The effect of vitamin E and docosahexaenoic acid ethyl ester on Metabolic Dysfunction-Associated steatotic Liver Disease (MASLD)-A randomised, double-blind, placebo-controlled, parallel-group clinical trial (PUVENAFLD).

AIMS: We conducted a clinical trial to determine the efficacy of the combination of vitamin E and/or docosahexaenoic acid (DHA) versus placebo in reducing liver fat content after 6 months of intervention in adults with MASLD. METHODS: Adults with MASLD were randomised to one of four treatment arms (vitamin E 1000 mg/daily + DHA 1.89 g/daily or combination arm, vitamin E 1000 mg alone, DHA 1.89 g alone or placebo) following a 2:1:1:2 randomisation. The primary objective was to determine the efficacy of DHA + vitamin E versus placebo in reducing hepatic fat fraction (%) relative to baseline after 6 months of intervention. Secondary objectives were to determine the effect of vitamin E or DHA alone versus placebo on reducing liver fat at 6 months. RESULTS: Our cohort consisted of 203 subjects with a mean age of 51 years, 53% female, 91% White, 59% Hispanic ethnicity. The combination of vitamin E + DHA had no effect on the primary endpoint of reducing hepatic steatosis as determined by MRI-PDFF (p = 0.98). Neither vitamin E alone (p = 0.91) nor DHA alone (p = 0.14) significantly reduced hepatic steatosis compared to placebo. However, the trial was not powered adequately for this analysis. Compared with placebo, no statistically significant differences were detected in the 3-month or 6-month levels for ALT (U/L) or AST (U/L) in all three intervention groups. CONCLUSIONS: The combination of DHA + vitamin E or either agent alone did not demonstrate efficacy on reducing liver fat or aminotransferases in the studied population.

Biomarkers of Docosahexaenoic Acid but Not Arachidonic Acid Reflect Dietary Intakes in Toddlers at Ages 1 and 2 Years Who Are Not Meeting Dietary Recommendations.

BACKGROUND: Long-chain n-6 and n-3 PUFAs are important for growth and development. However, little is known about requirements and current dietary intakes of these fatty acids in toddlers. OBJECTIVES: This study assessed dietary intakes of n-6 and n-3 PUFAs and determined the relation to circulating PUFAs in toddlers at ages 1 and 2 y. METHODS: This is a secondary analysis of data from toddlers enrolled in a double-blind randomized controlled trial of arachidonic acid (ARA) and DHA supplementation between ages 1 and 2 y. Dietary intakes of fatty acids were estimated by 3-d food records, and fatty acid composition in plasma total phospholipids, red blood cell phosphatidylethanolamine (PE), and phosphatidylcholine (PC) were assessed by GC at baseline in all subjects (n = 110; mean age 1.12 y; 64% male) and in the control subjects at 2 y (n = 43). RESULTS: The dietary intakes of ARA, EPA, and DHA at age 1 y (baseline) were [mean (median)] 36.8 (30.0), 16.0 (0.00), and 31.1 (10.0) mg/d, respectively. Dietary intakes increased to 52.7 (45.0), 35.8 (0.00), and 64.8 (20.0) mg/d, respectively, at age 2 y (P < 0.05). The predominant dietary source of EPA and DHA was fish/seafood; eggs were an important source of ARA and DHA. Dietary DHA intakes were positively associated with plasma PE and PC DHA (P < 0.05). No relations between dietary ARA intakes and plasma PE and PC ARA (P > 0.05) were observed. CONCLUSIONS: These findings suggest that most toddlers are not meeting the recommendation for dietary PUFA intakes and that higher dietary DHA intakes are reflected in plasma PE and PC DHA composition. Further work is required to investigate a biomarker for dietary ARA intake. This trial is registered at clinicaltrials.gov as NCT01263912.

Plasma Betaine Is Positively Associated with Developmental Outcomes in Healthy Toddlers at Age 2 Years Who Are Not Meeting the Recommended Adequate Intake for Dietary Choline.

Background: Choline is an important nutrient during development. However, there are limited data on dietary choline intake and status in toddlers and the relation to neurodevelopmental outcomes. Objective: This study assessed dietary choline intake and status in healthy toddlers at ages 1 and 2 y and determined the relation to neurodevelopmental outcomes. Methods: This is a secondary analysis of data from healthy toddlers enrolled in a double-blind, randomized controlled trial of long-chain polyunsaturated fatty acid supplementation between ages 1 and 2 y. Dietary intakes of betaine and choline were estimated by 3-d food records; plasma free choline, betaine, and dimethylglycine were quantified by liquid chromatography-tandem mass spectrometry. Developmental outcomes were assessed at age 2 y with the use of the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), Cognitive and Language composites, and the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI). Results: The mean ± SD daily intake for total choline at age 1 y was 174 ± 56.2 mg/d and increased (P < 0.001) to 205 ± 67.5 mg/d at age 2 y. At ages 1 and 2 y, 71.8% and 55.8%, respectively, of toddlers did not meet the recommended 200-mg/d Adequate Intake (AI) for dietary choline. At age 1 y, mean ± SD plasma free choline, betaine, and dimethylglycine concentrations were 10.4 ± 3.3, 41.1 ± 15.4, and 4.1 ± 1.9 µmol/L, respectively. Plasma free choline (8.5 ± 2.3 µmol/L) and dimethylglycine (3.2 ± 1.3 µmol/L) concentrations were lower (P < 0.001) at age 2 y. Plasma betaine concentrations were positively associated with the Beery-VMI (ß = 0.270; 95% CI: 0.026, 0.513; P = 0.03) at age 2 y. Conclusions: These findings suggest that most toddlers are not meeting the recommended AI for dietary choline and that higher plasma betaine concentrations are associated with better visual-motor development at age 2 y. Further work is required to investigate choline metabolism and its role in neurodevelopment in toddlers. The trial is registered at clinicaltrials.gov as NCT01263912.

Developmental Outcomes at 24 Months of Age in Toddlers Supplemented with Arachidonic Acid and Docosahexaenoic Acid: Results of a Double Blind Randomized, Controlled Trial.

Little is known about arachidonic acid (ARA) and docosahexaenoic acid (DHA) requirements in toddlers. A longitudinal, double blind, controlled trial in toddlers ( n = 133) age 13.4 ± 0.9 months (mean ± standard deviation), randomized to receive a DHA (200 mg/day) and ARA (200 mg/day) supplement (supplement) or a corn oil supplement (control) until age 24 months determined effects on neurodevelopment. We found no effect of the supplement on the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) cognitive and language composites and Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) at age 24 months. Supplemented toddlers had higher RBC phosphatidylcholine (PC), phosphatidylethanolamine (PE), and plasma DHA and ARA compared to placebo toddlers at age 24 months. A positive relationship between RBC PE ARA and Bayley III Cognitive composite (4.55 (0.21-9.00), B (95% CI), p = 0.045) in supplemented boys, but not in control boys, was observed in models adjusted for baseline fatty acid, maternal non-verbal intelligence, and BMI z-score at age 24 months. A similar positive relationship between RBC PE ARA and Bayley III Language composite was observed for supplemented boys (11.52 (5.10-17.94), p < 0.001) and girls (11.19 (4.69-17.68), p = 0.001). These findings suggest that increasing the ARA status in toddlers is associated with better neurodevelopment at age 24 months.

Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline.

BACKGROUND: Docosahexaenoic acid (DHA) plays an important role in neural function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly adults and in patients with Alzheimer's disease. Higher DHA intake is inversely correlated with relative risk of Alzheimer's disease. The potential benefits of DHA supplementation in age-related cognitive decline (ARCD) have not been fully examined. OBJECTIVE: Determine effects of DHA administration on improving cognitive functions in healthy older adults with ARCD. METHODS: Randomized, double-blind, placebo-controlled, clinical study was conducted at 19 U.S. clinical sites. A total of 485 healthy subjects, aged ≥55 with Mini-Mental State Examination >26 and a Logical Memory (Wechsler Memory Scale III) baseline score ≥1 standard deviation below younger adults, were randomly assigned to 900 mg/d of DHA orally or matching placebo for 24 weeks. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. RESULTS: Intention-to-treat analysis demonstrated significantly fewer PAL six pattern errors with DHA versus placebo at 24 weeks (difference score, -1.63 ± 0.76 [-3.1, -0.14, 95% CI], P = .03). DHA supplementation was also associated with improved immediate and delayed Verbal Recognition Memory scores (P < .02), but not working memory or executive function tests. Plasma DHA levels doubled and correlated with improved PAL scores (P < .02) in the DHA group. DHA was well tolerated with no reported treatment-related serious adverse events. CONCLUSIONS: Twenty-four week supplementation with 900 mg/d DHA improved learning and memory function in ARCD and is a beneficial supplement that supports cognitive health with aging. TRIAL REGISTRATION: Clinicaltrials.gov, Identifier: NCT0027813.

Bioequivalence of Docosahexaenoic acid from different algal oils in capsules and in a DHA-fortified food.

Docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid, is important for eye and brain development and ongoing visual, cognitive, and cardiovascular health. Unlike fish-sourced oils, the bioavailability of DHA from vegetarian-sourced (algal) oils has not been formally assessed. We assessed bioequivalence of DHA oils in capsules from two different algal strains versus bioavailability from an algal-DHA-fortified food. Our 28-day randomized, placebo-controlled, parallel group study compared bioavailability of (a) two different algal DHA oils in capsules ("DHASCO-T" and "DHASCO-S") at doses of 200, 600, and 1,000 mg DHA per day (n = 12 per group) and of (b) an algal-DHA-fortified food (n = 12). Bioequivalence was based on changes in plasma phospholipid and erythrocyte DHA levels. Effects on arachidonic acid (ARA), docosapentaenoic acid-n-6 (DPAn-6), and eicosapentaenoic acid (EPA) were also determined. Both DHASCO-T and DHASCO-S capsules produced equivalent DHA levels in plasma phospholipids and erythrocytes. DHA response was dose-dependent and linear over the dose range, plasma phospholipid DHA increased by 1.17, 2.28 and 3.03 g per 100 g fatty acid at 200, 600, and 1,000 mg dose, respectively. Snack bars fortified with DHASCO-S oil also delivered equivalent amounts of DHA on a DHA dose basis. Adverse event monitoring revealed an excellent safety and tolerability profile. Two different algal oil capsule supplements and an algal oil-fortified food represent bioequivalent and safe sources of DHA.

Lipid responses to a dietary docosahexaenoic acid supplement in men and women with below average levels of high density lipoprotein cholesterol.

OBJECTIVE: To assess fasting lipid responses to a docosahexaenoic acid (DHA) supplement in men and women with below-average levels of high-density lipoprotein (HDL) cholesterol. METHODS: This randomized, double-blind, controlled clinical trial included 57 subjects, 21-80 years of age, with fasting HDL cholesterol concentrations < or =44 mg/dL (men) and < or =54 mg/dL (women), but > or =35 mg/dL. Subjects were randomly assigned to receive either 1.52 g/day DHA from capsules containing DHA-rich algal triglycerides or olive oil (control) for six weeks. RESULTS: There were no significant differences between groups in baseline lipid values. The DHA supplemented group showed significant changes [-43 (DHA) vs. -14 (controls) mg/dL, p = 0.015] and percent changes [-21% (DHA) vs. -7% (controls), p = 0.009] in triglycerides, total (12 vs. 3 mg/dL; p = 0.021 and 6% vs. 2%; p = 0.018) and low-density lipoprotein (17 vs. 3 mg/dL; p = 0.001 and 12% vs. 3%; p = 0.001) cholesterol concentrations, and in the triglyceride to HDL cholesterol ratio (-1.33 vs. -0.50, p = 0.010), compared with controls. In addition, there was a significant reduction in the percentage of LDL cholesterol carried by small, dense particles in the DHA supplemented group (changes = -10% vs. -3%, p = 0.025). CONCLUSIONS: Supplementation with 1.52 g/d of DHA in men and women with below-average HDL cholesterol concentrations raised the LDL cholesterol level, but had favorable effects on triglycerides, the triglyceride/HDL cholesterol ratio and the fraction of LDL cholesterol carried by small, dense particles. Further research is warranted to evaluate the net impact of these alterations on cardiovascular risk.

Lipid responses in mildly hypertriglyceridemic men and women to consumption of docosahexaenoic acid-enriched eggs.

This randomized, double-blind, controlled clinical trial assessed lipid responses in mildly hyper-triglyceridemic men and women to consumption of docosahexaenoic acid (DHA)-enriched eggs or ordinary chicken eggs. The study included 153 subjects aged 21-80 years, with serum triglyceride concentrations between 140 and 450 mg/dL, inclusive, and serum total cholesterol concentrations < 300 mg/dL. Subjects were randomly assigned to receive either DHA-enriched (147 mg DHA/egg) or ordinary eggs (20 mg DHA/egg), added to their usual diets for six weeks (10 eggs/week). Both treatments significantly lowered triglycerides and increased high-density lipoprotein (HDL) cholesterol levels from baseline; however, these changes were not significantly different between treatments. Low-density lipoprotein (LDL) cholesterol concentrations increased significantly in subjects who consumed DHA-enriched eggs (p = 0.047 vs. control). This increase was significantly higher than that observed with ordinary eggs. However, there was no significant increase in cholesterol carried by small, dense LDL particles, as determined by nuclear magnetic resonance analysis. Results of exploratory analyses suggest favorable effects of the DHA-enriched eggs over ordinary eggs on triglyceride and HDL cholesterol levels in subjects with body mass index > or = 30 kg/m2; the DHA treatment produced a larger reduction in serum triglyceride concentration vs. ordinary eggs (-12.3 vs. 2.1%; p = 0.027), and there was a greater increase for HDL cholesterol in the DHA-enriched vs. ordinary egg group (5.0 vs. 1.1%; p = 0.040).