underrecognized early consequence of liver transplantation. Dig Dis Sci. 2013;58:3103-3111.  [PubMed]  [DOI]
39.  Yoshizumi T, Shirabe K, Nakagawara H, Ikegami T, Harimoto N, Toshima T, Yamashita Y, Ikeda T, Soejima Y, Maehara Y. Skeletal muscle area correlates with body surface area in healthy adults. Hepatol Res. 2014;44:313-318.  [PubMed]  [DOI]
40.  Prado CM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, Baracos VE. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. 2008;9:629-635.  [PubMed]  [DOI]
41.  Marini E, Buffa R, Saragat B, Coin A, Toffanello ED, Berton L, Manzato E, Sergi G. The potential of classic and specific bioelectrical impedance vector analysis for the assessment of sarcopenia and sarcopenic obesity. Clin Interv Aging. 2012;7:585-591.  [PubMed]  [DOI]
42.  Tandon P, Ney M, Irwin I, Ma MM, Gramlich L, Bain VG, Esfandiari N, Baracos V, Montano-Loza AJ, Myers RP. Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value. Liver Transpl. 2012;18:1209-1216.  [PubMed]  [DOI]
43.  Bergerson JT, Lee JG, Furlan A, Sourianarayanane A, Fetzer DT, Tevar AD, Landsittel DP, DiMartini AF, Dunn MA. Liver transplantation arrests and reverses muscle wasting. Clin Transplant. 2015;29:216-221.  [PubMed]  [DOI]
44.  Kouz J, Vincent C, Leong A, Dorais M, Räkel A. Weight gain after orthotopic liver transplantation: is nonalcoholic fatty liver disease cirrhosis a risk factor for greater weight gain? Liver Transpl. 2014;20:1266-1274.  [PubMed]  [DOI]
45.  Rezende Anastácio L, García Ferreira L, Costa Liboredo J, de Sena Ribeiro H, Soares Lima A, García Vilela E, Correia MI. Overweight, obesity and weight gain up to three years after liver transplantation. Nutr Hosp. 2012;27:1351-1356.  [PubMed]  [DOI]
46.  Wawrzynowicz-Syczewska M, Karpińska E, Jurczyk K, Laurans L, Boroń-Kaczmarska A. Risk factors and dynamics of weight gain in patients after liver transplantation. Ann Transplant. 2009;14:45-50.  [PubMed]  [DOI]
47.  Richards J, Gunson B, Johnson J, Neuberger J. Weight gain and obesity after liver transplantation. Transpl Int. 2005;18:461-466.  [PubMed]  [DOI]
48.  Palmer M, Schaffner F, Thung SN. Excessive weight gain after liver transplantation. Transplantation. 1991;51:797-800.  [PubMed]  [DOI]
49.  Choudhary NS, Saigal S, Saraf N, Mohanka R, Rastogi A, Goja S, Menon PB, Mishra S, Mittal A, Soin AS. Sarcopenic obesity with metabolic syndrome: a newly recognized entity following living donor liver transplantation. Clin Transplant. 2015;29:211-215.  [PubMed]  [DOI]
50.  Anastácio LR, Ferreira LG, Ribeiro Hde S, Liboredo JC, Lima AS, Correia MI. Metabolic syndrome after liver transplantation: prevalence and predictive factors. Nutrition. 2011;27:931-937.  [PubMed]  [DOI]
51.  Plauth M, Cabré E, Campillo B, Kondrup J, Marchesini G, Schütz T, Shenkin A, Wendon J. ESPEN Guidelines on Parenteral Nutrition: hepatology. Clin Nutr. 2009;28:436-444.  [PubMed]  [DOI]
52.  Plauth M, Merli M, Kondrup J, Weimann A, Ferenci P, Müller MJ. ESPEN guidelines for nutrition in liver disease and transplantation. Clin Nutr. 1997;16:43-55.  [PubMed]  [DOI]
53.  Montejo González JC, Mesejo A, Bonet Saris A. Guidelines for specialized nutritional and metabolic support in the critically-ill patient: update. Consensus SEMICYUC-SENPE: liver failure and liver transplantation. Nutr Hosp. 2011;26 Suppl 2:27-31.  [PubMed]  [DOI]
54.  Dolz C, Raurich JM, Ibáñez J, Obrador A, Marsé P, Gayá J. Ascites increases the resting energy expenditure in liver cirrhosis. Gastroenterology. 1991;100:738-744.  [PubMed]  [DOI]
55.  Ferreira LG, Santos LF, Anastácio LR, Lima AS, Correia MI. Resting energy expenditure, body composition, and dietary intake: a longitudinal study before and after liver transplantation. Transplantation. 2013;96:579-585.  [PubMed]  [DOI]
56.  Amodio P, Bemeur C, Butterworth R, Cordoba J, Kato A, Montagnese S, Uribe M, Vilstrup H, Morgan MY. The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus. Hepatology. 2013;58:325-336.  [PubMed]  [DOI]
57.  Córdoba J, López-Hellín J, Planas M, Sabín P, Sanpedro F, Castro F, Esteban R, Guardia J. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004;41:38-43.  [PubMed]  [DOI]
58.  Metcalfe EL, Avenell A, Fraser A. Branched-chain amino acid supplementation in adults with cirrhosis and porto-systemic encephalopathy: systematic review. Clin Nutr. 2014;33:958-965.  [PubMed]  [DOI]
59.  Charlton M. Branched-chain amino acid enriched supplements as therapy for liver disease. J Nutr. 2006;136:295S-298S.  [PubMed]  [DOI]
60.  Shu X, Kang K, Zhong J, Ji S, Zhang Y, Hu H, Zhang D. [Meta-analysis of branched chain amino acid-enriched nutrition to improve hepatic function in patients undergoing hepatic operation]. Zhonghua Gan Zang Bing Zazhi. 2014;22:43-47.  [PubMed]  [DOI]
61.  Gluud LL, Dam G, Borre M, Les I, Cordoba J, Marchesini G, Aagaard NK, Risum N, Vilstrup H. Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials. J Nutr. 2013;143:1263-1268.  [PubMed]  [DOI]
62.  Tsien C, Davuluri G, Singh D, Allawy A, Ten Have GA, Thapaliya S, Schulze JM, Barnes D, McCullough AJ, Engelen MP. Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology. 2015;61:2018-2029.  [PubMed]  [DOI]
63.  Kabadi UM. The association of hepatic glycogen depletion with hyperammonemia in cirrhosis. Hepatology. 1987;7:821-824.  [PubMed]  [DOI]
64.  Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploiting a period of anabolic opportunity in cirrhosis. J Gastroenterol Hepatol. 2012;27:430-441.  [PubMed]  [DOI]
65.  Holte K, Krag A, Gluud LL. Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy. Hepatol Res. 2012;42:1008-1015.  [PubMed]  [DOI]
66.  McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev. 2011;CD008716.  [PubMed]  [DOI]
67.  Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol. 2012;107:1043-1050.  [PubMed]  [DOI]
68.  Cabré E, Abad-Lacruz A, Núñez MC, González-Huix F, Fernández-Bañares F, Gïl A, Esteve-Comas M, Moreno J, Planas R, Guilera M. The relationship of plasma polyunsaturated fatty acid deficiency with survival in advanced liver cirrhosis: multivariate analysis. Am J Gastroenterol. 1993;88:718-722.  [PubMed]  [DOI]
69.  Cabré E, Periago JL, Abad-Lacruz A, González-Huix F, González J, Esteve-Comas M, Fernández-Bañares F, Planas R, Gil A, Sánchez-Medina F. Plasma fatty acid profile in advanced cirrhosis: unsaturation deficit of lipid fractions. Am J Gastroenterol. 1990;85:1597-1604.  [PubMed]  [DOI]
70.  Zhu X, Wu Y, Qiu Y, Jiang C, Ding Y. Effects of ω-3 fish oil lipid emulsion combined with parenteral nutrition on patients undergoing liver transplantation. JPEN J Parenter Enteral Nutr. 2013;37:68-74.  [PubMed]  [DOI]
71.  Ginanni Corradini S, Zerbinati C, Maldarelli F, Palmaccio G, Parlati L, Bottaccioli AG, Molinaro A, Poli E, Boaz M, Serviddio G. Plasma fatty acid lipidome is associated with cirrhosis prognosis and graft damage in liver transplantation. Am J Clin Nutr. 2014;100:600-608.  [PubMed]  [DOI]
72.  Hirsch S, Bunout D, de la Maza P, Iturriaga H, Petermann M, Icazar G, Gattas V, Ugarte G. Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis. JPEN J Parenter Enteral Nutr. 1993;17:119-124.  [PubMed]  [DOI]
73.  Mendenhall CL, Moritz TE, Roselle GA, Morgan TR, Nemchausky BA, Tamburro CH, Schiff ER, McClain CJ, Marsano LS, Allen JI. A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: results of a Department of Veterans Affairs cooperative study. Hepatology. 1993;17:564-576.  [PubMed]  [DOI]
74.  Le Cornu KA, McKiernan FJ, Kapadia SA, Neuberger JM. A prospective randomized study of preoperative nutritional supplementation in patients awaiting elective orthotopic liver transplantation. Transplantation. 2000;69:1364-1369.  [PubMed]  [DOI]
75.  Leevy CM, Moroianu SA. Nutritional aspects of alcoholic liver disease. Clin Liver Dis. 2005;9:67-81.  [PubMed]  [DOI]
76.  Sokol RJ. Fat-soluble vitamins and their importance in patients with cholestatic liver diseases. Gastroenterol Clin North Am. 1994;23:673-705.  [PubMed]  [DOI]
77.  Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci. 2010;55:2624-2628.  [PubMed]  [DOI]
78.  Malham M, Jørgensen SP, Ott P, Agnholt J, Vilstrup H, Borre M, Dahlerup JF. Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than aetiology. World J Gastroenterol. 2011;17:922-925.  [PubMed]  [DOI]
79.  Mawer EB, Klass HJ, Warnes TW, Berry JL. Metabolism of vitamin D in patients with primary biliary cirrhosis and alcoholic liver disease. Clin Sci (Lond). 1985;69:561-570.  [PubMed]  [DOI]
80.  Henkel AS, Buchman AL. Nutritional support in patients with chronic liver disease. Nat Clin Pract Gastroenterol Hepatol. 2006;3:202-209.  [PubMed]  [DOI]
81.  Nakchbandi IA. Osteoporosis and fractures in liver disease: relevance, pathogenesis and therapeutic implications. World J Gastroenterol. 2014;20:9427-9438.  [PubMed]  [DOI]
82.  Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, Curtis JR, Furst DE, McMahon M, Patkar NM. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2010;62:1515-1526.  [PubMed]  [DOI]
83.  Nangliya V, Sharma A, Yadav D, Sunder S, Nijhawan S, Mishra S. Study of trace elements in liver cirrhosis patients and their role in prognosis of disease. Biol Trace Elem Res. 2015;165:35-40.  [PubMed]  [DOI]
84.  Weimann A, Braga M, Harsanyi L, Laviano A, Ljungqvist O, Soeters P, Jauch KW, Kemen M, Hiesmayr JM, Horbach T. ESPEN Guidelines on Enteral Nutrition: Surgery including organ transplantation. Clin Nutr. 2006;25:224-244.  [PubMed]  [DOI]
85.  Sugihara K, Yamanaka-Okumura H, Teramoto A, Urano E, Katayama T, Morine Y, Imura S, Utsunomiya T, Shimada M, Takeda E. Recovery of nutritional metabolism after liver transplantation. Nutrition. 2015;31:105-110.  [PubMed]  [DOI]
86.  Plank LD, Mathur S, Gane EJ, Peng SL, Gillanders LK, McIlroy K, Chavez CP, Calder PC, McCall JL. Perioperative immunonutrition in patients undergoing liver transplantation: a randomized double-blind trial. Hepatology. 2015;61:639-647.  [PubMed]  [DOI]
87.  Bodziak KA, Hricik DE. New-onset diabetes mellitus after solid organ transplantation. Transpl Int. 2009;22:519-530.  [PubMed]  [DOI]
88.  Pham PT, Pham PC, Lipshutz GS, Wilkinson AH. New onset diabetes mellitus after solid organ transplantation. Endocrinol Metab Clin North Am. 2007;36:873-890; vii.  [PubMed]  [DOI]
89.  Bethke PC, Jansky SH. The effects of boiling and leaching on the content of potassium and other minerals in potatoes. J Food Sci. 2008;73:H80-H85.  [PubMed]  [DOI]
90.  Avery RK, Michaels MG. Strategies for safe living after solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:304-310.  [PubMed]  [DOI]
91.  Giusto M, Lattanzi B, Di Gregorio V, Giannelli V, Lucidi C, Merli M. Changes in nutritional status after liver transplantation. World J Gastroenterol. 2014;20:10682-10690.  [PubMed]  [DOI]
92.  Parekh J, Corley DA, Feng S. Diabetes, hypertension and hyperlipidemia: prevalence over time and impact on long-term survival after liver transplantation. Am J Transplant. 2012;12:2181-2187.  [PubMed]  [DOI]
93.  Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129:S102-S138.  [PubMed]  [DOI]
94.  Klein WS, Merz CN, Jenkins MR. Guidelines for managing high blood pressure. JAMA. 2014;312:294-295.  [PubMed]  [DOI]
95.  Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752.  [PubMed]  [DOI]
96.  James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.  [PubMed]  [DOI]
97.  Executive summary: Standards of medical care in diabetes--2013 Diabetes Care. 2013;36 Suppl 1:S4-S10.  [PubMed]  [DOI]
98.  American Diabetes Association. Standards of medical care in diabetes--2013. Diabetes Care. 2013;36 Suppl 1:S11-S66.  [PubMed]  [DOI]