The Benefits of Nutrition Therapy in the Liver Transplant Patient

Cancer:
Nutrition is an integral part of healing and maintenance of health. Poor nutritional status in surgical patients leads to less than optimal outcomes. Nutrition intervention is necessary for a malnourished patient's recovery, and it is cost-effective. This is especially true for liver transplant patients who, prior to transplantation, commonly suffer from malnutrition and are at high risk for nutritionally-mediated complications. Loss of body cell mass was associated with a significantly increased posttransplant mortality in a study of 123 patients with cirrhosis. In a separate study, Pikul et al retrospectively evaluated the effect of malnutrition on the postoperative morbidity and mortality in 68 liver transplant recipients; malnutrition was present in 79% of the subjects. Moderate-to-severe malnutrition was associated with prolonged ventilatory support, increased incidence of tracheostomy, and longer intensive care unit and hospital stays. A trend toward increased mortality among malnourished patients also existed (p=0.13).

A similar study by Hasse et al evaluated the influence of nutritional status on posttransplant morbidity and mortality rates. The records of 500 liver transplant patients were analyzed to determine the effect of nutritional status on survival, infection rates, and length of stay (LOS). Malnutrition was present in 70% of the subjects. Nutritional status did not influence graft or patient survival rates, incidence of infection, or rejection. However, severely malnourished patients had significantly longer intensive care unit and hospital stays compared with well nourished patients (p=0.052 for ICU stay, p<0.006 for hospital stay).

These studies demonstrated the deleterious effects of malnutrition in patients undergoing liver transplantation. Because malnutrition lengthened hospital and intensive care stays, costs of care increased. Patient charges for initial posttransplant hospitalization were $13,827 higher for severely malnourished when compared with well-nourished patients (p<0.05). In addition, malnutrition may contribute to increased morbidity through its effects on immune function, infection, and wound healing. Although other factors influence posttransplant outcomes, nutritional status may be the only reversible factor.

Although the majority of liver transplant candidates are malnourished, a small percentage are morbidly obese. One study of 263 renal transplant patients found an increased incidence of wound infection in 40 obese patients compared with the nonobese subjects. Blue et al did not find any difference between nonobese and severely obese liver transplant patients in regard to infection, days on the ventilator, hospital length of stay, or rejection. Keeffe and colleagues evaluated the feasibility of transplanting severely obese patients and concluded that severe obesity may result in increased but manageable morbidity associated with wound infection, diabetes mellitus, and hypertension.

Nutritional Assessment
Many factors contribute to malnutrition in individuals with end-stage liver disease .7-11 To determine the presence of malnutrition in a liver transplant candidate, a thorough nutritional assessment must be performed. A Subjective Global Assessment (SGA) approach is the preferred assessment method for liver transplant candidates. 9-15 Traditional assessment parameters such as weight loss, serum protein concentrations, total lymphocyte count, delayed hypersensitivity testing, urinary -methylhistidine excretion, creatinine-height index, and anthropometric measure ments are affected by liver disease or its symptoms.2,9,11,13-16 Subjective global assessment evaluates nutritional status by eliciting a history from the patient, evaluating the patient's physical condition, and determining a nutrition ranking (Table 2).2,9,12-14 The SGA technique has been found reliable when used to evaluate liver transplant patients.2,12

Pretransplant Nutrition Therapy
Once malnutrition has been identified, the depleted patient must be treated to reverse or prevent further malnutrition and related complications. The nutritional condition of a patient awaiting a liver transplant will decline unless nutrition therapy is provided. Nutrition therapy includes provision of adequate calories, protein, vitamins, minerals, fluid, and electrolytes without precipitating or aggravating symptoms of end-stage liver disease such as encephalopathy or ascites.10,11,13,14,17-20 Table 3 outlines some general pretransplant nutritional goals.

Energy Requirements
Some evidence suggests that cirrhotic patients have increased metabolic rates. A study by Shanbhogue et al21 determined that when energy expenditure was related to lean tissue, 10 patients with end- stage liver disease had greater energy expenditure than 31 normal control subjects. Another study of 10 patients with cirrhosis and ascites concluded that ascites may be associated with an increase in resting energy expenditure (REE).22 On the other hand, Pierrugues and colleagues23 found no significant difference in REE adjusted for lean body mass between well-nourished and malnourished cirrhotics. Finally, Muller et al1 were unable to determine a standard energy expenditure in 123 cirrhotics. Resting energy expenditures varied between 1,090 and 2,300 calories per day and differed from the predicted values in 70% of the patients. Eighteen percent of the subjects were hypermetabolic and 31% were hypometabolic. Increased REE was associated with significant loss of muscle and body cell mass but unchanged fat mass. Fat and fat-free mass were increased in the hypometabolic patients. In conclusion, it appears that energy needs of liver transplant candidates are highly variable and best determined by indirect calorimetry.

Protein Requirements
Although the value of nutrition intervention in patients with end-stage liver disease is well accepted, the composition of the appropriate supplement is controversial. Derangements of plasma amino acid concentrations occur in individuals suffering from end-stage liver disease.17,18,24-26 Concentrations of plasma aromatic amino acids (AAA: phenylalanine, tyrosine, tryptophan) as well as methionine increase. Some studies have shown a decrease in plasma branched-chain amino acid levels (BCAA: valine, leucine, isoleucine). The resulting alteration in the plasma molar ratio of BCAA:AAA may play an etiologic role in hepatic encephalopathy.

Nutrition formulas enhanced with additional BCAAs may be superior to standard formulas for patients with chronic liver disease. Several studies have evaluated the effects of enteral BCAA supplementation in patients with liver disease.27-38 Although not all of these studies were randomized, controlled trials with isocaloric and isonitrogenous diets, supplements enriched with BCAA were superior in some studies (compared with controls) with respect to improved nutritional indices27,32-38 and improved psychometric tests.27,33,34,36-38 None of these studies demonstrated improved survival rates with BCAA supplementation. One study showed that the combination of oxandrolone and supplementation with a BCAA-enhanced formula decreased mortality in patients with alcoholic hepatitis.39 However, the study design did not allow the effect of the nutritional supplement to be distinguished from that of the oxandrolone.

Oral supplementation is the best choice for nutritional intervention in any population. Early satiety, anorexia, dysgeusia, nausea, diarrhea, or a combination of these symptoms may preclude a liver transplant candidate from achieving adequate oral dietary intake. Tube feeding is indicated for malnourished patients who have a functional gastrointestinal tract but are unable to ingest adequate nutrition orally. Although wide-bore nasoenteric feeding tubes may rupture esophageal varices, the presence of varices is not a contraindication to placement of a small-bore nasoenteric feeding tube.15 Researchers evaluated nasogastric feedings in 10 children awaiting liver transplantation and concluded that enteral feeding improved nutritional status in the pretransplant period without causing adverse clinical or biochemical effects.40 To date, no studies have evaluated the effect of pretransplant nutritional support on posttransplant outcome in malnourished adult patients.

Nutrition Therapy in the Acute Posttransplant Phase
Catabolism occurs in the acute posttransplant phase secondary to the release of catabolic hormones due to surgery and corticosteroid administration. During the catabolic posttransplant phase, early postoperative tube feeding is preferred over total parenteral nutrition (TPN) unless a patient has a nonfunctional gastrointestinal tract or requires complete bowel rest. Absence of bowel sounds is not a contraindication to early jejunal feeding in liver transplant patients. Although gastric and colonic ileus may be present following transplantation, small-bowel feeding is tolerated. In general, administration of TPN is associated with a higher rate of death, organ failure, and decreased gut mass than tube feeding.41,42 Tube feeding results in lower infection rates, decreased metabolic response to stress, fewer technical and metabolic problems, and enhanced visceral protein synthesis at a much lower cost than TPN.41-44 Animal models have shown an increased rate of bacterial translocation in TPN-fed animals than in animals fed enterally.45 Tube feeding reduces septic complications compared with TPN in trauma patients.43,44,46-48

Hasse et al49 demonstrated that early postoperative tube feeding is beneficial for liver transplant recipients. Seventeen liver transplant patients receiving maintenance intravenous solutions prior to initiation of an oral diet were compared to 14 patients who received enteral feeding via a nasoenteric feeding tube prior to oral diet initiation. The feeding tubes were placed during surgery, and enteral feeding was initiated 12 hours after liver transplantation. The tube-fed patients had significantly greater cumulative 12-day calorie and protein intakes than controls. Nitrogen balance and hand-grip strength appeared to recover slightly faster in the supplemented group. In addition, trends showed decreased rates of viral and bacterial infections and fewer infected patients in the tube-fed group than in the control group.

Patients should progress from nutrition support to oral diets as soon as possible after liver transplantation. Early satiety and taste changes due to medication side effects are common patient complaints. Small, frequent feedings of high protein foods help patients achieve adequate intakes. During the transition from tube feeding to oral diet, tube feeding can be administered on a cyclic, nocturnal schedule. Tube feeding should not be discontinued until patients are able to consistently eat two-thirds to three-fourths of their estimated nutrient requirements.

Acute Posttransplant Energy Requirements
Liver transplant patients are commonly assumed to have elevated energy requirements during their acute posttransplant recovery. Resting energy expenditure has been measured by indirect calorimetry following transplantation. Mean REE was increased only 36%-38% above the predicted basal energy expenditure (BEE using the Harris-Benedict equation) on the first two days posttransplant in eight patients.50 Resting energy expenditure was 7% higher than BEE (calculated on actual versus dry weight*) in 11 posttransplant patients.51 Plevak et al52 measured REE in 16 patients during the first two weeks posttransplant and concluded that calories should be provided at 20% above the BEE in the acute posttransplant phase. Finally, a gradual rise in REE occurred in 31 patients over the first 12 days posttransplant, but the peak mean REE was only 27% above the predicted BEE.49 These studies suggest that posttransplant energy needs are not elevated, and calories should be provided at approximately 120%-130% of the calculated BEE.

Acute Posttransplant Protein Requirements
Protein catabolism increases markedly after liver transplantation as evidenced by excretion of large amounts of urinary nitrogen.49-51,53 (Actual patient weight includes ascites and edema. Weight is one of the factors in the BEE calculation; therefore, using actual weight would probably increase BEE; ie, BEE would be lower if dry weight was used.)

Urinary nitrogen losses in the first 12 days posttransplant in 17 non-tube-fed patients ranged from 9.6 + 5.1 grams to 11.7 + 6.3 grams. This compared with a range of 2.9 + 4.3 grams to 15.0 + 7.7 grams of nitrogen per day in 14 tube-fed transplant patients.49 Daily nitrogen losses were measured at 20.1 and 24.6 grams in the first two days posttransplant by other researchers.50 Mean urinary nitrogen excretion was 12.9 + 4.4 grams per day on postoperative day 3 in a study by Shanbhogue and colleagues.51 Finally, O'Keefe et al53 studied 42 liver transplant patients and observed that a relatively stable nitrogen state was achieved on the fourth postoperative day, with mean daily nitrogen losses of 14.4 to 16.0 grams/day. Because of the elevated nitrogen loss, liver transplant patients should receive 1.5 to 2.0 grams of protein per kilogram of dry weight during the acute posttransplant phase.

Nutrient alterations occur as a result of immunosuppressive medications. Table 4 lists potential nutritional side effects and proposed medical nutritional interventions.13,14,54-63 Other acute posttransplant nutrition guidelines are outlined in Table 5.

Nutrition Therapy During the Chronic Posttransplant Phase
While the focus of the acute posttransplant phase is to replenish lost nutritional stores, the aim of chronic medical nutrition therapy is prevention. Aggressive nutrition therapy can improve the common posttransplant problems of obesity, hyperlipidemia, hypertension, diabetes mellitus, and osteoporosis.

Excessive Weight Gain
Excessive weight gain is an overwhelming long-term posttransplant problem that has been documented by several researchers. An analysis of 46 liver transplant patients at least one year posttransplant identified a median weight gain of 6.5 kg.64 An obesity rate of 43% was identified by Munoz et al65 in 21 patients at least 18 months posttransplant. Nearly two-thirds of 28 patients studied by Palmer and colleagues were obese, and obesity was associated with a higher incidence of hepatic abnormalities including elevated liver function tests.66 FK-506 (tacrolimus)-based immunosuppression may help to reduce weight gain that has been seen with cyclosporine-based immunosuppression. In the U.S. multicenter FK-506 trial, the mean body mass index of cyclosporine-treated patients (27.4 kg/m2) was significantly higher than that of patients treated with tacrolimus (25.5 kg/m2) at one year posttransplant. In addition, only 10.9% of the tacrolimus-treated patients were obese one year following transplantation compared with 18.2% of cyclosporine-treated patients.

Hyperlipidemia
Hypercholesterolemia is a risk factor for cardiovascular disease and occurs frequently in post-liver transplant patients. The incidence of elevated cholesterol in 21 liver transplant survivors was 43%.65 Another study identified 15 of 86 patients (16%) who had serum cholesterol levels >250 mg/dL.68 In addition, nine of those patients also had elevated triglyceride, LDL-cholesterol, and apolipoprotein-B concentrations. Some believe that steroid withdrawal may normalize hypercholesterolemia, but this theory has not been tested in liver transplant patients. However, one study demonstrated a positive correlation between serum cholesterol levels and steroid dose in renal transplant patients,57 but another study found that steroid withdrawal also lowered levels of serum HDL- and LDL-cholesterol and apolipoproteins A1 and B.58 The net result was no significant change in the ratio of serum cholesterol:HDL cholesterol or apolipoprotein A1:B or potential cardiac risk. Tacrolimus-based immunosuppression appears to reduce hyperlipidemia compared with cyclosporine regimens. In the U.S. multicenter FK-506 trial, the mean serum cholesterol and LDL cholesterol levels one year posttransplant were significantly lower in the FK-506 group compared with the cyclosporine group.

Hypertension
Hypertension occurs in most liver transplant recipients maintained on a cyclosporine-based immunosuppressive regimen. Twenty-one transplant survivors had an 81% overall incidence of hypertension. Hypertension was only slightly more prevalent in obese (89%) than in nonobese subjects (75%). A second study found hypertension in 31 of 46 (67%) patients.64 Patients treated with cyclosporine-based immunosuppression have a higher incidence of hypertension one year following transplantation than patients on a tacrolimus-based regimen.

Diabetes Mellitus
Levy et al70 evaluated 522 liver transplant patients and reported a 9% incidence of new onset posttransplant diabetes mellitus, similar to the 7% incidence of insulin-dependent diabetes in 46 patients reported by Eid et al.64 Munoz and colleagues65 reported a higher incidence of diabetes mellitus: 33% of 9 obese liver transplant patients and 17% of 12 nonobese patients. There appears to be no difference in glucose tolerance between patients treated with cyclosporine or tacrolimus-based immunosuppression.

Osteoporosis
Bone mineral density (BMD) decreases following liver transplantation.56,71 Over half of liver transplant patients with cholestatic liver disease have BMD levels below the fracture threshold before transplantation, with a 15- to 30-fold increase in the posttransplant rate of bone mineral loss per year.71 Patients with a pretransplant lumbar spine BMD below the fracture threshold (0.98 g/cm2) had a significantly higher incidence of fractures than patients with a BMD greater than the fracture threshold.

Long-Term Posttransplant Nutritional Requirements
All of the chronic nutritional problems following transplantation are caused in part by diet. Table 6 outlines proposed causative factors of these nutrition-related problems. A long-term diet prescription for a transplant patient aims at prevention of chronic problems.9,10,13,14,54,55 Caloric intake must be adjusted to maintain a healthy weight. A moderate protein intake of 1 to 1.2 grams/kg should be sufficient unless steroid doses are increased. Dietary carbohydrate should provide 50-70% of calories, with emphasis on inclusion of complex carbohydrate and restriction of simple carbohydrate sources. Fat should be limited to < 30% of calories to help prevent weight gain and hyperlipidemia. A moderate sodium restriction of three to four grams per day may help alleviate hypertension and edema. An intake of 1000 to 1500 mg calcium/day is recommended. Estrogen and vitamin D supplements should be considered if a patient is at high risk of developing osteoporosis. Serum magnesium and phosphorus concentrations should be monitored because cyclosporine causes wasting of these nutrients. Serum potassium levels can be elevated as a result of the effects of cyclosporine or tacrolimus, and diuretics affect the excretion of this electrolyte. Dietary restriction or supplementation of potassium may be required, depending upon the serum level. Finally, although there are no studies evaluating vitamin and mineral needs in the liver transplant patient, it is prudent to recommend a basic multivitamin/mineral supplement.

Although these dietary guidelines are important for long-term survival and well-being of transplant patients, many patients choose not to comply. Twenty-nine of 105 patients who received kidney transplants failed to comply with diet.72 Nutrition counseling should be provided by a Registered Dietitian so that individual dietary habits can be considered in developing a workable plan of action. The importance of nutrition should be supported by all members of the health care team. Repeated counseling sessions are usually necessary to achieve compliance.

Summary
Medical nutrition therapy is necessary and beneficial during all phases of liver transplantation. The Registered Dietitian plays an integral role as part of the transplant team by providing appropriate therapy. A pretransplant assessment identifies nutritional inadequacies, and a nutritional intervention plan can be implemented to improve nutritional health prior to transplantation. In the acute posttransplant phase, early nutrition support can aid the healing process and reduce complications such as infection. The long-term outcome of liver transplantation can be affected by nutrition-related complications of "overnutrition." Provision of optimal nutrition therapy during all phases of transplantation will lead to improved outcomes.