Patients with liver diseases, especially decompensated cirrhosis, commonly have weight loss and muscle wasting. It is known that such patients have poorer clinical outcomes than patients with similar diagnoses but without such weight loss or muscle wasting. If the problem is just deprivation of nutrients, it would be expected that the provision of some type of nutrition should result in better outcomes. Nutrients in addition to food, or in place of food when food is not taken in sufficient amounts, can be provided in a manner whereby the patient voluntarily consumes them by drinking various nutrient formulations. Nutrients can also be provided in an involuntary manner; tubes can be placed in the vein (parenteral nutrition) or intestinal tract (enteral nutrition) and nutrient solutions infused through them. All of these nutritional interventions have associated economic costs and also can produce a variety of complications (including vomiting, diarrhoea, and altered metabolic functions (for example, high blood sugar)). Thus, it is important to determine if such nutritional interventions (that is, the provision of nutrients in some manner other than just as food) do result in improvements in clinical outcomes. Since the best way to make such a determination is to undertake randomised trials, in which patients are assigned by chance to receive, or not receive, one or another of these treatments, this systematic review was undertaken to identify and summarise this information. Randomised trials comparing patients with liver diseases who were assigned to receive parenteral nutrition, enteral nutrition, or oral nutritional supplements to similar patients assigned not to receive any nutritional intervention were collected. The three nutritional interventions were considered separately. In addition, within each category of nutritional intervention, patients with medical conditions were compared separately from patients with surgical conditions. Thus there were six primary analyses, medical patients receiving or not receiving parenteral nutrition, surgical patients receiving or not receiving parenteral nutrition, medical patients receiving or not receiving enteral nutrition, surgical patients receiving or not receiving enteral nutrition, medical patients receiving or not receiving supplements by mouth, and surgical patients receiving or not receiving supplements by mouth. The outcomes of interest were mortality, hepatic morbidity (ascites, gastrointestinal bleeding, encephalopathy), quality of life, adverse events, infections, cost, duration of hospitalisation, jaundice, postoperative complications (only for the surgical trials), and nutritional outcomes (for example, body weight). A total of 37 randomised trials were identified. All but one had a high risk of systematic error (bias, that is overestimation of benefits and underestimation of harms). When the data were combined, most of the analyses failed to demonstrate a difference. There were some significant differences observed. These were that 1) parenteral nutrition reduced serum bilirubin more rapidly and improved one type of nutritional outcome (nitrogen balance) in medical patients with jaundice, and may have reduced some postoperative complications; 2) enteral nutrition may have improved nitrogen balance in medical patients, and reduced postoperative complications in surgical patients; and 3) supplements reduced the occurrence of ascites and also may have decreased the number of infections. Furthermore, the receipt of supplements (especially ones containing branched-chain amino acids) may have been helpful in the treatment of patients with hepatic encephalopathy. No significant effects were seen from the use of supplements in surgical patients. None of these observed benefits can be said to be definitively present because of the presence of methodologic flaws in the trials, which may have produced an overestimation of the observed effect. Moreover, due to too few patients included in the trials with two few outcome measures, both spurious significant findings and spurious insignificant findings cannot be excluded. The data are not strong enough to justify a recommendation to use these nutritional interventions routinely. We need well-designed and well-conducted randomised trials to prove that such therapy is indeed efficacious.
The data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. The fact that all but one of these trials were at high risks of bias even casts doubt on the few benefits that were demonstrated. Data from well-designed and executed randomised trials that include an untreated control group are needed before any such recommendation can be made. Future trials have to be powered adequately to see small, but clinically important, differences.
Weight loss and muscle wasting are commonly found in patients with end-stage liver disease. Since there is an association between malnutrition and poor clinical outcome, such patients (or those at risk of becoming malnourished) are often given parenteral nutrition, enteral nutrition, or oral nutritional supplements. These interventions have costs and adverse effects, so it is important to prove that their use results in improved morbidity or mortality, or both.
To assess the beneficial and harmful effects of parenteral nutrition, enteral nutrition, and oral nutritional supplements on the mortality and morbidity of patients with underlying liver disease.
The following computerised databases were searched: the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, and Science Citation Index Expanded (January 2012). In addition, reference lists of identified trials and review articles and Clinicaltrials.gov were searched. Trials identified in a previous systematic handsearch of Index Medicus were also considered. Handsearches of a number of medical journals, including abstracts from annual meetings, were done. Experts in the field and manufacturers of nutrient formulations were contacted for potential references.
Randomised clinical trials (parallel or cross-over design) comparing groups of patients with any underlying liver disease who received, or did not receive, enteral or parenteral nutrition or oral nutritional supplements were identified without restriction on date, language, or publication status. Six categories of trials were separately considered: medical or surgical patients receiving parenteral nutrition, enteral nutrition, or supplements.
The following data were sought in each report: date of publication; geographical location; inclusion and exclusion criteria; the type of nutritional support and constitution of the nutrient formulation; duration of treatment; any nutrition provided to the controls; other interventions provided to the patients; number, sex, age of the study participants; hospital or outpatient status; underlying liver disease; risks of bias (sequence generation, allocation concealment, blinding, incomplete outcome reporting, intention-to-treat analysis, selective outcome reporting, others (vested interests, baseline imbalance, early stopping)); mortality; hepatic morbidity (development or resolution of ascites or hepatic encephalopathy, occurrence of gastrointestinal bleeding); quality of life scores; adverse events; infections; lengths of stay in the hospital or intensive care unit; costs; serum bilirubin; postoperative complications (surgical trials only); and nutritional outcomes (nitrogen balance, anthropometric measurements, body weight). The primary outcomes of this review were mortality, hepatic morbidity, quality of life, and adverse events. Data were extracted in duplicate; differences were resolved by consensus.
Data for each outcome were combined in a meta-analysis (RevMan 5.1). Estimates were reported using risk ratios or mean differences, along with the 95% confidence intervals (CI). Both fixed-effect and random-effects models were employed; fixed-effect models were reported unless one model, but not the other, found a significant difference (in which case both were reported). Heterogeneity was assessed by the Chi2 test and I2 statistic. Subgroup analyses were planned to assess specific liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma), acute or chronic liver diseases, and trials employing standard or branched-chain amino acid formulations (for the hepatic encephalopathy outcomes). Sensitivity analyses were planned to compare trials at low and high risk of bias and trials reported as full papers. The following exploratory analyses were undertaken: 1) medical and surgical trials were combined for each nutritional intervention; 2) intention-to-treat analyses in which missing dichotomous data were imputed as best- and worst-case scenarios; 3) all trials were combined to assess mortality; 4) effects were estimated by absolute risk reductions.
Thirty-seven trials were identified; only one was at low risk of bias. Most of the analyses failed to find any significant differences. The significant findings that were found were the following: 1) icteric medical patients receiving parenteral nutrition had a reduced serum bilirubin (mean difference (MD) -2.86 mg%, 95% CI -3.82 mg% to -1.89 mg%, 3 trials) and better nitrogen balance (MD 3.60 g/day, 95% CI 0.86 g/day to 6.34 g/day, 1 trial); 2) surgical patients receiving parenteral nutrition had a reduced incidence of postoperative ascites only in the fixed-effect model (RR 0.65, 95% CI 0.48 to 0.87, 2 trials, I2 = 70%) and one trial demonstrated a reduction in postoperative complications, especially infections (pneumonia in particular); 3) enteral nutrition may have improved nitrogen balance in medical patients (although a combination of the three trials was not possible); 4) one surgical trial of enteral nutrition found a reduction in postoperative complications; and 5) oral nutritional supplements had several effects in medical patients (reduced occurrence of ascites (RR 0.57, 95% CI 0.37 to 0.88, 3 trials), possibly (significant differences only seen in the fixed-effect model) reduced rates of infection (RR 0.49, 95% CI 0.24 to 0.99, 3 trials, I2 = 14%), and improved resolution of hepatic encephalopathy (RR 3.75, 95% CI 1.15 to 12.18, 2 trials, I2 = 79%). While there was no overall effect of the supplements on mortality in medical patients, the one low risk of bias trial found an increased risk of death in the recipients of the supplements. Three trials of supplements in surgical patients failed to show any significant differences. No new information was derived from the various subgroup or sensitivity analyses. The exploratory analyses were also unrevealing except for a logical conundrum. There was no difference in mortality when all of the trials were combined, but the trials of parenteral nutrition found that those recipients had better survival (RR 0.53, 95% CI 0.29 to 0.98, 10 trials). Either the former observation represents a type II error or the latter one a type I error.