The role of basic nutritional research in pediatric liver disease : an historical perspective

The advent of liver transplantation for end-stage liver disease (ESLD) in children has necessitated a major rethink in the preoperative preparation and management from simple palliative care to active directed intervention. This is particularly evident in the approach to the nutritional care of these patients with the historical understanding of the nutritional pertubations in ESLD being described from a single pediatric liver transplant center. ESLD in children is a hypermetabolic process adversely affecting nutritional status, metabolic, and non-metabolic body compartments. There is a complex dynamic process affecting metabolic activity within the metabolically active body cell mass, as well as lipid oxidation during fasting and at rest, with other factors operating in conjunction with daily activities. We have proposed that immediately ingested nutrients are a more important source of energy in patients with ESLD than in healthy children, among whom energy may be stored in various body compartments.

Body composition and components of energy expenditure in children with end-stage liver disease

Background: Better understanding of body composition and energy metabolism in pediatric liver disease may provide a scientific basis for improved medical therapy aimed at achieving optimal nutrition, slowing progression to end-stage liver disease (ESLD), and improving the outcome of liver transplantation. Methods: Twenty-one children less than 2 years of age with ESLD awaiting liver transplantation and 15 healthy, aged-matched controls had body compartment analysis using a four compartment model (body cell mass, fat mass, extracellular water, and extracellular solids). Subjects also had measurements of resting energy expenditure (REE) and respiratory quotient (RQ) by indirect calorimetry. Nine patients and 15 control subjects also had measurements of total energy expenditure (TEE) using doubly labelled water. Results: Mean weights and heights were similar in the two groups. Compared with control subjects, children with ESLD had higher relative mean body cell mass (33 ± 2% vs 29 ± 1% of body weight, P < 0.05), but had similar fat mass, extracellular water, and extracellular solid compartments (18% vs 20%, 41% vs 38%, and 7% vs 13% of body weight respectively). Compared with control subjects, children with ESLD had 27% higher mean REE/body weight (0.285 ± 0.013 vs 0.218. ± 0.013 mJ/kg/24h, P < 0.001), 16% higher REE/unit cell mass (P < 0.05); and lower mean RQ (P < 0.05). Mean TEE of patients was 4.70 ± 0.49 mJ/24h vs 3.19 ± 0.76 in controls, (P < 0.01). Conclusions: In children, ESLD is a hypermetabolic state adversely affecting the relationship between metabolic and non-metabolic body compartments. There is increased metabolic activity within the body cell mass with excess lipid oxidation during fasting and at rest. These findings have implications for the design of appropriate nutritional therapy.

Acute liver failure in children : a regional experience

Objective: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia. Methodology: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia. Results: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function. Conclusions: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.

Value of total body potassium in assessing the nutritional status of children with end-stage liver disease

Malnutrition is a common problem in children with end-stage liver disease (ESLD), and accurate assessment of nutritional status is essential in managing these children. In a retrospective study, we compared nutritional assessment by anthropometry with that by body composition. We analyzed all consecutive measurements of total body potassium (TBK, n = 186) of children less than 3 years old with ESLD awaiting transplantation found in our database. The TBK values obtained by whole body counting of 40K were compared with reference TRK values of healthy children. The prevalence of malnutrition, as assessed by weight (weight Z score < -2) was 28%, which was significantly lower (chi-square test, p < 0.0001) than the prevalence of malnutrition (76%) assessed by TBK (< 90% of expected TRK for age). These results demonstrated that body weight underestimated the nutritional deficit and stressed the importance of measuring body composition as part of assessing nutritional status of children with ESLD.

Growth hormone resistance and somatomedins in children with end-stage liver disease awaiting transplantation

Background: The success of orthotopic liver transplantation as treatment for end-stage liver disease has prompted investigation of strategies to maintain or improve nutrition and growth in children awaiting transplantation, because malnutrition is an adverse prognostic factor. The purpose of this study was to evaluate the effect of recombinant human growth hormone therapy on body composition and indices of liver function in patients awaiting transplant. Methods: The study was designed as a placebo- controlled, double-blind, crossover trial. Patients received 0.2 U/kg growth hormone, subcutaneously, or placebo daily for 28 days during two treatment periods, separated by a 2-week washout period. Ten patients (mean age, 3.06 ± 1.15 years; range, 0.51-11.65 years, five men), with extrahepatic biliary atresia (n = 8) or two with Alagille's syndrome (n = 2), with end-stage liver disease, completed the trial while awaiting orthotopic liver transplantation. Height, weight, total body potassium, total body fat, resting energy expenditure, respiratory quotient, hematologic and multiple biochemical profile, number of albumin infusions, insulin-like growth factor-1 and 1, growth hormone binding protein (GHBP), and insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein (IGFBP-3) were measured at the beginning and end of each treatment period. Results: Growth hormone treatment was associated with a significant decline in serum bilirubin (-34.6 ± 16.5 μmol/l vs. 18.2 ± 11.59 μmol/l; p < 0.02) but there was no significant effect on any anthropometric or body composition measurements, or on any biochemical or hematologic parameters. Conclusions: These children with end-stage liver disease displayed growth hormone resistance, particularly in relation to the somatomedin axis. Exogenous growth hormone administration may be of limited value in these patients

Cytomegalovirus infection after liver transplantation in children

Post-liver transplant cytomegalovirus (CMV) infection (seroconversion or virus isolation) and CMV disease (infection plus clinical signs and symptoms) were studied in relation to pretransplant recipient and donor serology, age, nutritional status and the effect of paediatric versus adult (reduced size) grafts. Of 70 children receiving 79 transplants, 26 (37%) had evidence of CMV infection, and eight (11.5%) had evidence of CMV disease, four of whom died. The primary infection rate (where the recipients were CMV negative) was 71% with mortality of 7% with most receiving a CMV-positive graft. The active secondary infection rate (reactivation or reinfection, where the recipients were CMV positive) was 60% with mortality of 12.5%. No significant differences in infection on disease rates were found comparing malnourished versus well-nourished patients, or between those who received whole or reduced-size grafts. The high prevalence of CMV infections supports the view that clinical signs alone are inadequate to direct investigations for CMV. Both primary and active secondary CMV infection can result in serious morbidity and mortality in children receiving liver transplants. These data do not support the strategy of providing immunoprophylaxis to seronegative recipients only, at least in paediatric liver transplantation.

Nutritional support in children with end-stage liver disease : a randomized crossover trial of a branched-chain amino acid supplement

Malnutrition is common in children with end-stage liver disease (ESLD) awaiting orthotopic liver transplantation (OLT), and nutritional support is assuming an important role in preoperative management. To evaluate preoperative nutritional therapy, 19 children (median age 1.25 y) with ESLD awaiting OLT were prospectively studied. Two high-energy, isoenergetic and isonitrogenous nutritional formulations delivered nasogastrically were compared: a branched-chain amino acid (BCAA)-enriched semielemental formulation and a matched standard semielemental formulation. Twelve of 19 patients completed a randomized controlled study before OLT and 10 of 19 completed a full crossover study. Improvements in weight and height occurred during the BCAA supplements, with no statistical change on the standard formulation. Significant increases in total body potassium, midupper arm circumference, and subscapular skinfold thickness occurred during the BCAA supplements, whereas no significant changes occurred during the standard formulation period. Significantly fewer albumin infusions were required during the BCAA supplement. These findings suggest that BCAA-enriched formulas have advantages over standard semielemental formulas in improving nutritional status in children with ESLD. and are deserving of wider application and study.

The nature of malnutrition in children with end-stage liver disease awaiting orthotopic liver transplantation

To evaluate malnutrition in chronic liver disease, and its relationship to nutrient deficiencies and hepatic dysfunction. 27 children with end-stage liver disease were studied. Mean protein-energy intakes were 70% of recommended daily intakes. The patients were underweight and stunted with reduced mean triceps and subscapular skinfold thicknesses and midupper arm circumference. Mean total body potassium was only 63 ± 18% of that expected for age and sex. Deficiency of essential fatty acids (32%), and low concentrations of fat-soluble vitamins (A, 92%; E, 32%), iron (32%), zinc (42%), and selenium (13%) were common. Serum ammonia concentrations were raised in all patients, and increased methionine, tyrosine, and glutamic acid, and reduced glutamine concentrations were noted. There was no correlation between the degree of malnutrition and the degree of liver synthetic function, the degree of cholestasis, or the degree of liver injury. We suggest that potentially correctable factors in addition to liver failure (eg, inadequate absorbed intake) were important determinants of malnutrition in these patients.

Malnutrition in children with chronic liver disease accepted for liver transplantation : clinical profile and effect on outcome

The nutritional profiles of 37 children (aged 0.5-14.0 years) with chronic liver disease at the time of acceptance for orthotopic liver transplantation (OLTP) have been evaluated using clinical, biochemical and body composition methods. Nutritional progress while waiting for a donor has been related to outcome, whether transplanted or not. At the time of acceptance, most children were underweight (mean standard deviation (s.d.) weight = -1.4 ± 0.2) and stunted (mean s.d. height = - 2.2 ± 0.4), had low serum albumin (27/35) and had reduced body fat and depleted body cell mass (measured by total body potassium - mean % expected for age = 58 ± 5%, n = 15). Mean ad libitum nutrient intake was 63 ± 5% of recommended daily intake (RDI). Those who died while waiting (n = 8) had significantly lower mean initial s.d. weight compared with those transplanted. The overall actuarial 1 year survival of those who were transplanted (mean waiting time = 75 days) was 81% but those who were initially well nourished (s.d. weight >-1.0) had an actuarial 1 year survival of 100%. There were no significant differences in actuarial survival in relationship to age, type of transplant (whole liver or segmental), liver biochemistry or the presence or absence of ascites. Of the total group accepted for OLTP, whether transplanted or not, the overall 1 year survival for those who were relatively well nourished was 88% and for those undernourished (initial s.d. weight <-1.0) was 38% (P<0.003). Declining nutritional status during the waiting period also adversely affected outcome. We conclude that malnutrition and/or declining nutritional status is a major factor adversely affecting survival in children awaiting OLTP. In transplant units where waiting time is greater than 40 days, earlier referral, prioritization of cases and the use of adult donor livers may reduce this risk and efforts to maintain or improve nutritional status deserve further study.

Survival, growth and quality of life in children after orthotopic liver transplantation: A 5 year experience

The aims of this study were to investigate outcome and to evaluate areas of potential ongoing concern after orthotopic liver transplantation (OLT) in children. Actuarial survival in relation to age and degree of undernutrition at the time of OLT was evaluated in 53 children (age 0.58-14.2 years) undergoing OLT for endstage liver disease. Follow-up studies of growth and quality of life were undertaken in those with a minimum follow-up period of 12 months (n = 26). The overall 3 year actuarial survival was 70%. Survival rates did not differ between age groups (actuarial 2 year survival for ages <1, 1-5 and >5 years were 70, 70 and 69% respectively) but did differ according to nutritional status at OLT (actuarial 2 year survival for children with Z scores for weight <-1 was 57%, >-1 was 95%; P = 0.004). Significant catch-up weight gain was observed by 18 months post-transplant, while height improved less rapidly. Quality of life (assessed by Vineland Adaptive Behaviour Scales incorporating socialization, daily living skills, communication and motor skills) was good (mean composite score 91 ± 19). All school-aged children except one were attending normal school. Two children had mild to moderate intellectual handicap related to post-operative intracerebral complications. Satisfactory long-term survival can be achieved after OLT in children regardless of age but the importance of pre-operative nutrition is emphasized. Survivors have an excellent chance of a good quality of life and of satisfactory catch-up weight gain and growth.

Pre-operative nutritional support in children with end-stage liver disease accepted for liver transplantation: An approach to management

Pre-operative nutritional support was studied in 28 children with end-stage liver disease awaiting orthotopic liver transplantation. Nasogastric supplemental administration of a standard semi-elemental enteral nutritional formula was compared with a similar formula enriched with branched chain amino acids, and with a group receiving oral nutrition only. The duration of treatment in all groups was similar (mean 90 days). Energy intakes in the supplemented groups were 120-150% of recommended daily intakes (RDI), whereas ad libitum intakes in the oral group ranged 58-100% RDI. A significant improvement in mean Z-score for body weight (denoting catch-up) was noted only in those children who received nasogastric supplements enriched with branched-chain amino acids. The standard enterally-fed group maintained their body weight and Z-scores did not change significantly. In contrast, body weight Z-scores in those fed orally declined significantly. Nutritional supportive therapy of malnourished children with end-stage liver disease can minimize or improve nutritional status in children awaiting liver transplantation. The use of nutritional formulae rich in branche-chain amino acids may have nutritional advantages in children with chronic liver disease which require further study and evaluation.