Paul B. Pencharz

Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome.

Background: Parenteral omega-3 fatty acids, such as Omegaven, may benefit patients with pediatric short bowel syndrome (SBS) who develop parenteral nutrition–associated liver disease (PNALD). Patients and Methods: Retrospective cohort describing the outcome of all 12 children with SBS and advanced PNALD who were treated with Omegaven (target omega-6 to omega-3 fatty acid ratio = 1:1 to 2:1). Results: The median age was 7.5 (range 3.6–46) months, and median parenteral nutrition duration before starting Omegaven was 28.4 (range 15.3–55.3) weeks. Median initial serum conjugated bilirubin was 137 (range 54–203) μmol/L (8.06 [3.18–11.94] mg/dL). Of the 12 patients, 9 had complete and sustained resolution of hyperbilirubinemia within a median of 24 (range 7–37) weeks, and all are no longer being considered for liver transplantation. Improvements in markers of hepatic inflammation as well as nutritional status also were noted in these patients. Three patients received a liver-intestine transplant while taking Omegaven. There were no complications attributable to Omegaven. Conclusions: Omegaven is associated with restoration of liver function in patients with SBS and advanced liver disease. Parenteral omega-3 fatty acids, such as Omegaven, have the potential to fundamentally alter the paradigm of neonatal SBS from one of early death or transplantation from liver failure to a more chronic disease. More children with SBS should achieve full enteral tolerance and those who do not have the capacity for intestinal adaptation should be able to survive and receive an intestinal graft when older.

Children, cancer, and nutrition—A dynamic triangle in review

The overall cure rate for cancer in childhood now exceeds 70% and is projected to reach 85% by the year 2010 in industrialized countries. Therefore, major attention is being placed on reducing the side effects of therapy. However, 85% of the worlds children live in developing countries, where access to adequate care often is limited and health status frequently is influenced adversely by prevalent infectious diseases and malnutrition. Despite several confounding factors (different definitions of nutritional status, the wide variety of measures used for its assessment, the selection biases by disease and stage, treatment protocols of variable dose intensity and efficacy, small sample sizes of the studies conducted in the last 20 years), it is accepted that the prevalence of malnutrition at diagnosis averages 50% in children with cancer in developing countries; whereas, in industrialized countries, it is related to the type of tumor and the extent of the disease, ranging from < 10% in patients with standard‐risk acute lymphoblastic leukemia to 50% in patients with advanced neuroblastoma. The importance of nutritional status in children with cancer is related to its possible influence on the course of the disease and survival. Some authors have described decreased tolerance of chemotherapy associated with altered metabolism of antineoplastic drugs, increased infection rates, and poor clinical outcome in malnourished children. In this article, the authors review methods of nutritional assessment and the pathogenesis of nutritional morbidity in children with cancer as well as correlations of nutritional status with diagnosis, treatment, and outcome. Cancer 2004;100:677–87.

Energy expenditure of patients with cystic fibrosis

Resting energy expenditure was measured by open-circuit indirect calorimetry in 71 patients, aged 8.9 to 35.5 years, with cystic fibrosis who had no recent history of acute lung infection. Pulmonary function and nutritional status were studied simultaneously. In most patients, resting energy expenditure was above normal (range 95% to 153% of predicted values for age, sex, and weight as derived from the Harris Benedict equations), and was negatively correlated with pulmonary function (P less than 0.01) and nutritional status (P less than 0.01) when expressed as a percentage of body fat. Pulmonary status was positively correlated with nutritional status (P less than 0.01). We conclude that resting energy expenditure in patients with cystic fibrosis exceeds normal values and that the increase correlates with a deterioration in lung function and nutritional status.

Effects of long-term nutritional rehabilitation on body composition and clinical status in malnourished children and adolescents with cystic fibrosis

Fourteen patients aged 4.9 to 21.5 years with cystic fibrosis and moderate to severe lung disease, malnutrition, or growth failure were given nocturnal supplemental feeding by gastrostomy tube. Mean follow-up was for 1.1 years (range 0.8 to 2.78 years). Patients were studied to observe the effect of nutritional support on body composition, growth, pulmonary function, and quality of life. A contemporary group of patients with CF was retrospectively pair matched to the study group. The supplemental feeding resulted in positive changes in body composition and in growth velocity. Weight, as a percentage of standard in the control group, declined by 3% over 1 year, whereas it increased by 2% in the treatment group (P less than 0.05). Pulmonary function, assessed as a percent of predicted FVC and FEV1, did not change significantly in the treatment group over 1.1 years, whereas FVC declined by 12% (P less than 0.01) and FEV1 declined by 13% (P less than 0.01) in the control group. There was a marked increase in patient ability to participate in activities of daily living, even in those patients in whom pulmonary function deteriorated during the study.

A cross-sectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home

We performed a cross-sectional evaluation of deep vein thrombosis (DVT) related to the use of central venous lines (CVLs) in all pediatric patients receiving home total parenteral nutrition at our institution (N = 12). All children (5 months to 17 years of age) were examined with bilateral upper limb venography. All CVLs were flushed daily with heparin (200 units). At the time of evaluation, 49 CVLs had been placed in the 12 children. Of the 39 CVLs removed, 27 (66%) were blocked; venograms had not been previously obtained except of one child. Eight children had clinical evidence of superficial collateral circulation in the upper portion of the chest and the upper extremities; five had intermittent symptoms of superior vena cava obstruction. On venography, 8 of the 12 children had extensive evidence of DVT; two were unilateral and six bilateral. Five children were treated with warfarin (0.12 to 0.28 mg/kg per day) to achieve an international normalized ratio of 1.4 to 1.8. Neither bleeding nor further CVL-related DVT has occurred. We conclude that the risk of CVL-related DVT in children requiring home total parenteral nutrition is high, and that venography should be performed early in the event of CVL blockage. A multicenter, controlled trial assessing optimal warfarin therapy in this patient population is indicated.

Skeletal Morbidity in Childhood Acute Lymphoblastic Leukemia

PURPOSE Treatment for acute lymphoblastic leukemia (ALL) in childhood results in a reduction in bone mineral density (BMD). Whether there is a recovery of this lost bone mass in survivors of ALL is not known. We sought to determine if changes in BMD are common long-term sequelae in children with ALL. METHODS Bone mineral densitometry of the lumbar spine and femoral neck was performed on 106 patients. The results were compared with those of age-matched normal controls. The effect of treatment was examined in those with low BMD compared with the remainder of the study group. RESULTS When data were tested with respect to age, sex, and age and sex, no difference was observed in BMD between survivors of childhood ALL and controls. In the subgroup of patients with low BMD, the difference was not related to age, age at diagnosis, or years since diagnosis. Low BMD of the spine was not explained by radiotherapy (RT), methotrexate (MTX) dose, or corticosteroid dose. Low BMD of the femur was not explained by RT. However, those with low femoral BMD were more likely to have received high-dose MTX or higher-dose corticosteroids compared with the remainder of the group. CONCLUSION It appears that survivors of childhood ALL as a whole recover normal BMD. However, those patients who received a total MTX dose of greater than 40000 mg/m(2) or a total corticosteroid dose of greater than 9000 mg/m(2) may not recover normal BMD and therefore should be screened for decreased BMD of the femoral neck.

Effect of television viewing at mealtime on food intake after a glucose preload in boys.

Television viewing (TVV) is considered a contributing factor to the development of childhood obesity yet it is unclear whether obesity results, in part, from increased energy intake during TVV. The objective of this study was to determine the effect of TVV on food intake (FI) of boys at a meal and its effect on caloric compensation at the test meal after a premeal glucose drink. On four separate mornings and in random order, boys received equally sweetened preloads containing Splenda sucralose or glucose [1.0 g/kg body weight (BW)] in 250 mL of water 2 h after a standard breakfast. Food intake from a pizza meal was measured 30 min later with or without TVV. Both preload treatment (p < 0.01) and TVV (p < 0.001) affected FI (kcal). TVV increased lunchtime FI by an average of 228 kcal. Glucose suppressed FI in the no TVV condition compared with control, but the effect was not statistically significant during TVV. Body composition and subjective appetite scores were positively associated with FI at the test lunch. In conclusion, TVV while eating a meal contributes to increased energy intake by delaying normal mealtime satiation and reducing satiety signals from previously consumed foods.

The cystic fibrosis gene and resting energy expenditure

To determine whether the increase in resting energy expenditure in cystic fibrosis is associated with the primary genetic defect (delta F508) or with declining pulmonary function, or both, we tested resting every energy expenditure prospectively in 32 male subjects (aged 7 to 39 years) who were normally nourished and had good pulmonary function. They were categorized into three genotype groups on the basis of the presence or absence of delta F508 and pancreatic function. Mean resting energy expenditure was 104% of the predicted value and was not associated with genotype. When 29 subjects with normal nutritional status but variable lung function were added to the group, there was a strong correlation between declining pulmonary function and increased resting energy expenditure. We conclude that increased resting energy expenditure in normally nourished boys and men with cystic fibrosis appears to be more closely associated with declining pulmonary function than with genotype.

Energy expenditure in chronic spinal cord injury.

Purpose of reviewObesity is a common secondary complication of chronic spinal cord injury and is associated with adverse metabolic sequelae. Because positive energy balance is the fundamental cause of obesity, we herein review the current knowledge pertaining to total daily energy expenditure, including resting metabolic rate, the thermic effect of food, and physical activity, in the spinal cord injury population. Recent findingsCommonly used equations to predict resting metabolic rate overestimate measured requirements in chronic spinal cord injury by 5-32%. Measured resting metabolic rate is 14-27% lower in persons with spinal cord injury versus those without, due to decreased fat-free mass and sympathetic nervous system activity in this population. However, preliminary evidence suggests that neither the metabolic activity of the fat-free body, nor the obligatory phase of the thermic effect of food is different between those with and without injury. Physical activity levels, especially in those with tetraplegia and complete lesions, are lower than recommended or lower than those of able-bodied persons. SummaryNew equations to predict resting metabolic rate should be validated and prospectively tested in a large sample of men and women with complete and incomplete paraplegia and tetraplegia. Whether the facultative phase of the thermic effect of food is different between those with and without SCI remains to be elucidated. Persons with chronic spinal cord injury, and perhaps those with tetraplegia and complete lesions especially, should be encouraged to engage in increased frequency, intensity and/or duration of physical activity. Future research efforts should explore the effects of level and completeness of neurological lesion on resting metabolic rate, thermic effect of food, and physical activity.

Identification of EpCAM as the Gene for Congenital Tufting Enteropathy

BACKGROUND & AIMS Congenital tufting enteropathy (CTE) is a rare autosomal recessive diarrheal disorder presenting in the neonatal period. CTE is characterized by intestinal epithelial cell dysplasia leading to severe malabsorption and significant morbidity and mortality. The pathogenesis and genetics of this disorder are not well understood. The objective of this study was to identify the gene responsible for CTE. METHODS A family with 2 children affected with CTE was identified. The affected children are double second cousins providing significant statistical power for linkage. Using Affymetrix 50K single nucleotide polymorphism (SNP) chips, genotyping was performed on only 2 patients and 1 unaffected sibling. Direct DNA sequencing of candidate genes, reverse-transcription polymerase chain reaction, immunohistochemistry, and Western blotting were performed on specimens from patients and controls. RESULTS SNP homozygosity mapping identified a unique 6.5-Mbp haplotype of homozygous SNPs on chromosome 2p21 where approximately 40 genes are located. Direct sequencing of genes in this region revealed homozygous G>A substitution at the donor splice site of exon 4 in epithelial cell adhesion molecule (EpCAM) of affected patients. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 in affected patients. Immunohistochemistry and Western blot of patient intestinal tissue revealed decreased expression of EpCAM. Direct sequencing of EpCAM from 2 additional unrelated patients revealed novel mutations in the gene. CONCLUSIONS Mutations in the gene for EpCAM are responsible for CTE. This information will be used to gain further insight into the molecular mechanisms of this disease.