Nutritional Aspects of Transplantation in Adults

The Role of the Liver in Nutrient Metabolism

The liver is a key organ in the metabolism of nutrients. The high metabolic activity of the liver accounts for approximately 20% to 30% of the body’s oxygen consumption and energy expenditure. Liver dysfunction induces a catabolic state accompanied by increased energy expenditure; elevated serum insulin, glucagon, epinephrine, and cortisol concentrations; and insulin resistance. Because the liver is vitally involved in nutrient metabolism ( Table 37-1 ), liver disease causes alterations in protein, calorie, carbohydrate, fat, fluid, vitamin, and mineral needs.

Protein metabolism is altered in patients with end-stage liver disease (ESLD). Protein catabolism and hyperammonemia are enhanced, and synthesis of serum proteins, including albumin, secretory proteins, and clotting factors, is decreased. Deamination and transamination of amino acids, which normally takes place in the liver, can be affected. Derangement of plasma amino acid concentrations also occurs. Concentrations of plasma aromatic amino acids (AAAs; phenylalanine, tyrosine, tryptophan) plus methionine and cysteine increase, whereas levels of plasma branched-chain amino acids (BCAAs; valine, leucine, isoleucine) decrease. The resulting alteration in the plasma molar BCAA/AAA ratio has been proposed, but not proven, as a causative factor in hepatic encephalopathy.

Liver disease may increase caloric requirements and affect energy substrate metabolism. The presence of ascites has been shown to elevate resting energy expenditure (REE) in patients with liver cirrhosis. Other studies have found an increase in REE in patients with ESLD only when REE was expressed as energy expenditure per gram of creatinine excreted. This measure represents REE in relation to lean body mass. However, another study corrected REE for urinary creatinine excretion in 40 alcoholic cirrhotic patients and did not find that an increase in metabolic rate was dependent on the severity of the cirrhosis, nutritional status, or existence of alcoholic hepatitis.

Liver failure alters energy metabolism as well. Liver glucose transport is reduced, and peripheral glucose metabolism decreases. The rate of gluconeogenesis is increased, and the body prefers noncarbohydrate fuels such as lipids and amino acids to provide energy. Plasma free fatty acids, glycerol, and ketone concentrations increase in cirrhosis, and the body favors fat as a fuel substrate. Gluconeogenic capacity is retained in the early stages of liver failure, but elevated blood glucose levels can develop chronically. In patients with cirrhosis, decreased first-pass hepatic uptake of glucose and reduced insulin-mediated glucose uptake in peripheral tissues increase glucose levels after an oral load. In addition, hyperglycemia occurs as a result of the reduced insulin action. Circulating insulin levels may be increased, but insulin sensitivity is reduced. In the late stages of liver disease, liver glycogen stores can become depleted, and gluconeogenic capacity deteriorates. The result is fasting hypoglycemia.

Vitamin and mineral alterations also occur as a result of liver disease. Fat malabsorption is common in patients with cholestatic liver disease and leads to loss of energy and fat-soluble vitamins. Deficiencies in fat-soluble vitamins can also occur as a result of other mechanisms. Low vitamin A levels may occur because of the inability of the liver to synthesize retinol-binding protein. Decreased biliary excretion of 1,25-dihydroxycholecalciferol can result from liver disease. Because vitamin E is transported in lipoproteins, the hyperlipidemias associated with cholestatic liver disease may affect vitamin E status. Vitamin B ₆ , vitamin B ₁₂ , thiamine, folate, and niacin levels are often depleted as a result of alcoholism. Some vitamins, including folic acid, thiamine, pyridoxine, and vitamin D, undergo conversion to their active form in the liver; this process can be impaired when the liver is diseased. Minerals excreted via the biliary system, such as manganese and copper, can be affected by an interruption in enterohepatic circulation. Magnesium, phosphorus, and zinc stores are commonly depleted in liver disease secondary to malnutrition, malabsorption, alcoholism, and diuretic use. Finally, mineral bioavailability, tissue distribution, and toxicity can be affected by decreased liver production of their protein carriers.

Nutritional Assessment

Debility, malnutrition, obesity, encephalopathy, and massive ascites are considered risk factors for increased morbidity before and after liver transplantation. All of these factors are nutrition related and can be treated with nutrition therapy. Therefore it is vital that a registered dietitian conduct a thorough nutritional assessment of all liver transplant candidates to identify patients at nutritional risk and implement appropriate nutrition therapy. Determining nutritional status in a patient with ESLD can be difficult because common objective nutritional assessment parameters are affected by liver disease ( Table 37-2 ). Anthropometric measurements such as arm muscle circumference and handgrip strength can serve as objective markers of body cell mass depletion in patients with ESLD. As an alternative nutritional assessment tool, the Subjective Global Assessment (SGA) method should be considered. SGA nutritional ratings are based on a thorough patient history, patient examination, and existing conditions ( Table 37-3 ). SGA has been found to be a valid and reliable tool to assess nutritional status. The SGA method has shortcomings, however; there can be interrater differences if raters are not trained similarly to identify physical signs of malnutrition. In addition, it is not a sensitive test to determine small improvements or declines in nutritional status.

Malnutrition in Transplant Candidates

Prevalence

Figure 37-1 illustrates a malnourished patient awaiting liver transplantation. The prevalence of malnutrition among liver transplant candidates depends on the nutritional assessment criteria, the type of liver disease, and the severity of liver disease. For example, in a study by Ferreira et al malnutrition prevalence in a group of 159 liver transplant patients ranged from 6% to 80% depending on the parameter used to define malnutrition. Malnutrition has been reported to occur in 53% to 74% of candidates based on SGA.

The prevalence of malnutrition also depends on the type of liver disease and the severity of the liver disease. DiCecco et al showed that patients with alcoholic liver disease had depletion of both fat and muscle stores, patients with primary sclerosing cholangitis lost a greater proportion of muscle versus fat tissue, patients with primary biliary cirrhosis had significant losses of both lean and fat tissue, and patients with acute hepatitis lost a greater proportion of lean versus fat tissue. A more recent study also found that low body mass index (BMI, <18.5 kg/m ² ) was more prevalent in patients with cholestatic or metabolic liver disease compared with BMI in patients with other diseases.

Disease severity also seems to be directly correlated with degree of malnutrition. Increased Child-Turcotte-Pugh (CTP) scores (B or C) tend to be associated with worsened nutritional status. However, Model for End-Stage Liver Disease (MELD) scores do not appear to be correlated with degree of malnutrition.

The cause of malnutrition in ESLD is multifactorial. Nutritional depletion can result from a poor diet (in both quantity and quality), anorexia, nausea, vomiting, metabolic aberrations, hypermetabolism, malabsorption, and psychological stress. In addition, the diet restrictions used to control ESLD symptoms can limit food choices and optimal nutrient intake.

Obesity in Transplant Candidates

As the rate of obesity has increased in the general population, so has it increased in the transplant population. Morbid obesity is often considered a relative contraindication for liver transplantation. Not only does morbid obesity present a technical challenge to transplantation surgeons, there are also concerns regarding postoperative complications such as infections and pulmonary problems or overall reduced survival. Because obesity may be associated with adverse transplant outcomes, many transplant centers have set weight limits for transplant candidacy. Limits are often based on BMI, with upper limits of 35 or 40 kg/m being considered relative or absolute contraindications for transplantation.

Despite the concern that obesity may affect posttransplant outcomes, not all studies are convincing that obese patients (when selected carefully) will not do as well as nonobese patients in the postoperative period. Prevalence of postoperative wound infections tend to be increased in obese versus nonobese patients. One study showed that when compared with nonobese patients, obese transplant patients had prolonged hospitalizations, increased hospital costs, and increased rates of respiratory failure, whereas others have not. Two single-center studies demonstrated adverse mortality associated with obesity ; but several other studies did not. An analysis of multicenter data from the United Network for Organ Sharing (UNOS) database found reduced survival at 1, 2, and 5 years after transplantation in morbidly obese subjects. Cardiovascular events accounted for reduced 5-year survival rates in severely and morbidly obese patients. In another study evaluating obesity in liver transplant patients based on the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) liver transplant database, BMI when corrected for ascites did not affect mortality, graft survival, or hospital and ICU length of stay, or other outcomes such as treated infections and rejections. Despite concerns that severe obesity may increase morbidity and mortality risks after transplantation, transplantation has been found to confer a survival benefit in these patients compared with waiting on the transplant list. Nevertheless, this does not mean that all obese candidates are acceptable for transplantation. Most of the patients in these studies were carefully selected; obese patients with several comorbidities or deconditioning are likely not be candidates for transplantation.

Some transplant centers that have specific weight criteria for transplant candidacy require patients to lose weight before transplantation if the patients do not meet the weight guidelines. Traditional caloric restriction and increased activity can be difficult to achieve when patients are deconditioned and fatigued from ESLD. There are case studies of patients undergoing bariatric surgery before or during transplantation, but there have been no studies to evaluate if pretransplant weight loss improves transplant outcomes.

Pretransplant Nutritional Management

Potential benefits of providing nutritional support to a patient include enhanced immunological defense, improved wound healing, and replacement of energy stores. It has been theorized that if nutritional support is provided early enough, it may help maintain quality of life before transplantation, decrease perioperative mortality, and shorten recovery time after transplantation. While transplant candidates wait to receive a transplant, malnutrition often worsens and thus warrants nutritional intervention. The goal of pretransplant nutrition therapy is to treat nutrition-related symptoms, prevent further depletion, and possibly replenish lost stores. A summary of pretransplantation nutritional needs is shown in Table 37-4 .

Oral dietary supplementation is the first intervention that should be attempted to replenish energy stores. In a controlled trial of oral supplementation in 51 alcoholic cirrhosis patients, 26 received enhanced calorie and protein supplements and had shortened hospitalization (especially secondary to infections). Nutritional parameters also improved significantly in the supplemented group in comparison to the 25 controls.

LeCornu et al provided oral supplements to 42 malnourished liver transplant candidates and compared outcomes with 40 control patients not drinking supplements. Both groups improved their caloric intake, probably because of the influence of nutritional intervention and counseling. The supplemented group had improved midarm circumference, midarm muscle circumference, and grip strength, but outcomes were not changed, most likely because there was not a difference in overall nutrient intake between the two groups.

In another study, malnourished pre–liver transplant patients with a history of encephalopathy were randomized to receive either diet plus a BCAA-enriched supplement (n = 19), diet plus a casein-based supplement (n = 21), or diet alone (n = 10). Each supplement was dosed to provide 0.5 g protein/kg/day. Patients receiving supplements had significantly higher caloric intake than the control group did. Patients receiving the BCAA supplement had reduced frequency and length of hospitalizations before liver transplantation.

If patients are not able to eat adequate nutrients, enteral tube feeding (TF) is the most desirable alternative. Two studies compared a group of patients with liver disease who were receiving TF and matched groups receiving oral diets. Thirty-one patients with alcoholic liver disease were randomized to receive either a regular diet alone or a diet supplemented with casein-based TF. The TF group had greater mean nutrient intake, an improvement in hepatic encephalopathy scores, reduced serum bilirubin levels, and a shorter antipyrine half-life in comparison to the control group. In a similar study 35 cirrhotic patients were randomized to receive either a low-sodium diet or TF. The TF group had significantly higher calorie intake, an improvement in CTP score, and a decreased mortality rate when compared with controls.

Another study compared effects of enteral nutrition versus corticosteroids in 71 patients with alcoholic hepatitis and cirrhosis; treatment was administered for 28 days, and patients were followed for 1 year. One group of patients was fed 2000 kcal/day of enteral nutrition via a feeding tube. The other group of patients was encouraged to eat 2000 kcal/day, but this was supplemented with 40 mg/day of oral prednisone. Eight patients dropped out of the enteral arm because of complications or repeated voluntary removal of the tube. Mortality during treatment was no different between the groups; however, mortality occurred earlier in the enteral versus corticosteroid group (median 7 versus 23 days, P = .025). Mortality during the 1-year follow-up period was higher in the corticosteroid group versus the enteral group, mainly because of increased infections. Because these trials did not involve transplant patients, controlled trials are necessary to evaluate the effect of TF on outcomes in patients with ESLD who undergo liver transplantation.

Obtaining access for a feeding tube can be problematic in patients with liver disease. A large-bore nasogastric feeding tube is not a feasible long-term option. A gastrostomy tube is contraindicated in patients with ascites. Therefore a small-bore, nasointestinal tube is typically the best option.

Parenteral nutrition (PN) remains an option only in patients with absent gut function or significant malabsorption. PN is costly and results in a higher incidence of infection and electrolyte imbalance than TF does. PN can also potentially worsen liver function. The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines on parenteral nutrition for liver cirrhosis suggest that patients with cirrhosis should receive early postoperative PN only if patients cannot tolerate adequate oral/enteral nutrition.

Other recommendations made by ESPEN, although rated only a grade C, are to provide PN to patients who are moderately to severely malnourished and unable to eat or receive adequate enteral nutrition, or those who have hepatic encephalopathy and unprotected airways.

Supplementation (either enterally or parenterally) with formulas enriched with BCAAs and depleted in AAAs has been proposed to improve nutritional status without inducing or worsening hepatic encephalopathy. Some studies have supported this theory, whereas others have failed to show the same benefit. The use of these formulas remains controversial.