Reappraisal of serum retinol-binding protein as a surrogate marker for retinol and discovery of a novel retinol estimation formula.

BACKGROUND & AIMS: Serum retinol (ROH) is commonly used for population level assessment of vitamin A status. High-performance liquid chromatography (HPLC) is considered most accurate method for measuring ROH. However, with the technical difficulty of using HPLC for routine assays, serum retinol-binding protein (RBP) measured by immunological assays is expected to be a surrogate marker for ROH, with reports of a close correlation between serum RBP and ROH. Nevertheless, RBP is not commonly tested to assess vitamin A status with concerns over RBP alterations under various physiopathological conditions. Thus, we reappraised the extent to which RBP could be used as a surrogate marker in representative disorders that alter serum RBP levels. As a related marker, diagnostic utility of transthyretin (TTR) was also evaluated. METHODS: To evaluate the reliability of ROH and RBP assays, specimen stability was assessed in terms of (1) storage at 25, 4, -20, and -80 °C for 1-28 days, (2) five-cycle freeze-thawing, and (3) fluorescent light exposure for 1-14 days. Sources of variation (sex, age, body mass index [BMI], and drinking habits) and reference intervals for ROH, RBP, and TTR were determined in 617 well-defined healthy individuals. To investigate the influence of disorders that affect serum RBP, patients with five diagnostic groups were enrolled: 26 with chronic kidney disease (CKD); 13 with various malignancies in advanced stages (AdM), 12 with acute bacterial infections (ABI), 6 with liver cirrhosis (LC), and 26 with simple obesity (BMI ≥ 27 kg/m2). RESULTS: The stability of RBP and ROH in serum was confirmed under all conditions. In healthy individuals, serum ROH, RBP, and TTR were appreciably high in males with a slight increase in proportion to age and BMI. The major-axis regression line between RBP (x) and ROH (y) in healthy individuals was y = x, with a correlation coefficient of 0.986. In the LC, AdM, and ABI groups, similar strong correlations were observed; however, the regression lines were shifted slightly rightward from the healthy group line, indicating a positive bias in estimating ROH. Interestingly, the same analyses between TTR and ROH revealed similar strong linear relationships in all groups; however, the regression line of each group showed a leftward (opposite) shift from the healthy group line. Based on these observations, we developed a novel regression model composed of RBP and TTR, which gave much improved accuracy in estimating ROH, even under these pathological conditions. CONCLUSIONS: The perfect RBP-ROH correlation in healthy individuals indicates the utility of RPB as a surrogate marker for ROH. Nevertheless, under RBP-altered conditions, a slight overestimation of ROH is inevitable. However, when the TTR was tested together, the bias can be corrected almost perfectly using the novel ROH estimation formula comprising RBP and TTR.

Vitamin Status in Patients with Phenylketonuria: A Systematic Review and Meta-Analysis.

The published data on the vitamin status of patients with phenylketonuria (PKU) is contradictory; therefore, this systematic review and meta-analysis evaluated the vitamin status of PKU patients. A comprehensive search of multiple databases (PubMed, Web of Sciences, Cochrane, and Scopus) was finished in March 2024. The included studies compared vitamin levels between individuals diagnosed with early-treated PKU and healthy controls while excluding pregnant and lactating women, untreated PKU or hyperphenylalaninemia cases, control groups receiving vitamin supplementation, PKU patients receiving tetrahydrobiopterin or pegvaliase, and conference abstracts. The risk of bias in the included studies was assessed by the Newcastle-Ottawa scale. The effect sizes were expressed as standardised mean differences. The calculation of effect sizes with 95% CI using fixed-effects models and random-effects models was performed. A p-value < 0.05 was considered statistically significant. The study protocol was registered in the PROSPERO database (CRD42024519589). Out of the initially identified 11,086 articles, 24 met the criteria. The total number of participants comprised 770 individuals with PKU and 2387 healthy controls. The meta-analyses of cross-sectional and case-control studies were conducted for vitamin B12, D, A, E, B6 and folate levels. PKU patients demonstrated significantly higher folate levels (random-effects model, SMD: 1.378, 95% CI: 0.436, 2.320, p = 0.004) and 1,25-dihydroxyvitamin D concentrations (random-effects model, SMD: 2.059, 95% CI: 0.250, 3.868, p = 0.026) compared to the controls. There were no significant differences in vitamin A, E, B6, B12 or 25-dihydroxyvitamin D levels. The main limitations of the evidence include a limited number of studies and their heterogeneity and variability in patients' compliance. Our findings suggest that individuals with PKU under nutritional guidance can achieve a vitamin status comparable to that of healthy subjects. Our study provides valuable insights into the nutritional status of PKU patients, but further research is required to confirm these findings and explore additional factors influencing vitamin status in PKU.

Vitamin A - discovery, metabolism, receptor signaling and effects on bone mass and fracture susceptibility.

The first evidence of the existence of vitamin A was the observation 1881 that a substance present in small amounts in milk was necessary for normal development and life. It was not until more than 100 years later that it was understood that vitamin A acts as a hormone through nuclear receptors. Unlike classical hormones, vitamin A cannot be synthesized by the body but needs to be supplied by the food as retinyl esters in animal products and ß-carotene in vegetables and fruits. Globally, vitamin A deficiency is a huge health problem, but in the industrialized world excess of vitamin A has been suggested to be a risk factor for secondary osteoporosis and enhanced susceptibility to fractures. Preclinical studies unequivocally have shown that increased amounts of vitamin A cause decreased cortical bone mass and weaker bones due to enhanced periosteal bone resorption. Initial clinical studies demonstrated a negative association between intake of vitamin A, as well as serum levels of vitamin A, and bone mass and fracture susceptibility. In some studies, these observations have been confirmed, but in other studies no such associations have been observed. One meta-analysis found that both low and high serum levels of vitamin A were associated with increased relative risk of hip fractures. Another meta-analysis also found that low levels of serum vitamin A increased the risk for hip fracture but could not find any association with high serum levels of vitamin A and hip fracture. It is apparent that more clinical studies, including large numbers of incident fractures, are needed to determine which levels of vitamin A that are harmful or beneficial for bone mass and fracture. It is the aim of the present review to describe how vitamin A was discovered and how vitamin A is absorbed, metabolized and is acting as a ligand for nuclear receptors. The effects by vitamin A in preclinical studies are summarized and the clinical investigations studying the effect by vitamin A on bone mass and fracture susceptibility are discussed in detail.

Exploration of circulating metabolic signature of erythrodermic psoriasis based on LC-MS metabolomics.

Erythrodermic psoriasis (EP) is a rare and life-threatening disease, the pathogenesis of which remains to be largely unknown. Metabolomics analysis can provide global information on disease pathophysiology, candidate biomarkers, and potential intervention strategies. To gain a better understanding of the mechanisms of EP and explore the serum metabolic signature of EP, we conducted an untargeted metabolomics analysis from 20 EP patients and 20 healthy controls. Furthermore, targeted metabolomics for focused metabolites were identified in the serum samples of 30 EP patients and 30 psoriasis vulgaris (PsV) patients. In the untargeted analysis, a total of 2992 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed significant difference between groups. After screening, 98 metabolites were found to be significantly dysregulated in EP, including 67 down-regulated and 31 up-regulated. EP patients had lower levels of L-tryptophan, L-isoleucine, retinol, lysophosphatidylcholine (LPC), and higher levels of betaine and uric acid. KEGG analysis showed differential metabolites were enriched in amino acid metabolism and glycerophospholipid metabolism. The targeted metabolomics showed lower L-tryptophan in EP than PsV with significant difference and L-tryptophan levels were negatively correlated with the PASI scores. The serum metabolic signature of EP was discovered. Amino acid and glycerophospholipid metabolism were dysregulated in EP. The metabolite differences provide clues for pathogenesis of EP and they may provide insights for therapeutic interventions.

Protective effect of provitamin A dietary carotenoid intake on overweight/obesity and their relation to inflammatory and oxidative stress biomarkers - a case-control study.

This investigation assessed associations between dietary carotenoid intake and the odds of overweight/obesity, as well as inflammatory/oxidative stress biomarkers, in 851 participants with overweight/obesity (BMI ≥25 kg m-2) and 754 normal-weight controls. A 124-item food-frequency-questionnaire (FFQ) and food composition databases were employed to estimate carotenoid intake. Binary logistic regressions assessed the association of carotenoid intake with the odds of overweight/obesity, adjusting for several potential confounders. Multiple linear regression models revealed associations between carotenoid intake and biomarkers (anthropometrics, blood lipids, inflammation, antioxidant status). Logistic regression models adjusted for various confounders and fruits and vegetables showed protective associations for provitamin A carotenoids (i.e., ß-carotene + α-carotene + ß-cryptoxanthin; odds ratio (OR): 0.655, p = 0.041) and astaxanthin (OR: 0.859, p = 0.017). Similarly adjusted multiple linear regressions revealed significant associations between several carotenoids and lower levels of interleukin (IL)-6, IL-1ß, and TNF-α and increased IL-10 and total antioxidant capacity. Further analysis revealed that lycopene was significantly associated with increased odds of overweight/obesity (OR: 1.595, p = 0.032) in a model adjusted for various confounders and vegetables (i.e., unadjusted for fruits). A protective association between the sum of provitamin A carotenoid and astaxanthin dietary intake and the odds of having overweight/obesity was found. The findings that carotenoids other than lycopene were not or inversely associated with the odds of overweight/obesity may point toward differentiating effects of various carotenoids or their associations with different food groups. Provitamin A rich food items including fruits and vegetables appear to be a prudent strategy to reduce inflammation and the odds of having overweight/obesity.

Association between serum vitamin A and body mass index in adolescents from NHANES 1999 to 2006.

Vitamin A plays a pivotal role in health, particularly in regulating fat metabolism. Despite its significance, research into the direct relationship between vitamin A levels and obesity, especially among adolescents, is sparse. This study aims to explore this association within the adolescent population in the United States. This cross-sectional study analyzed the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2006, with 8218 participants. The levels of vitamin A in the serum were determined based on utilizing high-performance liquid chromatography with photodiode array detection. The relationship between serum vitamin A concentrations and body mass index (BMI) was evaluated using weighted multiple linear regression models, incorporating subgroup analyses by sex and race/ethnicity to provide nuanced insights. A positive correlation was observed between serum vitamin A levels and BMI, with BMI increasing progressively across vitamin A quartiles (P < 0.001). Using the lowest quartile of serum vitamin A as a reference, the BMI of the highest quartile of serum vitamin A was 1.236 times higher (95% CI 0.888, 1.585). Subgroup analyses revealed that this positive association persisted across different genders and racial/ethnic groups (P < 0.001). Notably, smooth curve fitting and saturation threshold analysis unveiled an inverted U-shaped relationship between serum vitamin A and BMI among female adolescents, non-Hispanic Whites, Mexican Americans, and other races/ethnicities groups. Our study substantiates the association between serum vitamin A levels and the risk of obesity/overweight status in adolescents. The findings suggest the potential serum vitamin A is an early biomarker for identifying obesity risk, although further studies are needed to determine to clarify its role as a contributing factor to obesity. This study contributes to the understanding of nutritional influences on adolescent obesity, highlighting the need for targeted interventions based on serum biomarkers.

Retinol and retinol binding protein 4 levels and COVID-19: a Mendelian randomization study.

BACKGROUND: The Corona Virus Disease 2019 (COVID-19) pandemic has struck globally. Whether the related proteins of retinoic acid (RA) signaling pathway are causally associated with the risk of COVID-19 remains unestablished. We conducted a two-sample Mendelian randomization (MR) study to assess the associations of retinol, retinol binding protein 4 (RBP4), retinol dehydrogenase 16 (RDH16) and cellular retinoic acid binding protein 1 (CRABP1) with COVID-19 in European population. METHODS: The outcome utilized the summary statistics of COVID-19 from the COVID-19 Host Genetics Initiative. The exposure data were obtained from public genome wide association study (GWAS) database. We extracted SNPs from exposure data and outcome data. The inverse variance weighted (IVW), MR-Egger and Wald ratio methods were employed to assess the causal relationship between exposure and outcome. Sensitivity analyses were performed to ensure the validity of the results. RESULTS: The MR estimates showed that retinol was associated with lower COVID-19 susceptibility using IVW (OR: 0.69, 95% CI: 0.53-0.90, P: 0.0065), whereas the associations between retinol and COVID-19 hospitalization or severity were not significant. RBP4 was associated with lower COVID-19 susceptibility using the Wald ratio (OR: 0.83, 95% CI: 0.72-0.95, P: 0.0072). IVW analysis showed RDH16 was associated with increased COVID-19 hospitalization (OR: 1.10, 95% CI: 1.01-1.18, P: 0.0199). CRABP1 was association with lower COVID-19 susceptibility (OR: 0.95, 95% CI: 0.91-0.99, P: 0.0290) using the IVW. CONCLUSIONS: We found evidence of possible causal association of retinol, RBP4, RDH16 and CRABP1 with the susceptibility, hospitalization and severity of COVID-19. Our study defines that retinol is significantly associated with lower COVID-19 susceptibility, which provides a reference for the prevention of COVID-19 with vitamin A supplementation.

Overall and Sex-Specific Associations of Serum Lipid-Soluble Micronutrients with Metabolic Dysfunction-Associated Steatotic Liver Disease among Adults in the United States.

This study examined overall and sex-specific associations of serum lipid-soluble micronutrients including α- and γ-tocopherols, 25-hydroxy-vitamin D (25(OH)D), retinol, and six major carotenoids with metabolic dysfunction-associated steatotic lever disease (MASLD) using the 2017-2018 National Health and Nutrition Examination Survey. This analysis included 3956 adults (1991 men, 1965 women) aged ≥ 20 years. Steatotic liver disease was determined through transient elastography examination. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for MASLD associated with micronutrients were estimated using logistic regressions. Higher serum α-tocopherol (highest vs. lowest quartile: OR = 1.53, 95% CI = 1.05-2.22, p = 0.03) and γ-tocopherol (highest vs. lowest quartile: OR = 4.15, 95% CI = 3.00-5.74, p < 0.0001) levels were associated with increased odds of MASLD. Higher serum 25(OH)D levels were associated with reduced odds of MASLD (highest vs. lowest quartile: OR = 0.41, 95% CI = 0.27-0.61, p = 0.0001). Inverse associations with the condition were also observed for carotenoids (α-carotene, ß-carotene, α-cryptoxanthin, ß-cryptoxanthin, combined lutein and zeaxanthin, and lycopene) in the serum (Ps < 0.05). The results were comparable between men and women, except for those on α-tocopherol, for which a positive association was only observed for men (p = 0.01). Our results suggest potential protective associations of serum 25(OH)D and carotenoids with MASLD. The positive associations between tocopherols and MASLD may reflect pathophysiological conditions associated with the condition.

Changes in Nutritional Outcomes After Roux-en-Y Gastric Bypass: A Systematic Review and Meta-Analysis.

BACKGROUND: Bariatric surgery (BS) is the most effective treatment for severe obesity and it has beneficial effects on glycemic control and metabolism outcomes. However, the effects of BS on nutritional outcomes are controversial. Therefore, we aimed to evaluate the changes in several nutritional outcomes after Roux-en-Y gastric bypass (RYGB). METHODS: A comprehensive search was performed using the following databases: PubMed, Embase, Web of Science, Cochrane Library, WanFang and Chinese National Knowledge Infrastructure. The following outcomes were evaluated: vitamin A, 25-hydroxyvitamin D [25(OH)D], calcium, phosphorus, parathormone (PTH), iron, ferritin, vitamin B12, folate, and zinc. The pooled outcomes were expressed as standard mean difference (SMD) and 95% confidence interval (CI) using a random effects model. RESULTS: Fifty-six studies including 5645 individuals with obesity met the inclusion criteria. Serum 25(OH)D (SMD = 0.78, 95%CI 0.38 to 1.20, P < 0.001), phosphorus (SMD = 0.48, 95%CI 0.22 to 0.74, P < 0.001), PTH (SMD = 0.35, 95%CI 0.11 to 0.59, P = 0.005), vitamin B12 (SMD = 1.11, 95%CI 0.41 to 1.80, P = 0.002), and folate (SMD = 1.53, 95%CI 0.77 to 2.28, P < 0.001) significantly increased after RYGB compared with the baseline. Serum ferritin (SMD = - 1.67, 95%CI - 2.57 to - 0.77, P < 0.001), vitamin A (SMD = - 0.64, 95%CI - 0.99 to - 0.29, P < 0.001), and plasma zinc (SMD = - 0.58, 95%CI - 1.09 to - 0.06, P = 0.027) significantly decreased after RYGB. No significant changes in serum calcium (SMD = - 0.14, 95%CI - 0.40 to 0.11, P = 0.219) and iron (SMD = 0.26, 95%CI - 0.11 to 0.64, P = 0.165) were observed after RYGB. CONCLUSIONS: Despite the increased levels of 25(OH)D, phosphorus, vitamin B12 and folate, this meta-analysis revealed the unfavorable nutritional consequences after RYGB.

Evaluation of inflammatory biomarkers and vitamins in hospitalized patients with SARS-CoV-2 infection and post-COVID syndrome.

OBJECTIVES: Concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios predict prognosis and the need for oxygen therapy in patients hospitalized for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aims of the present study were to evaluate the changes of these biomarkers early in the course of infection, the association with the prior coronavirus disease (COVID-19) vaccination and therapeutic administration of Anti-SARS-CoV-2 monoclonal antibodies, investigation of other potential biomarkers including neuropilin, 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanosine in patients hospitalized with SARS-CoV-2 infection and an assessment of these biomarkers and vitamins A, E and D in patients with post-COVID syndrome. METHODS: Urine and blood samples were obtained on the 1st to the 4th day and 4th to 7th day from 108 patients hospitalized with COVID-19. Chromatography tandem mass spectrometry methods were used to analyse neopterin, kynurenine, tryptophan, liposoluble vitamins, and DNA damage biomarkers. RESULTS: A statistically significant decrease of neopterin, kynurenine and kynurenine/tryptophan ratios was observed on after 4th to 7th day of hospitalization, and concentrations of these biomarkers were increased in patients with poor prognosis and subsequent post-COVID syndrome. The concentrations of remaining biomarker and vitamins were not associated with outcomes, although markedly decreased concentrations of vitamin A, E and D were noted. CONCLUSIONS: The concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios decrease during the course of infection SARS-CoV-2 and are associated with the post-COVID syndrome. No other prognostic biomarkers were identified.

Antioxidant defense of children and adolescents with atopic dermatitis: Association with disease severity

Background: Atopic dermatitis (AD) is a relapsing, chronic cutaneous inflammatory disease with onset, in general, in early childhood. Chronic skin inflammation is associated with overproduction of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. Oxidative stress, an imbalance between the production of free radicals and antioxidant defense, results in tissue inflammation due to the upregulation of genes that encode inflammatory cytokines. This condition plays an important role in the pathogenesis of AD. Objective: To compare the antioxidant defense in children and adolescents with AD with that of healthy individuals and to verify the association of antioxidant defense with disease severity and nutritional status. Methods: Cross-sectional study that evaluated 48 children and adolescents with AD and 25 controls for nutritional assessment (body mass index z score [BMIZ] and height for age z score [HAZ]) and levels of vitamins A, C, E, and D, zinc (Zn), copper (Cu), antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx]), high-sensitivity C-reactive protein (CRP) and interleukin 33 (IL-33). Results: There was no significant difference in the comparison between AD and control groups for serum levels of vitamins (A, D, C, and E), copper, and antioxidant enzymes. Serum zinc levels were higher in the AD group (β = 24.20; 95% CI 13.95–34.91; P < 0.001) even after adjusting the BMIZ, HAZ, gender, IL-33, and CRP. Children and adolescents with moderate or severe AD compared to mild AD (SCORAD – 36.7±17.4 vs 11.8 ± 3.9; P < 0.001) had lower values of the vitamin E/total lipid ratio (3.68 [0.29;12.63] vs 5.92 [3.27;17.37]; P = 0.013) (AU)

Plasma Retinol Concentrations and Dietary Intakes of Mother-Infant Sets in Singleton versus Twin Pregnancy.

Vitamin A (retinol) is essential for normal fetal development, but the recommendation for maternal dietary intake (Retinol Activity Equivalent, RAE) does not differ for singleton vs. twin pregnancy, despite the limited evaluation of retinol status. Therefore, this study aimed to evaluate plasma retinol concentrations and deficiency status in mother-infant sets from singleton vs. twin pregnancies as well as maternal RAE intake. A total of 21 mother-infant sets were included (14 singleton, 7 twin). The HPLC and LC-MS/HS evaluated the plasma retinol concentration, and data were analyzed using the Mann-Whitney U test. Plasma retinol was significantly lower in twin vs. singleton pregnancies in both maternal (192.2 vs. 312.1 vs. mcg/L, p = 0.002) and umbilical cord (UC) samples (102.5 vs. 154.4 vs. mcg/L, p = 0.002). The prevalence of serum-defined vitamin A deficiency (VAD) <200.6 mcg/L was higher in twins vs. singletons for both maternal (57% vs. 7%, p = 0.031) and UC samples (100% vs. 0%, p < 0.001), despite a similar RAE intake (2178 vs. 1862 mcg/day, p = 0.603). Twin pregnancies demonstrated a higher likelihood of vitamin A deficiency in mothers, with an odds ratio of 17.3 (95% CI: 1.4 to 216.6). This study suggests twin pregnancy may be associated with VAD deficiency. Further research is needed to determine optimal maternal dietary recommendations during twin gestation.

Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patients.

The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, or in the transcriptionally active form as retinoic acid. The main function of retinol binding protein 4 (RBP4), synthesized in the liver, is to transport hydrophobic vitamin A to various tissues. Vitamin A has an important role in the innate and acquired immune system. In particular, it is involved in the repair of lung tissue after infections. In viral respiratory diseases such as influenza pneumonia, vitamin A supplementation has been shown to reduce mortality in animal models. In critically ill COVID-19 patients, a significant decrease in plasma vitamin A levels and an association with increased mortality have been observed. However, there is no evidence on RBP4 in relation to COVID-19. This prospective, multicenter, observational, cross-sectional study examined RBP4 (enzyme-linked immunosorbent assay) and vitamin A plasma levels (high-performance liquid chromatography) in COVID-19 patients, including 59 hospitalized patients. Of these, 19 developed critical illness (ARDS/ECMO), 20 developed severe illness (oxygenation disorder), and 20 developed moderate illness (no oxygenation disorder). Twenty age-matched convalescent patients following SARS-CoV-2 infection, were used as a control group. Reduced RBP4 plasma levels significantly correlated with impaired liver function and elevated inflammatory markers (CRP, lymphocytopenia). RBP4 levels were decreased in hospitalized patients with critical illness compared to nonpatients (p < 0.01). In comparison, significantly lower vitamin A levels were detected in hospitalized patients regardless of disease severity. Overall, we conclude that RBP4 plasma levels are significantly reduced in critically ill COVID-19 patients during acute inflammation, and vitamin A levels are significantly reduced in patients with moderate/severe/critical illness during the acute phase of illness.

Blood retinol and retinol-binding protein concentrations are associated with diabetes: a systematic review and meta-analysis of observational studies.

PURPOSE: The associations between blood retinol, retinol-binding protein (RBP) concentrations and diabetes mellitus were inconsistent in literature. The objective is to investigate these associations by a systematic review and meta-analysis and provide basis for clinical intervention. METHODS: PubMed, Web of science, and Cochrane databases were searched from the beginning to July 1, 2021. A total of 13 studies on retinol and 31 studies on RBP are included in the current meta-analysis. RESULTS: The blood retinol concentration was significantly lower in the type I diabetes mellitus (T1DM) [standardized mean difference (SMD) (95% CI): - 0.59 (- 0.81, - 0.37), P < 0.01] and gestational diabetes mellitus (GDM) patients [SMD (95% CI): - 0.54 (- 0.87, - 0.20), P < 0.01] than in the controls. However, the difference was not significant between the type II diabetes mellitus (T2DM) patients and the controls. The RBP concentration was significantly higher in the diabetic patients than in the controls [SMD (95% CI): 0.24 (0.12, 0.35), P < 0.01]. Particularly, the RBP concentration was significantly higher in the T2DM and GDM patients. CONCLUSION: The blood retinol concentration was negatively associated with T1DM and GDM, while the blood RBP concentration was positively associated with T2DM and GDM. Future work should use a more sensitive retinol measurement method like retinol isotope dilution method to confirm whether blood retinol concentration differs between the diabetes patients and the controls.

Baseline Levels of Retinol-Binding Protein 4 and Vitamin A in Healthy Subjects, Stargardt Disease, and Geographic Atrophy Patients.

INTRODUCTION: The accumulation of lipofuscin is a hallmark in the pathogenesis of Stargardt disease type 1 (STGD1) and geographic atrophy (GA) secondary to age-related macular degeneration. Limiting lipofuscin accumulation by inhibiting the retinol-binding protein 4 (RBP4) is being explored as a potential treatment target for those diseases. In this study, we aimed to establish the concentration of RBP4 in the systemic circulation in different age cohorts of healthy individuals and to check if patients with STGD1 or GA may show abnormal RBP4 levels. METHODS: Forty healthy subjects of various age-groups, 15 Stargardt patients, and 15 GA patients were included in the study. We measured RBP4 levels, serum retinol (SR) levels, complete blood count, and blood chemistry including liver function tests. RESULTS: Mean RBP4 for all cohorts was 26,911.40 ± 6,198.61 ng/mL, and mean SR 1.75 ± 0.36 µmol/L. Age was not found to significantly impact levels neither of RBP4 and SR nor of the RBP4-to-SR ratio. Also, the 2 patient groups showed similar blood levels to their age-matched controls. CONCLUSION: Serum RBP4 and SR do not appear to be affected by age in healthy individuals and remain within normal limits in both STGD1 and GA.

Higher serum vitamin A is associated with a worsened progression of non-alcoholic fatty liver disease in adults: a prospective study.

Background: The association between serum vitamin A and non-alcoholic fatty liver disease (NAFLD) remains uncertain due to inconsistent results and scarce longitudinal data. We examined the prospective associations between serum vitamin A and the evolution of the NAFLD severity score as well as the potential mediating effects in middle-aged and older Chinese adults. Method: A total of 2658 adults (between 40-75 years of age) were included in the analysis. We determined the serum concentrations of vitamin A at the onset of the study (the baseline), and the degree of NAFLD after years 3 and 6. Results: Subjects were classified into stable, progressed, and improved groups according to the changes in their severity score (0-3) of NAFLD between two visits. Analyses of covariance showed that the serum VA concentrations were positively associated with NAFLD progression (all p-trend < 0.05). After adjusting for potential confounders, the mean differences in the serum vitamin A were 7.7% lower in the improved group than those in the progressed group among the total population. Path analyses showed that vitamin A was positively associated with the serum retinol-binding protein 4, triglycerides, insulin resistance, and body mass index (standardized ß 0.065-0.304, all p < 0.001), and all of these factors positively correlated with the prevalence and progression of NAFLD (standardized ß 0.045-0.384, all p < 0.01). Conclusions: A higher serum vitamin A concentration was associated with NAFLD progression, which might be mediated by increases in the serum retinol-binding protein 4, triglycerides, insulin resistance, and body mass index.

Essential metals, vitamins and antioxidant enzyme activities in COVID-19 patients and their potential associations with the disease severity.

The role of micronutrient deficiency in the pathogenesis of COVID-19 has been reviewed in the literature; however, the data are limited and conflicting. This study investigated the association between the status of essential metals, vitamins, and antioxidant enzyme activities in COVID-19 patients and disease severity. We recruited 155 patients, who were grouped into four classes based on the Adults guideline for the Management of Coronavirus Disease 2019 at King Faisal Specialist & Research Centre (KFSH&RC): asymptomatic (N = 16), mild (N = 49), moderate (N = 68), and severe (N = 22). We measured serum levels of copper (Cu), zinc (Zn), selenium (Se), vitamin D3, vitamin A, vitamin E, total antioxidant capacity, and superoxide dismutase (SOD). Among the patients, 30%, 25%, 37%, and 68% were deficient in Se (< 70.08 µg/L), Zn (< 0.693 µg/mL), vitamin A (< 0.343 µg/mL), and vitamin D3 (< 20.05 µg/L), respectively, and SOD activity was low. Among the patients, 28% had elevated Cu levels (> 1.401 µg/mL, KFSH&RC upper reference limit). Multiple regression analysis revealed an 18% decrease in Se levels in patients with severe symptoms, which increased to 30% after adjusting the model for inflammatory markers. Regardless of inflammation, Se was independently associated with COVID-19 severity. In contrast, a 50% increase in Cu levels was associated with disease severity only after adjusting for C-reactive protein, reflecting its possible inflammatory and pro-oxidant role in COVID-19 pathogenesis. We noted an imbalance in the ratio between Cu and Zn, with ~ 83% of patients having a Cu/Zn ratio > 1, which is an indicator of inflammation. Cu-to-Zn ratio increased to 45% in patients with mild symptoms and 34%-36% in patients with moderate symptoms compared to asymptomatic patients. These relationships were only obtained when one of the laboratory parameters (lymphocyte or monocyte) or inflammatory markers (neutrophil-to-lymphocyte ratio) was included in the regression model. These findings suggest that Cu/Zn might further exacerbate inflammation in COVID-19 patients and might be synergistically associated with disease severity. A 23% decrease in vitamin A was seen in patients with severe symptoms, which disappeared after adjusting for inflammatory markers. This finding may highlight the potential role of inflammation in mediating the relationship between COVID-19 severity and vitamin A levels. Despite our patients' low status of Zn, vitamin D3, and antioxidant enzyme (SOD), there is no evidence of their role in COVID-19 progression. Our findings reinforce that deficiency or excess of certain micronutrients plays a role in the pathogenesis of COVID-19. More studies are required to support our results.

Persistent hypercobalaminemia three months after successful gradual attenuation of extrahepatic shunts in dogs: a prospective cohort study.

BACKGROUND: Deficiencies in vitamin A and D and disorders in the vitamin B complex are often present in people with chronic liver diseases. So far, the serum concentrations of these vitamins have not yet been studied in dogs with congenital extrahepatic portosystemic shunts (EHPSS), who also have some degree of liver dysfunction. The objective was to assess serum vitamin concentrations in dogs with EHPSS from diagnosis to complete closure. A prospective cohort study was performed using ten client-owned dogs with EHPSS, closed after gradual surgical attenuation. Serum concentrations of vitamin A, 25-hydroxyvitamin D, folic acid, cobalamin and methylmalonic acid (MMA) were measured at diagnosis prior to institution of medical therapy, prior to surgery, and three months after gradual attenuation and complete closure of the EHPSS. RESULTS: At diagnosis, median serum concentrations of vitamin A, 25-hydroxyvitamin D and folic acid were 18.2 µg/dL (8.8 - 79.5 µg/dL), 51.8 ng/mL (19.4 - 109.0 ng/mL), and 8.1 µg/L (5.2 - 14.5 µg/L), respectively, which increased significantly postoperatively (88.3 µg/dL (51.6 - 182.2 µg/dL, P=0.005), 89.6 ng/mL (49.3 - >150.0 ng/mL, P =0.005), and 14.8 µg/L (11.5 - 17.7 µg/L, P <0.001), respectively). Median serum cobalamin concentrations were 735.5 ng/L (470 - 1388 ng/L) at diagnosis and did not significantly decrease postoperatively (P =0.122). Both at diagnosis and three months postoperatively 7/10 dogs had hypercobalaminemia. CONCLUSIONS: Serum concentrations of vitamin A, 25-hydroxyvitamin D and folic acid significantly increase after surgical attenuation. Nevertheless, persistent hypercobalaminemia is suggestive of ongoing liver dysfunction, despite successful surgery.

Effect of Statin Therapy on the Plasma Concentrations of Retinol, Alpha-Tocopherol and Coenzyme Q10 in Children with Familial Hypercholesterolemia.

PURPOSE: Familial hypercholesterolemia (FH) requires early treatment. However, statins, which are regarded the first-line therapy, have an influence on redox balance. Antioxidant vitamins are important for many metabolic processes in the developing body. There are few data available on the long-term safety of statin use in children. The aim of this study was to evaluate the influence of statin treatment in children with FH on plasma concentrations of antioxidant vitamins: retinol, alpha-tocopherol and coenzyme Q10. METHODS: The first study group consisted of 13 children aged 10-18 years treated with simvastatin for at least 6 months, and the second group comprised 13 age- and sex-matched children with hypercholesterolemia, in whom pharmacological treatment had not been applied yet. Analyses were performed using a high-performance liquid chromatograph coupled with a MS detector. RESULTS: The analysis did not reveal significant differences in the concentration of retinol, alpha-tocopherol or coenzyme Q10 between the studied groups. The adjustment of the concentrations of the vitamins to the cholesterol level also indicated no significant differences. We found no deficits in antioxidant vitamins in patients treated with statins, or any risk of adverse effects associated with an increase in their concentration. CONCLUSION: There is no rationale for additional supplementation using antioxidant vitamins or modification of low-fat and low-cholesterol diet in pediatric patients treated with statins.