ABSTRACT
Objectives:
Although screening for biliary atresia (BA) is associated with improved outcomes, no screening program currently exists in the United States. In this study, we explore the ...possibility of a screening strategy based on newborn direct or conjugated bilirubin (DB or CB) measurements. Our objective is to estimate testing's sensitivity and specificity for BA.
Methods:
Two groups were examined retrospectively. For sensitivity calculations, a BA group consisting of infants born between January 2011 and December 2014, diagnosed with BA, and cared for at a pediatric gastroenterology referral center was examined. For specificity calculations, a non‐BA group that comprised of infants born between June 2009 and August 2011 in a hospital with a policy of checking newborn bilirubin concentrations was studied.
Results:
All 35 infants with newborn DB or CB measurements in the BA group had elevated concentrations, translating to a sensitivity of 100% (95% CI 87.7–100). In the non‐BA group, 8936 of 9102 infants had DB concentrations within the laboratory's reference interval, translating to a specificity of 98.2% (95% CI 97.9–98.4). Three methods—calculating direct:total bilirubin ratios, using 99% reference intervals, and repeat testing—changed specificity to different degrees.
Conclusions:
Newborn DB or CB measurements may have a high sensitivity and specificity for BA. Specificity can be further improved by using 99% reference intervals and/or repeat testing. Our findings can serve as the foundation for larger prospective studies, to determine whether newborn DB or CB measurements can be an effective screening strategy for BA.
The rotavirus vaccine is being widely implemented and must be given early in life to minimize the risk of intussusception. In this report, rotaviral infection with the vaccine strain was identified ...in three children who were vaccinated before they were found to have severe combined immunodeficiency, thus raising concern regarding the safety of this live attenuated vaccine in severely immunocompromised persons.
In this report, rotaviral infection with the vaccine strain was identified in three children who were vaccinated before they were found to have severe combined immunodeficiency, thus raising concern regarding the safety of this live attenuated vaccine in severely immunocompromised persons.
Rotavirus infection is a leading cause of childhood diarrhea worldwide.
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In 2006, a live oral pentavalent vaccine (RV5; marketed as RotaTeq, Merck) that contains five human–bovine reassortant rotavirus strains was licensed and recommended for use in infants in the United States
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after a large, national multicenter trial showed its efficacy.
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The individual reassortant strains were generated with the use of a bovine rotavirus parent strain, Wistar calf 3 (WC3), and four human rotavirus strains.
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The reassortant strains are attenuated in their ability to replicate. Each oral vaccine dose contains at least 2.0×10
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to 2.8×10
6
infectious units in a 2-ml solution. . . .
IMPORTANCE Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. ...OBJECTIVE To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% 41/70 of steroids group vs 48.6% 34/70 of placebo group; adjusted relative risk, 1.14 95% CI, 0.83 to 1.57; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, −10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 95% CI, 0.6 to 1.8; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% 57/70 of the steroids group and 80.0% 56/70 of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% 95% CI, 26.9% to 50.0% of steroids group vs 19.0% 95% CI, 11.5% to 30.4% of placebo group; P = .008). CONCLUSIONS AND RELEVANCE Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00294684
To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis‐1 ...(FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ‐glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder‐to‐colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postoperatively, respectively; P < 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. Conclusion: This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017;65:1645‐1654).
Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual‐energy X‐ray absorptiometry (DXA) analysis was performed in children with ...intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha‐1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height‐adjusted and weight‐adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height‐adjusted and weight‐adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.
YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.
We report 3 unrelated individuals with rare homozygous missense ...variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6KozakGAL4 allele to assess the expression pattern of dYkt6.
Two individuals are homozygous for YKT6 NM_006555.3:c.554A>G p.(Tyr185Cys) and exhibited normal prenatal course followed by failure to thrive, developmental delay, and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual is homozygous for YKT6 NM_006555.3:c.191A>G p.(Tyr64Cys) and exhibited neurodevelopmental disorders and optic atrophy. Fly dYkt6 is essential and is expressed in the fat body (analogous to liver) and central nervous system. Wild-type genomic rescue constructs can rescue the lethality and autophagic flux defects, whereas the variants are less efficient in rescuing the phenotypes.
The YKT6 variants are partial loss-of-function alleles, and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys).
Objectives To assess health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) in comparison with healthy and other liver disease cohorts, and to identify determinants of HRQOL ...in patients with ALGS. Study design Within the Childhood Liver Disease Research Network prospective study of cholestasis, Pediatric Quality of Life Inventory (PedsQL) questionnaires were administered to 70 children with ALGS, 95 children with alpha-1-antitrypsin deficiency (A1ATD), and 49 children with other causes of chronic intrahepatic cholestasis (IHC) aged 5-18 years. Parent proxy PedsQL scores were recorded for children aged 2-18 years (98 ALGS, 123 A1ATD, and 68 IHC). Results Mean ages and total bilirubin (mg/dL) were ALGS 9.4 years; 4.4, A1ATD 9.5 years; 0.7, and IHC 10.3 years; 2.9. ALGS child PedsQL scores were lower than in healthy children and children with A1ATD (mean 73 vs 83; P = .001). Children with ALGS and IHC were similar, except in physical scores (73 vs 79; P = .05). Parents of children with ALGS perceived their children to have worse HRQOL than A1ATD ( P ≤ .001) and marginally lower compared with IHC. Univariate analysis revealed ALGS child-reported scores were positively associated with better growth and inversely with total bilirubin. Growth failure, elevated international normalized ratio, and an intracardiac defect were predictive of poor parental scores ( P ≤ .05). In multivariate analysis, only weight z-score remained significant for child- and parent-reported scores. Conclusions HRQOL is impaired in children with ALGS compared with healthy and children with A1ATD, similar to children with IHC and is associated with growth failure, which is a potentially treatable cause of impaired HRQOL.
To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research ...Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants.
A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age.
Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life.
Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage.
ClinicalTrials.gov: NCT00294684.
Herbal and dietary supplements (HDS) are a common etiology of drug induced liver injury and, specifically, Herbalife® supplements have been implicated. Hepatitis associated aplastic anemia (HAAA) is ...a rare and potentially fatal complication after acute hepatitis characterized by pancytopenia. While there have been rare cases of HDS leading to HAAA, no cases of Herbalife® induced liver injury leading to HAAA have been reported from this specific HDS. We report a unique case of severe aplastic anemia developing after sub‐fulminant liver failure associated with chronic HDS use. This case illustrates the importance of warning the public about HDS as their use continues to increase. It is not only important to recognize HDS as etiology, but also for healthcare providers to carefully monitor these patients after resolution of liver injury for the development of HAAA.
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