Malnutrition is universally prevalent among pre-liver transplantation patients. Malnutrition among cirrhotic patients had been associated to increased morbidity and mortality rates. Also, severely malnourished patients before the transplant surgery have a higher rate of complications and a decreased overall survival rate after liver transplantation. In light of the high incidence of malnutrition and associated complications, it is essential to initiate treatment as early as it is assessed. This review addresses the aetiologies of malnutrition and appropriate treatment strategies to correct it in pre-liver transplant phase. Treatment should focus on maintaining nutrient intake and correcting various nutritional deficiencies. The dietician plays an integral role as part of the transplant team by providing appropriate nutrition therapy for solving various nutrition problems.
Keywords: End stage liver disease; liver transplantation; pre-liver transplant
Liver transplantation (LT) revolutionized the management of liver disease. LT is the only option for those with end stage liver disease (ESLD). According to Institute of Health Metrics and Evaluation of Global Burden of Disease, deaths from cirrhosis in all age groups is ranked 12th globally and 19th in South Asia in 1990 and was ranked 12th globally and 11th in South Asia in the year 2010. Hence, an increasing death from cirrhosis is seen in South Asia over a period of time.
Metabolic changes in ESLD
Various metabolic changes that occur in ESLD patients are presented in Table 1[3-7] which affect the nutrition state of pre-LT recipients. These factors are inadequate dietary intake, increased intestinal protein losses, malabsorption, low protein synthesis, hypermetabolism and disturbed substrate utilization.[8,9]
Table 1: Metabolic changes in ESLD for liver transplant candidatesClick here to view
Consequences of preoperative malnutrition on liver transplantation outcome
Survival in cirrhosis decreases according to the severity of malnutrition.[10,11] Preoperative hypermetabolism and body cell mass depletion was proven to be better predictors of the outcome of LT than the traditional Child-Pugh score. Undernutrition may induce an exaggerated cytokine response favouring postoperative systemic inflammatory response syndrome and multi-organ failure in these patients. Zinc deficiency is a precipitating factor for hepatic encephalopathy. Deficiencies of water-soluble vitamins (B and C) and fat soluble vitamins (A, E, D, and K) may occur in patients with cirrhosis which increases the susceptibility of cell membranes to lipid peroxidation. Low retinol levels leads to an increased risk of developing hepatocellular carcinoma.
Hence, careful nutritional assessment of candidates for LT is very important because the nutritional status of these patients may ultimately influence morbidity and mortality. Unfortunately, no gold standard exists to determine the extent of malnutrition in this population. An suitable nutritional assessment can include combination of nutrition tools like anthropometry, body composition analysis, subjective global assessment, and hand grip strength to formulate a composite score for assessment of malnutrition.
Nutrition treatment for pre-liver transplant patients
The goals of nutritional therapy are to improve protein energy malnutrition and correct nutrient deficiencies. This can be accomplished by meeting nutrient requirements.
When energy expenditure is related to lean body mass, patients with advanced liver disease have increased resting energy expenditure (REE).[18,19] Despite the usually offsetting errors of excess total body water in estimation of REE from the Harris-Benedict equation [Table 2],[18,19] it is still considered useful to measure the REE by way of indirect calorimetry in some patients with severe liver disease. Increased REE (hypermetabolic) was found over controls in patients with cirrhosis. But this is not a uniform finding since hypometabolism as well as normometabolism have been observed in patients with cirrhosis.[19-21] When related to predicted energy expenditure among stable cirrhotics, a subgroup of 15-20% may be considered as hypermetabolic, 25-30% as hypometabolic and the large majority as normometabolic. Increased REE has also been observed during complications of liver disease, such as acute hepatic failure, high volume ascites, or presence of hepatocellular carcinoma. Measurements of total energy expenditure in patients with cirrhosis indicate that the 24 h energy requirement of cirrhosis patients amounts to about 130% of the basal metabolic rate (BMR). Diet-induced thermogenesis[25,26] and the energy cost of defined physical activity in stable cirrhosis patients[27,28] and it also shows no deviation from values obtained in healthy patients. The spontaneous physical activity level is also low in cirrhotics.[5,28]
Table 2: Formula for REEClick here to view
In cirrhotics without ascites, the actual body weight should be used for the calculation of the BMR using Harris and Benedict formulae. In patients with ascites the ideal weight according to body height should be used. In general, non-protein energy provision of 1.3 × REE is sufficient.[29,30] For most patients, the daily caloric need equals (1.2-1.4) × REE (25-30 kcal/kg body weight).
Administration of adequate calories is critical for the efficient use of protein sources, particularly when patients are protein restricted. Excess calories particularly from carbohydrate, should be avoided because it promotes hepatic lipogenesis, liver dysfunction and increased carbon dioxide production leading to increased work of breathing.
For patients with steatorrhea, it is important to limit long-chain fatty acids and increase short-chain and medium-chain fatty acids in the formula. Pancreatic enzymes should be supplemented, especially in patients with alcohol-related cirrhosis. The serum lipid variables appeared to be more useful indicators of functional liver improvement than the classic liver function tests.
In clinical intervention trials proteins were given in amounts of 0.6-1.2 g/kg per day for patients with cirrhosis and severe encephalopathy and 0.5-1.6 g/kg per day in patients with alcoholic hepatitis with or without low grade encephalopathy. Patients with stable cirrhosis appear to have increased protein requirements of 1.2 g/kg per day to maintain nitrogen homeostasis as opposed to 0.8 g/kg per day in normal individuals. The reasons for this phenomenon are not yet clear, but the increased protein requirement seems to be due to increased whole body protein degradation which may be due to low plasma levels of insulin-like growth factor (IGF)-1.
According to Morgan et al. (2006) whole protein formula providing 35-40 kcal/kg per day energy and 1.2-1.5 g/kg per day protein is recommended for enteral feeding. Standard preparation contains approximately 100 kcal, 4 g protein, and 3.5 mmol of sodium and potassium per 100 mL. Concentrated high energy (1.5 kcal/mL) and protein formulas may be preferable in patients with hyponatremia and ascites to regulate fluid balance. This may also improve treatment adherence because less volume needs to be consumed.
A study by Nielsen et al. (1995) showed protein balance in a subgroup of patients did not change protein balance values. Protein intake increased from 1.0 g/kg per day to 1.8 g/kg per day. With increasing protein intake, 84% of the increase in intake was retained. The rate of protein retention was not saturated at the intakes obtained in this study.
Protein requirement and protein utilization were investigated further by measuring protein synthesis and degradation. In 2 separate studies, patients with cirrhosis of the liver were refed on a balanced diet for an average of 2-4 weeks. Protein and energy intakes were doubled in both studies. Refeeding caused a statistically significant increase of about 30% in protein synthesis in both studies while protein degradation was only slightly affected. The increase in protein synthesis was associated with significant increases in plasma concentrations of total amino acids while insulin, growth hormone, IGF-1 and IGF-3 were not changed significantly. The results indicate that the efficient protein utilization is due to increased protein synthesis, rather than decreased protein degradation.
Value of branched-chain amino acids
Branched-chain amino acids (BCAAs) (leucine, isoleucine, valine) are essential amino acids. In cirrhosis, there is a likely reduced total body pool of BCAAs due to reduced lean muscle mass and defective use secondary to hyperinsulinemia.
BCAAs compete with the serotonin precursor tryptophan for the same amino acid transporter in the blood-brain barrier, and the imbalance between the 2 in cirrhosis influences brain ammonia levels directly or indirectly. So supplementation with BCAAs may reduce brain uptake of tryptophan and improve encephalopathy.[41,42] Furthermore, BCAA supplementation by both enteral and parenteral routes of feeding has shown improved in cerebral perfusion by which encephalopathy may get improved but still basic mechanism is unclear. A large multicenter study showed that oral BCAAs given for 1 year improved the Child score, reduced hospital admissions, and prolonged/improved event-free survival. However, there have been no controlled studies and no mention of the timing of BCAA supplementation in cirrhotic patients. At 3 months, a significant increase in serum albumin level was observed in patients who were administered with nocturnal BCAAs but not daytime BCAAs. It is hypothized that BCAAs when consumed in daytime are utilized as calories, whereas nocturnal BCAAs are utilized for protein synthesis. European Society for Parenteral and Enteral Nutrition (ESPEN) guidelines [Table 3] recommends use of enteral feed enriched with BCAAs for patients who develop encephalopathy. The use of solutions rich in BCAA and low in aromatic acids and tryptophan in encephalopathy has been proposed. However, a Cochrane analysis based on 11 trials found no convincing evidence regarding benefit from BCAA. The use of BCAAs remains controversial, and they are not widely available in many centres due to their expense and unpalatability.
Table 3: Nutrition in chronic liver disease-recommendations 1997Click here to view
According to ESPEN Guidelines, for a positive effect on liver function and clinical outcome, non-protein energy was given in amounts of 35-40 kcal/kg per day plus protein up to 1.6 g/kg per day. In patients with encephalopathy, transient protein restriction can be instituted, but after a few days adequate nutrition should be reinstituted. Patients in coma (encephalopathy grade III-IV) can safely be given total parenteral nutrition (TPN) regimens providing 25-30 kcal/kg per day from non protein energy plus 1.0 g/kg per day using BCAA-enriched solutions. Fasting periods should not exceed 6 h due to the limited glycogen stores in malnourished cirrhotic patients. Generally, the oral or enteral routes are preferred. Parenteral nutrition should only be used when enteral feeding is not possible or impractable [Table 3].
Micronutrient deficiency has been observed in 10-50% of patients with cirrhosis. Multivitamin supplements may be considered in these patients.
Various vitamins deficiency occurs in LT recipients like folate deficiency is due to a combination of decreased intake, decreased absorption, as well as losses from renal excretion and poor hepatic storage. Supplementation of folate and B12 is crucial in alcoholic hepatitis to protect uninjured hepatocytes and stimulate the repair/replacement of damaged cells [Table 4]. The common recommendation for folate supplementation is 1 mg/day orally. Vitamin B1 deficiency is linked to primary tissue damage such as alcoholic polyneuropathy and also Wernicke’s encephalopathy. Usual supplementation is 100 mg/day orally or subcutaneously initially for 2 weeks or until repleted, the amount in a standard multivitamin should be sufficient. Deficiency of vitamin B6 (pyridoxine) is due to decreased intake or altered metabolism and storage. Standard supplementation is 50-100 mg/day orally, or more in severely depleted individuals. Liver stores are often depleted even in the setting of normal serum levels. Hypovitaminosis A has been linked to night blindness, impairment in immune function, and also to an increased risk of hepatic fibrosis [Table 4]. If malabsorption is suspected as a prime contributor to depletion, doses of 25,000-50,000 IU 3 times per week may be needed for repletion. Vitamin A supplementation improves the sense of taste and thereby may also improve dietary intake of the patients. Inadequate intake of calcium and vitamin D and losses from malabsorption and renal excretion are related to lower serum levels of albumin and magnesium. If the individual is unable to increase dietary intake to a consistent, adequate level of 1,000-1,500 mg/day, supplementation should be initiated, especially in those with suspected low bone mineral density. Osteoporosis has been confirmed in 17-23% of patients with liver disease. The role of vitamin D and calcium on bone mass in the setting of liver disease is unclear. Serum levels should be monitored in 3 months to assess tolerance and success of repletion. Low serum levels of vitamin D are thought to be the result of poor dietary intake, malabsorption from cholestasis, pancreatic insufficiency, and decreased sunlight exposure. Supplementation usually begins at 400 IU per day, with some patients requiring up to 800 IU per day of vitamin D or 12,000-50,000 IU per day of ergocalciferol, with serum levels reassessed in 2-3 months. Serum vitamin E levels are typically decreased in alcoholic patients, pancreatitis or fat malabsorption [Table 4]. A dose of 400 IU per day either as standard vitamin E or as α-tocopherol, if malabsorption is suspected, should provide for adequate supplementation in most individuals.
Table 4: Nutrition recommendations for a liver transplant candidateClick here to view
During the pre-LT phase patients suffer from various mineral deficiencies because of metabolic changes due to liver impairment. Zinc deficiency is very common in cirrhotics. Zinc supplementation may also be used for those patients with hepatic encephalopathy, with refractory response to vitamin A supplementation for night blindness, and for potential improvement in immune function and taste perception. Supplementation in the form of 220 mg zinc sulphate is given in 1-3 divided doses per day. Zinc and selenium deficiency has been observed in both alcoholic and non-alcoholic liver disease and may be associated with neurological symptoms. Depleted serum iron levels, blood losses can cause deficiency in LT patients. Hepatic iron overload is common and often secondary to increased intestinal iron absorption and transfusions, and may imitate hemochromatosis as well as increase the risk of developing progression of liver disease. Patients undergoing LT are prone to hypomagnesemia, with potential deleterious effects. A study evaluated the efficacy and safety of routine intraoperative magnesium supplementation to prevent hypomagnesemia. The results showed lower prevalence of postoperative hypomagnesemia in patients administered magnesium supplementation of 3 g [Table 4][58-63] but may not affect the occurrence of arrhythmias.
Challenge in pre-transplant nutrition support
Ascites, defined as the accumulation of fluid within the peritoneal cavity as a direct consequence of portal hypertension, is a common complication of ESLD and associated with a poor prognosis. The squeal of impaired renal perfusion and fluid volume expansion can precipitate hyponatremia as well. Spontaneous bacterial peritonitis may develop which is associated with increased mortality. Nutrition issues may occur in cirrhotics with ascites due to decreased intake from early satiety, increase in REE before paracentesis. Also, imposing dietary restrictions of sodium and fluid reduces the palatability of food.
The American Association for the Study of Liver Disease practice guidelines (2004), recommend sodium restricted diet and diuretic therapy as the mainstay of treatment for ascites, with their effectiveness demonstrated in about 90% of patients. A dietary sodium restriction of 2 g/day appropriately balances the need for adequate nutrition and fluid status. The reduction in ascitic fluid through careful diuresis can relieve early satiety. A 24-h urinary sodium excretion with a goal of ≥ 78 mEq urinary sodium per day can be measured to follow compliance to a sodium-restricted diet. A fluid restriction is appropriate in cirrhotic patients with dilutional hyponatremia or serum sodium levels < 125 mg/dL [Table 4]. Small, frequent feedings and an adequate intake of protein, in addition to the sodium restriction, are important dietary measures for the patient. Contraindication of these measures lead to large-volume paracentesis (intravenous albumin) or transjugular intrahepatic portosystemic shunt placement may be necessary.[66,67]
Other nutritional factors
Current evidences have shown the advantages of probiotic use in preventing post LT infection, as well as improving the hyperdynamic circulatory state of cirrhosis, hepatic encephalopathy, and Child-Pugh class.[68,69] Its evaluated that neutrophil phagocytic capacity improved in cirrhotic and hepatic encephalopathy patients after probiotics supplementation which prevents infections by altering gut microbiota, preventing bacterial translocation and decreasing endotoxin levels which leads to the restoration of the immune system.[70-72] The effect of probiotic mix (8 strains of Lactobacillus, Bifidobacterium and Streptococcus) for 2 months was assessed on portal hypertension, which showed no reduction on hepatic venous pressure gradient or bacterial translocation in patients with compensated or early decompensated cirrhosis. But, Lata et al. (2007) observed a trend towards decreased endotoxemia and an improvement in Child-Pugh scores (results not statistically significant) with use of the Escherichia coli Nissle [(2.5-25) × 109 bacteria in 1 capsula, for 42 days) in 39 cirrhotic patients.
The impact of nutritional interventions with immune modulating enteral diets in patients’ pre- and post-LT showed possibility of improved preoperative nutritional status of ESLD patients, thus reducing infectious complications after transplantation. Qiu et al. (2009) investigated the effect of TPN supplemented with alanyl-glutamine dipeptide in cirrhotic patients undergoing LT. Within 9 days, the group supplemented had a significant increase in the prognostic nutrition index and prealbumin levels compared with day 2 levels. It was observed better improvement in aspartate amino transferase and reduced hepatic cell injury compared with the traditional TPN group and a significant decrease in postoperative hospital stay.
A study by Plank et al. (2008) showed the effects of night-time and day time nutritional supplementation over a 12-month period on body protein stores in cirrhotic patients. Significant accretion of total body protein equivalent to about 2 kg of lean tissue was seen in patients having night-time supplementation. In the daytime group, no significant accretion was seen. Confirming this, a classical study showed nocturnal supplementation in cirrhotic patients would improve and prevent catabolic states and under nutrition.
Routes of feeding
Oral intake, including supplements, is the first line therapy to prevent and treat malnutrition in liver diseases. The data suggested that by providing medical nutrition therapy, nutrition status may be improved and complications of cirrhosis may be decreased (less hospital admissions, decreased hepatic encephalopathic symptoms, infections, gastrointestinal bleeding, ascites), although the true impact on survival is still unclear.[79,80] Various studies recommending use of nutrition supplementation for LT patients are depicted in Table 5.[32,81-84]
Table 5: Major studies recommending use of nutrition supplementationClick here to view
Enteral and parenteral nutrition
Studies show an increased dietary intake by oral nutrition, improves in liver function and lower hospital mortality than enetral and parenteral.[31,85] Most of the well-nourished patients admitted with variceal bleeding and other complications failed to show benefit in nutritional status or disease-related morbidity and mortality. In hospitalized patients with poor dietary intake, enteral nutrition (EN) should be initiated in about 24-48 h of admission. Hasse et al. demonstrated early enteral feeding benefits like improved nitrogen balance and fewer viral infections after LT.
PN should be used as a second line approach in those who cannot be fed adequately by the oral or enteral route, patients with unprotected airways and advanced hepatic encephalopathy, after visceral surgery in cirrhotics, a lower complication rate was observed when postoperative PN was given instead of just fluid and electrolytes; usually standard amino acid formula is recommended.[16,88] In a direct comparison between PN and early EN, both strategies proved to be equally effective with regard to the maintenance of nutritional state.
Different mechanisms are known for the nutritional derangement in ESLD patients. These include malabsorption, poor dietary intake, low protein synthesis, higher intestinal protein losses, disturbances in substrate utilization, and hypermetabolism. Poor dietary intake is one of the major contributors to ESLD malnutrition. Also, various metabolic disturbances like increased REE, insulin resistance, and low respiratory quotient which indicates decreased glucose and increased lipid oxidation which can contribute to nutritional depletion in liver disease. Early nutrition therapy intervention can improve response to treatment; alleviate symptoms, and quantity of life of ESLD patients. In this review, medical nutrition therapy goals for pre-LT patients are discussed. Various guidelines have been established for pre-LT nutrition care. ESPEN guidelines for chronic liver disease showed increased calorie and protein requirement in malnourished liver disease patients (30-35 kcal/kg per day and 1.5 g/kg per day). Also malabsorption of other nutrients increases requirements of other vitamins and minerals like Ca, Mg, vitamin A, B, D, E and complications like ascites recommends use of low sodium diet which can lead to hyponatermia. ESPEN guidelines for organ transplantation recommends enteral nutrition or oral nutritional supplementation which can improve nutritional status and survival in severely malnourished ESLD patients.[31,37,63,90,91] In patients with cirrhosis, enteral feeding improves nutritional status and liver function and reduces the rate of complications and prolongs survival. Another guideline that is ESPEN Guidelines for enteral nutrition for liver disease recommends use of more concentrated high-energy formulae in patients with ascites, BCAA-enriched formulae in hepatic encephalopathy patients. Administration of enteral nutrition has been shown to reduce the incidence of viral and bacterial infections.[69,87] Protein restriction is rarely required for encephalopathy patients, if necessary, usually for not more than 48 h. The recommended protein supplementation should be based on “dry” body weight and may need alteration in edematous patients [Table 6].
Table 6: Guidelines for pre-transplant nutrition supportClick here to view
ESPEN guidelines for parenteral nutrition in hepatology recommend indication and timing of PN in cirrhosis. Immediate commencement of PN is recommended in moderately or severely malnourished cirrhotics who cannot be nourished sufficiently by either oral or enteral route or patients who have to abstain from food temporarily (including nocturnal fasting), when this fasting period lasts longer than 72 h total PN is required. Carbohydrate should be given as glucose to cover 50-60% of non-protein energy requirements. PN related hyperglycaemia should be avoided by all means. In case of hyperglycaemia glucose infusion should be reduced to 2-3 g/kg per day and i.v. insulin infusion should be used. Lipids should be provided using emulsions with a content of n-6 unsaturated fatty acids lower than in traditional pure soybean oil emulsions and should cover 40-50% of non-protein energy requirements. PN should be considered in patients with unprotected airways and encephalopathy when cough and swallow reflexes is compromised [Table 6].
These recommendations clearly portray the need for nutrition intervention among ESLD patients at the earliest to treat the nutrition medicated complications before LT for improved outcomes after the surgery and overall wellbeing of the ESLD patient.
Malnutrition is a well-known complication of ESLD and is associated with detrimental consequences if left untreated. It is, therefore, of critical importance to assess the nutritional status of all patients with ESLD and to optimize nutritional support in these patients. Treatment should focus on maintaining adequate protein and caloric intake and correcting nutrient deficiencies. The dietician plays an integral role as part of the transplant team by providing appropriate nutrition therapy for solving various nutrition problems. Strategies include the consumption of frequent small meals and a late evening snack to reduce protein breakdown. When oral intake is insufficient, early implementation of enteral feeding should be considered. The use of BCAAs remains controversial, but the most recent data promote their therapeutic potential. Malnutrition is a potentially reversible condition that, when identified and treated appropriately, can lead to improved outcomes hence, more nutrition interventions should be planned with motive of attaining positive nutrition balance in patients undergoing LT.
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