by
Jeffrey B. Schwimmer;
Joel E. Lavine;
Laura A. Wilson;
Brent A. Neuschwander-Tetri;
Stavra A. Xanthakos;
Rohit Kohli;
Sarah E. Barlow;
Miriam Vos;
Saul Karpen;
Jean P. Molleston;
Peter F. Whitington;
Philip Rosenthal;
Ajay K. Jain;
Karen F. Murray;
Elizabeth M. Brunt;
David E. Kleiner;
Mark L. Van Natta;
Jeanne M. Clark;
James Tonascia;
Edward Doo
Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing > 65 to 80 kg, and 450 mg for patients weighing > 80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran–Mantel–Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8–2.1; P =.34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P =.02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P =.008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P =.03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3–12.3; P =.005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.
by
Jeffrey H. Teckman;
Philip Rosenthal;
Robert Abel;
Lee M. Bass;
Sonia Michail;
Karen F. Murray;
David A. Rudnick;
Daniel W. Thomas;
Cathie Spino;
Ronen Arnon;
Paula M. Hertel;
James Heubi;
Binita M. Kamath;
Wikrom Karnsakul;
Kathleen M. Loomes;
John C. Magee;
Jean P. Molleston;
Rene Romero;
Benjamin L. Shneider;
Averell H. Sherker;
Ronald J. Sokol
Objectives: α-1-Antitrypsin (A1AT) deficiency is a common genetic disease with an unpredictable and highly variable course. The Childhood Liver Disease Research and Education Network is a National Institutes of Health, multicenter, longitudinal consortium studying pediatric liver diseases, with the objective of prospectively defining natural history and identifying disease modifiers.
Methods: Longitudinal, cohort study of A1AT patients' birth through 25 years diagnosed as having liver disease, type PIZZ or PISZ. Medical history, physical examination, laboratory, imaging, and standardized survey tool data were collected during the provision of standard of care.
Results: In the present report of the cohort at baseline, 269 subjects were enrolled between November 2008 and October 2012 (208 with their native livers and 61 postliver transplant). Subjects with mild disease (native livers and no portal hypertension [PHT]) compared to severe disease (with PHT or postliver transplant) were not different in age at presentation. A total of 57% of subjects with mild disease and 76% with severe disease were jaundiced at presentation (P = 0.0024). A total of 29% of subjects with native livers had PHT, but age at diagnosis and growth were not different between the no-PHT and PHT groups (P > 0.05). Subjects with native livers and PHT were more likely to have elevated bilirubin, ALT, AST, INR, and GGTP than the no-PHT group (P << 0.001), but overlap was large. Chemistries alone could not identify PHT.
Conclusions: Many subjects with A1AT presenting with elevated liver tests and jaundice improve spontaneously. Subjects with PHT have few symptoms and normal growth. Longitudinal cohort follow-up will identify genetic and environmental disease modifiers.
by
Allison Ross Eckard;
Myrtle Thierry-Palmer;
Natalia Silvestrov;
Julia C. Rosebush;
Mary Ann O'Riordan;
Julie E. Daniels;
Monika Uribe-Leitz;
Danielle Labbato;
Joshua H. Ruff;
Ravinder J. Singh;
Vin Tangpricha;
Grace A. McComsey
Vitamin D insufficiency is widespread in HIV-infected patients. HIV and/or antiretroviral therapy (ART), particularly efavirenz (EFV), may interfere with vitamin D metabolism. However, few data from randomized, controlled trials exist. Here, we investigate changes in vitamin D metabolites and binding protein (VDBP) after 6 months of supplementation in a randomized, active-control, double-blind trial investigating 2 different monthly cholecalciferol (vitamin D 3 ) doses [60,000 (medium) or 120,000 (high) IU/month] vs. a control arm of 18,000 IU/month in 8–25 year old HIV-infected youth on ART with HIV-1 RNA < 1000 copies/mL and baseline 25-hydroxycholecalciferol (25(OH)D 3 ) ≤30 ng/mL. A matched healthy uninfected group was enrolled in a similar parallel study for comparison. Changes after 6 months were analyzed as intent-to-treat within/between groups [control group (low dose) vs. combined supplementation doses (medium + high)]. At 6 months, 55% vs. 82% of subjects in control and supplementation groups, respectively, reached 25(OH)D 3 ≥30 ng/mL (P = 0.01) with no difference between medium and high doses (both 82% ≥30 ng/mL). There were few differences for those on EFV vs. no-EFV, except serum VDBP decreased in EFV-treated subjects (both within- and between-groups P ≤ 0.01). There were no significant differences between the HIV-infected vs. healthy uninfected groups. The major finding of the present study is that cholecalciferol supplementation (60,000 or 120,000 IU/month) effectively raises serum 25(OH)D 3 in the majority of HIV-infected subjects, regardless of EFV use. Notably, response to supplementation was similar to that of uninfected subjects.
by
Tomi Akinyemiju;
Justin Xavier Moore;
Maria Pisu;
Suzanne E. Judd;
Michael Goodman;
James M. Shikany;
Virginia J. Howard;
Monika Safford;
Susan C. Gilchrist
Objective: This study examined whether metabolic health status is associated with risk of cancer mortality and whether this varies by body mass index (BMI) category. Methods: A prospective study of 22,514 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort was performed. Metabolically unhealthy status was defined as having three or more of the following: (1) elevated fasting glucose, (2) high triglycerides, (3) dyslipidemia, (4) hypertension, and (5) elevated waist circumference. Participants were categorized into normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obesity (BMI ≥ 30 kg/m2) groups. Cox proportional hazards regression was performed to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for cancer mortality during follow-up. Results: Among participants with normal weight, participants who were metabolically unhealthy had an increased risk of cancer mortality (HR: 1.65; 95% CI: 1.20-2.26) compared with metabolically healthy participants. The overall mortality risk for participants who were metabolically unhealthy and had normal weight was stronger for obesity-related cancers (HR: 2.40; 95% CI: 1.17-4.91). Compared with participants with normal weight, those who were metabolically healthy and overweight were at a reduced risk of any cancer mortality (adjusted HR: 0.79; 95% CI: 0.63-0.99). Conclusions: There was an increased risk of overall and obesity-related cancer mortality among metabolically unhealthy participants with normal weight.