Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children : An International Observational Study

Background and Aims Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. Approach and Results We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). Conclusions The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.Peer reviewe

Aging of the innate immune response in Drosophila melanogaster

Increased activation of the innate immune system is a common feature of aging animals, including mammals and Drosophila melanogaster. With age, D. melanogaster progressively express higher levels of many antimicrobial peptides. It is unknown, however, whether this pattern reflects age-dependent changes in the function of the immune system itself or arises simply because aged adults have greater cumulative exposure to pathogens. Here we demonstrate that aged D. melanogaster transcribe more antimicrobial diptericin when experimentally exposed to septic bacterial infections. This strong net response in older females is the result of persistent diptericin transcription upon septic exposure, whereas young females rapidly terminate this induction. In contrast to their response to septic exposure, when exposed to killed bacteria aged females have less capacity to induce diptericin. Because this functional capacity of innate immunity declines with age, we conclude that female Drosophila undergo immune senescence. Furthermore, we show that fecundity is reduced by induction of innate immunity via the immune deficiency pathway. Consequently, maximum reproduction will occur when the immune response is tightly controlled in young females, even if this increases infection risk at later ages

Diet and Exercise in Pediatric Liver Transplant Recipients

ObjectiveThe aim of the study is to analyze the impact of physical activity and eating behaviors on precursors of cardiovascular disease-including overweight/obesity, hypertension, low high-density lipoprotein, and impaired glucose tolerance-in pediatric liver transplant (LT) recipients and matched controls.MethodCross-sectional study of pediatric LT recipients 8 to 30 years, matched to controls from the National Health and Nutrition Examination Survey. Dietary intake assessed with 24-hour recall. Physical activity assessed by standardized questionnaires. LT recipients ≥12 years completed a confidential survey on alcohol consumption.ResultsLT recipients (n = 90) were 0.9 to 24.7 years post-transplant. LT recipients and controls were equally likely to consume excess carbohydrates (32% vs 34%) and sugar, per age- and gender-specific recommended dietary intake guidelines. LT recipients spent more hours sedentary or on the computer daily and fewer days each week physically active for &gt;60 minutes than controls. More overweight/obese LT recipients spent 3+ hours at the computer than non-overweight LT recipients (49% vs 27%; P = 0.02). Normal weight LT recipients spent more days doing vigorous activity each week (median 5 days, interquartile range 2-6) than did the overweight/obese LT recipients (median 3 days, interquartile range 2-4; P = 0.01). Among LT recipients, neither dietary intake nor physical activity were consistently associated with measures of hypertension, glucose intolerance, or dyslipidemia. Among LT adolescents and young adults (n = 38), 36% reported ever consuming alcohol; 38% of these reported significant alcohol consumption by frequency or quantity.ConclusionsAdditional counseling during routine post-LT care on the importance of physical activity and healthy diet may be useful. However, it is unlikely that these factors alone explain the increased prevalence of metabolic syndrome components in pediatric LT recipients

Effects of early vitamin D deficiency rickets

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children's Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency

High-Dose Neonatal Vitamin A Supplementation Transiently Decreases Thymic Function in Early Infancy

BackgroundVitamin A deficiency (VAD) impairs T-cell-mediated immunity. In regions where VAD is prevalent, vitamin A supplementation (VAS) reduces child mortality, perhaps by improving immune function.ObjectiveOur objective was to determine if neonatal VAS would improve thymic function in Bangladeshi infants, and to determine if such effects differed by sex or nutritional status (i.e., birth weight above/below the median).MethodsThree hundred and six infants were randomly assigned to 50,000 IU vitamin A (VA) or placebo (PL) within 48 h of birth. Primary outcomes were measured at multiple ages and included 1) thymic index (TI) at 1, 6, 10, and 15 wk; 2) T-cell receptor excision circles (TREC), an index of thymic output of naïve T cells; and 3) total/naïve T cells in peripheral blood at 6 wk, 15 wk, and 2 y. A mixed linear model for repeated measures was used to assess group differences at each age and identify interactions with sex and birth weight.ResultsVAS did not significantly (P&nbsp;=&nbsp;0.21) affect TI overall (i.e., at all ages) but decreased TI by 7.8% (P&nbsp;=&nbsp;0.029) at 6 wk: adjusted TI means for the PL and VA groups at 1, 6, 10, and 15 wk were 4.09 compared with 3.80 cm2, 7.78 compared with 7.18 cm2, 8.11 compared with 7.84 cm2, and 7.91 compared with 7.97 cm2, respectively. VAS did not significantly (P&nbsp;=&nbsp;0.25) affect TREC overall but decreased TREC by 19% (P&nbsp;=&nbsp;0.029) at 15 wk: adjusted TREC means for the PL and VA groups at 6 wk, 15 wk, and 2 y were 13.6 compared with 16.1 copies/pg DNA, 19.4 compared with 15.7 copies/pg DNA, and 11.8 compared with 10.0 copies/pg DNA, respectively. VAS did not significantly affect overall total (P&nbsp;=&nbsp;0.10) or naïve (P&nbsp;=&nbsp;0.092) T cells: adjusted naïve T-cell means for the PL and VA groups at 6 wk, 15 wk, and 2 y were 3259 compared with 3109 cells/µL, 3771 compared with 3487 cells/µL, and 1976 compared with 1898 cells/µL, respectively.ConclusionIn contrast to our hypothesis, VAS decreased thymic function early in infancy but health effects are presumably negligible owing to the transience and small magnitude of this effect. This trial was registered at clinicaltrials.gov as NCT01583972 and NCT02027610

Design and implementation of a cross-sectional nutritional phenotyping study in healthy US adults.

BackgroundMetabolic imbalance is a key determinant of risk of chronic diseases. Metabolic health cannot be assessed solely by body mass calculations or by static, fasted state biochemical readouts. Although previous studies have described temporal responses to dietary challenges, these studies fail to assess the environmental factors associated with certain metabolic phenotypes and therefore, provide little scientific rationale for potentially effective intervention strategies.Methods/designIn this phenotyping study of healthy US adults, we are evaluating lifestyle, biological and environmental factors in addition to metabolic parameters to determine the factors associated with variations in metabolic health. A series of practical fitness, dietary, and emotional challenges are introduced and temporal responses in various areas of specialization, including immunology, metabolomics, and endocrinology, are monitored. We expect that this study will identify key factors related to healthy or unhealthy metabolic phenotypes (metabotypes) that may be modifiable targets for the prevention of chronic diseases in an individual.DiscussionThis study will provide novel insights into metabolic variability among healthy adults in balanced strata defined by sex, age and body mass index. Usual dietary intake and physical activity will be evaluated across these strata to determine how diet is associated with health status defined using many indicators including immune function, metabolism, body composition, physiology, response to exercise andmeal challenges and neuroendocrine assessment. A principal study goal is to identify dietary and other personal factors that will differentiate different levels of "health" among study participants.Trial registrationClinicalTrials.gov NCT02367287

Design and implementation of a cross-sectional nutritional phenotyping study in healthy US adults

BACKGROUND: Metabolic imbalance is a key determinant of risk of chronic diseases. Metabolic health cannot be assessed solely by body mass calculations or by static, fasted state biochemical readouts. Although previous studies have described temporal responses to dietary challenges, these studies fail to assess the environmental factors associated with certain metabolic phenotypes and therefore, provide little scientific rationale for potentially effective intervention strategies. METHODS/DESIGN: In this phenotyping study of healthy US adults, we are evaluating lifestyle, biological and environmental factors in addition to metabolic parameters to determine the factors associated with variations in metabolic health. A series of practical fitness, dietary, and emotional challenges are introduced and temporal responses in various areas of specialization, including immunology, metabolomics, and endocrinology, are monitored. We expect that this study will identify key factors related to healthy or unhealthy metabolic phenotypes (metabotypes) that may be modifiable targets for the prevention of chronic diseases in an individual. DISCUSSION: This study will provide novel insights into metabolic variability among healthy adults in balanced strata defined by sex, age and body mass index. Usual dietary intake and physical activity will be evaluated across these strata to determine how diet is associated with health status defined using many indicators including immune function, metabolism, body composition, physiology, response to exercise andmeal challenges and neuroendocrine assessment. A principal study goal is to identify dietary and other personal factors that will differentiate different levels of "health" among study participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT02367287

Vedolizumab Therapy in Children With Primary Sclerosing Cholangitis: Data From the Pediatric Primary Sclerosing Cholangitis Consortium

OBJECTIVES: Most patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). The liver and colon express MAdCAM-1, a target of lymphocyte homing integrins. Vedolizumab (VDZ) is an α4β7 integrin antibody used to treat IBD. We investigated liver outcomes in children with PSC-IBD treated with VDZ. METHODS: Patients were identified within the Pediatric PSC Consortium, a multicenter research registry. Retrospective demographic, phenotypic, biochemical, radiological, histopathologic and IBD data for up to 1 year of VDZ therapy were collected. Liver biochemical and IBD responses were defined as: a 75% or greater reduction in initial γ-glutamyltransferase (GGT), or a GGT that fell to <50 IU/L and improved Mayo endoscopy grade or IBD activity scores after 9 to 12 months. RESULTS: Thirty-seven patients were identified from 19 centers. VDZ was initiated at median age of 16 years [IQR 15-18], 69% were male, 65% had large duct involvement, 19% had (Metavir F3/F4) fibrosis and 59% had ulcerative colitis. Of 32 patients with abnormal GGT at baseline, 22% had a liver biochemical response after 9 to 12 months. For IBD, 32% achieved remission, 30% had a clinical response, and 38% had no response. Final GGT after 9 to 12 months was 51 [IQR 28-71] in IBD patients in remission versus 127 [IQR 63-226] in those with active IBD, (P = 0.066). CONCLUSIONS: Liver biochemistry worsened over time in IBD unresponsive to VDZ but remained unchanged in IBD patients in remission. VDZ did not improve liver biochemistry in pediatric PSC-IBD. Progressive liver disease may be more common in patients with medically refractory IBD

Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children: An International Observational Study

Background and Aims: Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. Approach and Results: We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). Conclusions: The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population