Paediatric intestinal failure and transplantation.

Intestinal failure is a complex and debilitating condition characterised by inadequate small intestinal function requiring parenteral or intravenous nutrition to maintain health and, for children, to enable growth and development. Although parenteral nutrition can be prescribed in many hospitals, children with chronic intestinal failure have improved outcomes when managed at a paediatric centre by a multidisciplinary team with specialised expertise in the comprehensive management of intestinal failure. Recent advances in the medical, surgical and nutritional approach have been effective at optimising intestinal rehabilitation and achieving enteral autonomy while limiting complications of intestinal failure. The role of intestinal transplantation in the management of the child with intestinal failure continues to evolve as an option for children with life-threatening complications of intestinal failure. The aim of this review is to highlight key advances in the care of children with intestinal failure.

Pre-school neurocognitive and functional outcomes after liver transplant in children with early onset urea cycle disorders, maple syrup urine disease, and propionic acidemia: An inception cohort matched-comparison study.

BACKGROUND: Urea cycle disorders (UCD) and organic acid disorders classically present in the neonatal period. In those who survive, developmental delay is common with continued risk of regression. Liver transplantation improves the biochemical abnormality and patient survival is good. We report the neurocognitive and functional outcomes post-transplant for nine UCD, three maple syrup urine disease, and one propionic acidemia patient. METHODS: Thirteen inborn errors of metabolism (IEM) patients were individually one-to-two matched to 26 non-IEM patients. All patients received liver transplant. Wilcoxon rank sum test was used to compare full-scale intelligence-quotient (FSIQ) and Adaptive Behavior Assessment System-II General Adaptive Composite (GAC) at age 4.5 years. Dichotomous outcomes were reported as percentages. RESULTS: FSIQ and GAC median [IQR] was 75 [54, 82.5] and 62.0 [47.5, 83] in IEM compared with 94.5 [79.8, 103.5] and 88.0 [74.3, 97.5] in matched patients (P-value <.001), respectively. Of IEM patients, 6 (46%) had intellectual disability (FSIQ and GAC <70), 5 (39%) had autism spectrum disorder, and 1/13 (8%) had cerebral palsy, compared to 1/26 (4%), 0, 0, and 0% of matched patients, respectively. In the subgroup of nine with UCDs, FSIQ (64[54, 79]), and GAC (56[45, 75]) were lower than matched patients (100.5 [98.5, 101] and 95 [86.5, 99.5]), P = .005 and .003, respectively. CONCLUSION: This study evaluated FSIQ and GAC at age 4.5 years through a case-comparison between IEM and matched non-IEM patients post-liver transplantation. The neurocognitive and functional outcomes remained poor in IEM patients, particularly in UCD. This information should be included when counselling parents regarding post-transplant outcome.

Deficits in Muscle Strength and Physical Performance Influence Physical Activity in Sarcopenic Children After Liver Transplantation.

Sarcopenia is a muscle disease characterized by reduced skeletal muscle mass (SMM), muscle strength, and physical performance. Reduced SMM has been identified in children after liver transplantation (LT), but no information related to muscle strength/physical performance or lifestyle factors contributing to sarcopenia is available. We hypothesized that sarcopenia, as determined by measures of SMM, muscle strength, and physical performance, is highly prevalent in children after LT and is related to poor diet quality (DQ) and physical inactivity. A cross-sectional study in post-LT children (n = 22) and age-matched healthy controls (n = 47) between the ages of 6 and 18 years examining body composition (dual energy X-ray absorptiometry and multiple skinfold), measures of muscle strength (handgrip, sit-to-stand, and push-ups), physical performance (6-minute walk test and stair climb test), diet (3-day food intake), and physical activity (accelerometer) was conducted. Low muscle strength/physical performance and SMM (SMM z scores ≤-1.5) were defined by values 2 standard deviations below the mean values for age- and sex-matched controls. Sarcopenia occurred in 36% of children who underwent LT, and they had significantly lower scores for muscle strength (sit-to-stand and push-up tests) and physical performance (stair climb test) than controls (P < 0.05). Deficits in physical performance in children with sarcopenia were predominantly revealed by longer stair climbing times (P = 0.03), with no differences in other muscle tests. Low SMM, muscle strength, and physical performance were associated with a lower amount of time spent in fairly and very active physical activity, but no associations with DQ were found. Sarcopenia is highly prevalent in children after LT and is related to lower moderate-to-vigorous physical activity. Development of effective rehabilitation strategies to treat sarcopenia are needed in post-LT children.

Kindergarten-age neurocognitive, functional, and quality-of-life outcomes after liver transplantation at under 6 years of age.

BACKGROUND: We aimed to describe school-entry age neurocognitive, functional, and HRQL outcomes and their predictors after liver transplant done at age <6 years. METHODS: A prospective cohort of all (n = 69) children surviving liver transplant from 1999 to 2014 were assessed at age 55.4 (SD 7.2) months and 38.6 (12.4) months after transplant. Assessment included: the Wechsler Preschool and Primary Scales of Intelligence, Beery-Buktenica Developmental Test of VMI, Adaptive Behavior Assessment System caregiver-completed questionnaire, and PedsQL 4.0 Generic Core Scales. Univariate and multiple linear regression determined predictors of outcomes at P < .05. RESULTS: Neurocognitive and functional outcomes were on average within 1 SD of population norms, although shifted to the left (P ≤ .03), with more patients than expected having scores >2 (3.7-5.9 times more, P ≤ .007) SD below population norms. Total and Summary HRQL scores were statistically significantly lower than the healthy normative population (P ≤ .02) and a congenital heart disease group (P ≤ .02), but similar to children with other chronic health conditions; differences often exceeded the MCID and were lowest in the School functioning domain. There were few predictors on multiple linear regressions, and we could not confirm previous studies that suggested various inconsistent predictors of outcomes. Neurocognitive and functional outcomes scores were highly correlated with HRQL scores except for the School functioning domain, but did not fully explain them. CONCLUSIONS: Long-term follow-up of this vulnerable population is important in order to facilitate support for the patient and family, and early intervention for any difficulties identified.

Persistence of Sarcopenia After Pediatric Liver Transplantation Is Associated With Poorer Growth and Recurrent Hospital Admissions.

INTRODUCTION: Sarcopenia is prevalent in adults pre-liver transplantation (LTx) and post-LTx contributing to adverse outcomes. Little is known regarding the prevalence of sarcopenia in pediatric LTx recipients. This novel study examined sarcopenia prevalence and associations with post-LTx growth and healthcare utilization in pediatric LTx recipients. METHODS: We prospectively assessed body composition at annual clinical appointments in children (0.5-17 years; n = 58) by Dual-energy-X-ray absorptiometry (absolute/regional/percent fat mass [FM], fat-free mass [FFM], skeletal muscle mass [SMM]). Sarcopenia was defined as SMM z scores ≤2. Additional variables measured included age, gender, PELD, immunosuppressive therapies (dose/type), weight, weight-z, height, height-z, serum aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, albumin, total/conjugated bilirubin, prothrombin time, international normalized ratio, albumin, creatinine clearance, urea and creatinine at LTx assessment, LTx and annual clinic appointments. Healthcare variables studied included rejection (number/type/severity), length of in-patient stay (total, intensive care unit [ICU], emergency, readmission) and ventilator dependency. RESULTS: Sarcopenia occurred in 41% (n = 17) at 7.6 (± 3.1) years; with a mean time post-LTx of 1.1 ± 1.9 (1-8) years. Female children ≤9.8 years had a higher sarcopenia prevalence than children >9.8 years (83.1% vs 17.1%; p = 0.004). Sarcopenia was associated with lower weight velocity standard deviation scores, lower weight-z/height-z scores at 2-10 years post LTx, increased hospitalization (total, ICU, emergency and readmission) and ventilator dependency (p < 0.05), but not to rejection and/or corticosteroid therapy (p > 0.05). CONCLUSIONS: This is the first study demonstrating persistent sarcopenia associated with poorer growth and recurrent hospitalization in children post-LTx.

Prediction of esophageal and gastric histology by macroscopic diagnosis during upper endoscopy in pediatric celiac disease.

AIM: To determine the sensitivity of macroscopic appearance for predicting histological diagnosis at sites other than duodenum in pediatric celiac disease (CD). METHODS: Endoscopic and histologic findings in pediatric patients undergoing upper endoscopy for first-time diagnosis of CD at Stollery Children's Hospital from 2010-2012 were retrospectively reviewed. RESULTS: Clinical charts from 140 patients were reviewed. Esophageal and gastric biopsies were taken in 54.3% and 77.9% of patients, respectively. Endoscopic appearance was normal in the esophagus and stomach in 75% and 86.2%. Endoscopic esophageal diagnoses were eosinophilic esophagitis (EE) (11.8%), esophagitis (7.9%), glycogenic acanthosis (1.3%) and non-specific abnormalities (3.9%). Endoscopic gastric diagnoses were gastritis (8.3%), pancreatic rest (0.9%), and non-specific abnormalities (4.6%). Histology was normal in 76.3% of esophageal and 87.2% of gastric specimens. Abnormal esophageal histology was EE (10.5%), esophagitis (10.5%), glycogenic acanthosis (1.3%) and non-specific (1.3%). Gastritis was reported in 12.8% of specimens. Sensitivity and specificity of normal endoscopy for predicting normal esophageal histology was 86.2% and 61.1%, and for normal gastric histology was 87.4% and 21.4%. CONCLUSION: In the absence of macroscopic abnormalities, routine esophageal and gastric biopsy during endoscopy for pediatric CD does not identify major pathologies. These findings have cost and time saving implications for clinical practice.

Glucagon-Like Peptide-2 Alters Bile Acid Metabolism in Parenteral Nutrition--Associated Liver Disease.

BACKGROUND: We aim to study the mechanisms underlying our previous finding that exogenous glucagon-like peptide-2 (GLP-2) treatment in a preclinical model of neonatal parenteral nutrition-associated liver disease (PNALD) improves cholestasis. METHODS: Neonatal piglets received 17 days of parenteral nutrition (PN) therapy and either saline control (PN/Saline n = 8) or GLP-2 treatment at 11 nmol/kg/d (PN/GLP-2, n = 7). At terminal laparotomy, bile and liver samples were collected. The relative gene expression of enzymes involved in bile acid synthesis, regulation, and transport was measured in liver by reverse-transcriptase quantitative polymerase chain reaction. Bile acid composition in bile was determined using tandem mass spectrometry. Data were analyzed using 1-way analysis of variance (ANOVA) or Kruskal-Wallis ANOVA. RESULTS: GLP-2 increased the expression of bile acid export genes: multidrug resistance-associated proteins 2 (MRP2) (P = .002) and 3 (MRP3) (P = .037) over saline control. GLP-2 increased expression of Farnesoid X receptor (FXR) (P < .001) and CYP7A1 (cytochrome P450, family 7, subfamily A, polypeptide 1) (P = .03). GLP-2 treatment was associated with decreased concentrations of taurohyocholic acid and conjugates of toxic lithocholic acid (P < .01). GLP-2 treatment increased the liver bile acid content. CONCLUSIONS: GLP-2 treatment was associated with alterations in the hepatic expression of genes involved in bile acid metabolism. The transcriptomic results indicate the mechanisms at the transcriptional level acting to regulate bile acid synthesis and increase bile acid export. Differences in bile acid profiles further support a beneficial role for GLP-2 therapy in PNALD.

Neurocognitive outcomes at kindergarten entry after liver transplantation at <3 yr of age.

This prospective inception cohort study determines kindergarten-entry neurocognitive abilities and explores their predictors following liver transplantation at age <3 yr. Of 52 children transplanted (1999-2008), 33 (89.2%) of 37 eligible survivors had psychological assessment at age 54.7 (8.4) months: 21 with biliary atresia, seven chronic cholestasis, and five acute liver failure. Neurocognitive scores (mean [s.d.], 100 [15]) as tested by a pediatric-experienced psychologist did not differ in relation to age group at transplant (≤12 months and >12 months): FSIQ, 93.9 (17.1); verbal (VIQ), 95.3 (16.5); performance (PIQ), 94.3 (18.1); and VMI, 90.5 (15.9), with >70% having scores ≥85, average or above. Adverse predictors from the pretransplant, transplant, and post-transplant (30 days) periods using univariate linear regressions for FSIQ were post-transplant use of inotropes, p = 0.029; longer transplant warm ischemia time, p = 0.035; and post-transplant highest serum creatinine, (p = 0.04). For PIQ, they were pretransplant encephalopathy, p = 0.027; post-transplant highest serum creatinine, p = 0.034; and post-transplant inotrope use, p = 0.037. For VMI, they were number of post-transplant infections, p = 0.019; post-transplant highest serum creatinine, p = 0.025; and lower family socioeconomic index, p = 0.039. Changes in care addressing modifiable predictors, including reducing acute post-transplant illness, pretransplant encephalopathy, transplant warm ischemia times, and preserving renal function, may improve neurocognitive outcomes.

Diagnostic challenges of nonalcoholic fatty liver disease (NAFLD) in children of normal weight.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is generally regarded as affecting the overweight or obese. Though previously reported, the notion that NAFLD occurs in the presence of normal body weight (adult BMI<25) is unfamiliar in adults and problematic in children. Normal-body-weight NAFLD accounts for approximately 15% of all NAFLD and may be more prevalent with certain ethnicities. CASE: We describe a case of a child who appeared to have normal-body-weight NAFLD, on the basis of typical age of presentation, ultrasonographically evident hepatic steatosis and compatible liver histology, including a NAFLD activity score of 7, but was shown conclusively to have cystic fibrosis. Further we present a clinical strategy for diagnosis of childhood NAFLD, which would discriminate between this patient and actual normal-body-weight NAFLD children in our clinical practice. CONCLUSION: NAFLD requires affirmative diagnostic criteria and should not be merely a diagnosis of exclusion.