Efficacy of docosahexaenoic acid-choline-vitamin E (DHA-CHO-VE) in paediatric NASH: a randomized controlled clinical trial

Non-alcoholic steatohepatitis (NASH), a progressive form of non-alcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in children. We conducted a randomized controlled clinical trial on children with biopsy-proven NASH based on a combinatorial nutritional approach compared to placebo. Participants were assigned to lifestyle modification plus placebo, or lifestyle modification plus a mix containing docosahexaenoic acid, choline and vitamin E (DHA-CHO-VE). Forty children and adolescents concluded the trial. The primary outcome was the improvement of liver hyperechogenicity. Secondary outcomes included alterations of ALT and other metabolic parameters. Furthermore, changes of serum bile acids (BA) and plasma fibroblast growth factor 19 (FGF19) levels were evaluated as inverse biomarkers of disease severity. At the end of the study, we observed a significant decrease in severe steatosis in the treatment group (50% to 5%, p=0.001). Furthermore, although the anthropometric and biochemical measurements in the placebo and DHA-CHO-VE groups were comparable at baseline, at the end of the study ALT and fasting glucose levels improved only in the treatment group. Finally, we found that BA levels were not influenced whereas FGF19 levels were significantly increased by DHA-CHO-VE. The results suggest that a combination of DHA, vitamin E and choline could improve steatosis and reduce ALT and glucose levels in children with NASH. However, further studies are needed to assess the impact of a DHA and vitamin E combination on repair of liver damage in paediatric NASH.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Serum Bile Acids in Repaired Tetralogy of Fallot: A Marker for Liver and Heart?

Patients with repaired tetralogy of Fallot may develop chronic right ventricular dysfunction and hepatic congestion over time. We hypothesized that bile acid metabolism is altered in repaired tetralogy of Fallot patients and therefore sought to correlate right ventricular indices with serum bile acid levels.Indexed right ventricular end diastolic volume, as assessed by cardiac magnetic-resonance imaging, was classified as 150ml/m2 (Group 3, n = 6) in 29 patients with repaired tetralogy of Fallot. Pulmonary regurgitation fraction and right ventricular ejection fraction were calculated. The serum bile acid profile, including 15 species, in these patients was determined by liquid chromatography coupled with mass spectrometry.Serum bile acid levels increased from Group 1 to Group 3 (2.5 ± 0.7; 4.1 ± 2.5; 6.0 ± 2.8 μmol/l, respectively) with significantly increased bile acid values in Group 3 compared to Group 1 (p≤0.05). In Group 3, but not in Group 1 and 2, a significant increase in glycine-conjugated bile acids was observed. Pulmonary regurgitation fraction increased (12 ± 1; 28 ± 16; 43 ± 3%, Groups 1-3, respectively) and right ventricular ejection fraction decreased (48.4 ± 6.4; 48.5 ± 6.5; 42.1 ± 5.3%, Groups 1-3, respectively) with rising indexed right ventricular end diastolic volume.These preliminary results suggest that serum bile acid levels are positively correlated with indexed right ventricular end-diastolic volume in patients with repaired tetralogy of Fallot; however, this needs to be confirmed in a larger patient cohort

Serum Bile Acid Levels in Children with Nonalcoholic Fatty Liver Disease

Objective: Because the prevalence of obesity in children is increasing, the frequency of pediatric nonalcoholic fatty liver disease (NAFLD) is growing. A reliable noninvasive biomarker for monitoring progression of liver fibrosis would be useful. In cirrhotic persons serum bile acid (BA) levels are significantly elevated. We hypothesized that BA levels and composition in pediatric NAFLD vary depending on the stage of fibrosis. Methods: Children with NAFLD were compared with controls and classified by stages of fibrosis (NAFLD-F0, n = 27; NAFLD-F≥1, n = 65) based on liver-biopsy findings. Fasted metabolic and cholestasis status was assessed by several blood tests. BA profiles were measured by tandem mass spectrometry and compared with healthy controls (n = 105). Results: Compared with controls, all of the NAFLD patients were overweight and showed significantly elevated glucose, insulin, aspartate transaminase, and alanine transaminase levels. Total serum BAs were lower in nonfibrotic NAFLD children than in a control cohort (1.73 vs 3.6 μmol/L) because low glycine-conjugated BA levels were incompletely compensated by increases in taurine-conjugated or unconjugated BA. In patients with fibrotic NAFLD, BA levels were lower than in controls (2.45 vs 3.6 μmol/L) but higher than in nonfibrotic patients (2.45 vs 1.73 μmol/L), and the BA pattern resembled that of healthy controls. Fibroblast growth factor 19 levels were significantly lower in both NAFLD groups than in controls (P ≤ 0.001) and were positively correlated with ursodeoxycholic acid levels. Conclusions: Our data indicate that serum BA levels decrease in early NAFLD and increase during progression to fibrosis. Given that BA levels are increased in cirrhotic adults, we postulate a continuous rise as NAFLD advances. BA may have a value as a noninvasive biomarker in pediatric NAFLD progression. © 2015 by ESPGHAN and NASPGHAN

Correlation of total BA levels with RVEDVi.

<p>Together with increasing RVEDVi, total BA values also increased (r = 0.4; p≤0.05). <i>Abbreviations</i>: BA, bile acids; RVEDVi, indexed right ventricular end-diastolic volume.</p

Total BA levels in TOF patients with RVEDVi (1) <100 ml/m², (2) 100–150 ml/m², and (3) >150 ml/m².

<p>BA levels were significantly elevated in Group 3 compared to Group 1 (p≤0.05). Total BA levels rose in TOF patients with increasing RVEDVi.</p

BA pool composition in patients with RVEDVi (1) <100 ml/m², (2) 100–150 ml/m², and (3) >150 ml/m².

<p>In Group 2 T-conjugated and G-conjugated BA were increased compared to Group 1. In Group 3 T-conjugates were increased compared to Group 1, but decreased compared to Group 2. G-conjugates were significantly increased in Group 3 compared to Group 1 (p≤0.05). GCDCA was the predominant BA in all 3 groups, rising with increasing RVEDVi. White: unconjugated BA, light grey: G-conjugated BA, dark grey: T-conjugated BA. Abbreviations: BA, bile acids; G, glycine; T, taurine; RVEDVi, right ventricular end-diastolic volume.</p

Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis: Results of a European Survey

Objective: Inborn errors of primary bile acid (BA) synthesis are genetic cholestatic disorders leading to accumulation of atypical BA with deficiency of normal BA. Unless treated with primary BA, chronic liver disease usually progresses to cirrhosis and liver failure before adulthood. We sought to determine the prevalence of 2 common disorders, 3β-hydroxy-Δ 5-C 27-steroid dehydrogenase (3β-HSD) and Δ 4-3-oxosteroid-5β-reductase (Δ 4-3-oxoR) deficiencies and to describe current diagnostic and treatment strategies among different European paediatric hepatology centres. Methods: A total of 52 clinical paediatric centres were approached and 39 centres in 21 countries agreed to participate in the Web-based survey. The survey comprised questions regarding general information, number of cases, diagnostic, and therapeutic management. Results: Seventeen centres located in 11 countries reported patients with inborn errors in primary BA synthesis, 22 centres never had cases diagnosed. In total, we could identify 63 patients; 55 with 3β-HSD and 8 with Δ 4-3-oxoR deficiency in 21 countries. The minimum estimated combined prevalence of these diseases was 1.13 cases per 10 million (0.99 and 0.14 for 3β-HSD and Δ 4-3-oxoR deficiencies, respectively). The surveyed colleagues indicated their main challenges to be the rarity of diseases and the lack of convenient laboratory facilities nearby. Conclusion: We have identified the largest cohort of patients with 3β-HSD or Δ 4-3-oxoR deficiency described so far. These diseases are likely underdiagnosed mainly due to unawareness of their existence and the lack of laboratory facilities