Vitamin C Deficiency in the Young Brain-Findings from Experimental Animal Models.

Severe and long-term vitamin C deficiency can lead to fatal scurvy, which is fortunately considered rare today. However, a moderate state of vitamin C (vitC) deficiency (hypovitaminosis C)-defined as a plasma concentration below 23 µM-is estimated to affect up to 10% of the population in the Western world, albeit clinical hallmarks in addition to scurvy have not been linked to vitC deficiency. The brain maintains a high vitC content and uniquely high levels during deficiency, supporting vitC's importance in the brain. Actions include both antioxidant and co-factor functions, rendering vitamin C deficiency likely to affect several targets in the brain, and it could be particularly significant during development where a high cellular metabolism and an immature antioxidant system might increase sensitivity. However, investigations of a non-scorbutic state of vitC deficiency and effects on the developing young brain are scarce. This narrative review provides a comprehensive overview of the complex mechanisms that regulate vitC homeostasis in vivo and in the brain in particular. Functions of vitC in the brain and the potential consequences of deficiency during brain development are highlighted, based primarily on findings from experimental animal models. Perspectives for future investigations of vitC are outlined.

Circulating vitamin C and the risk of cardiovascular diseases: A Mendelian randomization study.

BACKGROUND AND AIMS: The impact of vitamin C supplementation on the risk of cardiovascular diseases (CVDs) remains uncertain with inconsistent evidence obtained from observational studies and randomized clinical trials (RCTs). We aimed to assess possible causal associations of vitamin C with major CVD events as well as their risk factors using Mendelian randomization (MR) design. METHODS AND RESULTS: Nine genetic variants associated with vitamin C at genome-wide significance (p < 5 × 10-8) were used as instrumental variables to predict plasma vitamin C levels. The primary outcomes were coronary artery disease (Ncase = 122,733 and Ncontrol = 424,528), atrial fibrillation (Ncase = 60,620 and Ncontrol = 970,216), heart failure (Ncase = 47,309 and Ncontrol = 930,014), and ischemic stroke (Ncase = 40,585 and Ncontrol = 406,111). Several CVD risk factors were also evaluated in secondary analyses. Two-sample MR analyses were performed using the inverse variance weighted method, with several sensitivity analyses. Genetically determined higher levels of plasma vitamin C were not significantly associated with any of the four examined CVD events. Likewise, there is no convincing evidence for the associations between genetically determined vitamin C and CVD risk factors, including higher blood lipids, higher blood pressure, and abnormal body composition. Sensitivity analyses using different analytical approaches yielded consistent results. Additionally, MR assumptions did not seem to be violated. CONCLUSION: This MR study does not support a causal protective role to circulate vitamin C levels on various types of CVD events. In combination with previous RCT results, our findings suggest that vitamin C supplementation to increase circulating vitamin C levels may not help in CVD prevention.

Plasma Vitamin C Concentrations Were Negatively Associated with Tingling, Prickling or Pins and Needles Sensation in Patients with Postherpetic Neuralgia.

Vitamin C deficiency increases the risk of postherpetic neuralgia (PHN). In this cross-sectional study, the relationships among plasma vitamin C concentrations, pain and Leeds assessment of neuropathic symptoms and signs (LANSS) items were investigated during their first pain clinic visit of 120 PHN patients. The factors associated with vitamin C deficiency were determined. Independent predictors of vitamin C deficiency were presented as adjusted odds ratios (AOR) and 95% confidence intervals (CI). The patients had a high prevalence (52.5%) of vitamin C deficiency. Their plasma vitamin C concentrations were negatively associated with spontaneous pain and tingling, prickling or pins and needles sensation according to the LANSS questionnaire. Based on the receiver operator characteristic curve, the cutoffs for plasma vitamin C to predict moderate-to-severe and severe symptoms of sharp sensation were <7.05 and <5.68 mg/L, respectively. By comparison, the patients well-nourished with vitamin C had lower incidences of sharp sensations, sharp pain, and reddish skin. Multivariate analyses revealed that vitamin C deficiency was associated with the low intake of fruit/vegetables (AOR 2.66, 95% CI 1.09-6.48, p = 0.032), peptic ulcer disease (AOR 3.25, 95% CI 1.28-8.28, p = 0.014), and smoking (AOR 3.60, 95% CI 1.33-9.77, p = 0.010). Future studies are needed to substantiate these findings.

Vitamin C Deficiency and the Risk of Osteoporosis in Patients with an Inflammatory Bowel Disease.

Recent research studies have shown that vitamin C (ascorbic acid) may affect bone mineral density and that a deficiency of ascorbic acid leads to the development of osteoporosis. Patients suffering from an inflammatory bowel disease are at a risk of low bone mineral density. It is vital to notice that patients with Crohn's disease and ulcerative colitis also are at risk of vitamin C deficiency which is due to factors such as reduced consumption of fresh vegetables and fruits, i.e., the main sources of ascorbic acid. Additionally, some patients follow diets which may provide an insufficient amount of vitamin C. Moreover, serum vitamin C level also is dependent on genetic factors, such as SLC23A1 and SLC23A2 genes, encoding sodium-dependent vitamin C transporters and GSTM1, GSTP1 and GSTT1 genes which encode glutathione S-transferases. Furthermore, ascorbic acid may modify the composition of gut microbiota which plays a role in the pathogenesis of an inflammatory bowel disease.

The neuropsychiatric effects of vitamin C deficiency: a systematic review.

BACKGROUND: Vitamin C deficiency may be more common than is generally assumed, and the association between vitamin C deficiency and adverse psychiatric effects has been known for centuries. This paper aims to systematically review the evidence base for the neuropsychiatric effects of vitamin C deficiency. METHODS: Relevant studies were identified via systematic literature review. RESULTS: Nine studies of vitamin C deficiency, including subjects both with and without the associated physical manifestations of scurvy, were included in this review. Vitamin C deficiency, including scurvy, has been linked to depression and cognitive impairment. No effect on affective or non-affective psychosis was identified. CONCLUSIONS: Disparate measurement techniques for vitamin C, and differing definitions of vitamin C deficiency were apparent, complicating comparisons between studies. However, there is evidence suggesting that vitamin C deficiency is related to adverse mood and cognitive effects. The vitamin C blood levels associated with depression and cognitive impairment are higher than those implicated in clinical manifestations of scurvy. While laboratory testing for ascorbic acid can be practically difficult, these findings nonetheless suggest that mental health clinicians should be alerted to the possibility of vitamin C deficiency in patients with depression or cognitive impairment. Vitamin C replacement is inexpensive and easy to deliver, although as of yet there are no outcome studies investigating the neuropsychiatric impact of vitamin C replacement in those who are deficient.

Vitamin C in Home Parenteral Nutrition: A Need for Monitoring.

To date, there are no recommendations about screening plasma vitamin C concentration and adjust its supplementation in patients on long-term home parenteral nutrition (HPN). The aim of this study was to evaluate vitamin C status and determine if a commercial multivitamin preparation (CMVP) containing 125 mg of vitamin C is sufficient in stable patients on HPN. All clinically stable patients receiving HPN or an intravenous fluid infusion at least two times per week for at least 6 months, hospitalized for nutritional assessment, were retrospectively included, for a total of 186 patients. We found that 29% of the patients had vitamin C insufficiency (i.e., <25 µmol/L). In univariate analysis, C-reactive protein (CRP) (p = 0.002) and intake of only 125 mg of vitamin C (p = 0.001) were negatively associated with vitamin C levels, and duration of follow-up in our referral center (p = 0.009) was positively associated with vitamin C levels. In multivariate analysis, only CRP (p = 0.001) and intake of 125 mg of vitamin C (p < 0.0001) were independently associated with low plasma vitamin C concentration. Patients receiving only CMVP with a low plasma vitamin C level significantly received personal compounded HPN (p = 0.008) and presented an inflammatory syndrome (p = 0.002). Vitamin C insufficiency is frequent in individuals undergoing home parenteral nutrition; therefore, there is a need to monitor plasma vitamin C levels, especially in patients on HPN with an inflammatory syndrome and only on CMVP.

Food Sources and Potential Determinants of Dietary Vitamin C Intake in Chinese Adults: A Cross-Sectional Study.

Vitamin C is essential for human health. It is important to estimate the dietary vitamin C intake in the Chinese population to examine the effects of the nutritional transition occurred in recent decades. The present study aimed to estimate the dietary vitamin C intake in Chinese adults by using cross-sectional data from the 2015 China Nutritional Transition Cohort Study and selecting those aged 18-65 years with complete records of sociodemographic characteristics and dietary measurements (n = 11,357). Wilcoxon rank-sum test, Kruskal-Wallis analysis, Chi-squared test, and multiple logistic regression were employed to analyze the daily dietary vitamin C intake on the basis of three-day 24 h dietary recalls and food sources in relation to demographic factors, to evaluate vitamin C intake status using the estimated average requirement cut-off point, and to explore underlying influencing factors. The mean (SD (standard deviation)) and median (interquartile range) levels of the dietary vitamin C intake in adults were 78.1 (54.6) and 65.4 (61.4) mg/day, respectively. Light vegetables, dark vegetables, fruits, and tubers were the top four food sources, contributing a combined 97.3% of total daily dietary vitamin C intake in the study population. The prevalence of risk of insufficient dietary vitamin C intake was 65.1%. Both the distribution of vitamin C intake and the prevalence of risk of insufficient dietary vitamin C intake differed by several demographic factors. Educational level, residence area, geographic location, vegetable consumption, and total energy intake were independent determinants of the risk of insufficient dietary vitamin C intake. In conclusion, dietary vitamin C intake is inadequate in Chinese adult population, and an increase in vitamin C intake should be recommended especially to the population at risk for vitamin C insufficiency.

Dietary Intake of Ascorbic Acid Attenuates Lipopolysaccharide-Induced Sepsis and Septic Inflammation in ODS Rats.

The aim of this study was to verify the protective effects of ascorbic acid (AsA) against lipopolysaccharide (LPS)-induced sepsis. The study was conducted using osteogenic disorder Shionogi (ODS) rats, which are unable to synthesize AsA. Male ODS rats (6 wk old) were fed either an AsA-free diet (AsA-deficient group), a diet supplemented with 300 mg/kg AsA (control group), or a diet supplemented with 3,000 mg/kg AsA (high-AsA group) for 8 d. On day 8, all the rats were intraperitoneally injected with LPS (15 mg/kg body weight). Forty-eight hours after the injection, the survival rates of the rats in the control (39%) and the high-AsA (61%) groups were significantly higher than that in the AsA-deficient group (5.5%). Next, we measured several inflammatory parameters during 10 h after administering LPS. At 6 h, elevated serum levels of markers for hepatic and systemic injuries were suppressed in rats fed AsA. Similarly, 10 h after LPS injection, the elevation in the serum levels of markers for renal injury were also suppressed proportionally to the amount of AsA in the diet. The elevated serum concentrations of TNFα and IL-1ß by LPS in the AsA-deficient group decreased in groups fed AsA. Hematic TNFα mRNA levels at 6 h after the LPS injection were also lowered by feeding AsA. These results demonstrated that the dietary intake of AsA improved the survival rates and suppressed the inflammatory damage, in a dose-dependent manner, caused during sepsis induced by LPS in ODS rats.

Plasma concentrations of ascorbic acid in a cross section of the German population.

Objectives Vitamin C deficiency is considered extremely rare in modern industrialized countries. This study was performed to assess vitamin C concentrations in the German population. Methods As part of a consultant-patient seminar on nutrition and food intolerances, patients were asked to participate in this study on a voluntary basis. Blood samples were taken for analysis of serum vitamin C concentrations, and all patients were asked to complete a questionnaire. The vitamin C concentration was determined by high-performance liquid chromatography. Results Of approximately 300 patients attending the seminar, 188 (62.6%) consented to vitamin C blood sample analysis and 178 (59.3%) answered the questionnaire. The mean vitamin C concentration was 7.98 mg/L (range, 0.50-17.40; reference range, 5-15 mg/L). A low plasma level with vitamin C insufficiency (<5 mg/L) was found in 31 patients (17.4%), and a potential scorbutogenic deficiency (<1.5 mg/L) was found in 6 (3.3%). Conclusions Potential vitamin C insufficiency and deficiency is common. It is therefore possible, even in modern developed populations, that certain individuals may require a higher intake of vitamin C.

Vitamin C Deficiency, High-Sensitivity C-Reactive Protein, and Cardiac Event-Free Survival in Patients With Heart Failure.

BACKGROUND: Vitamin C is related to lower levels of high-sensitivity C-reactive protein (hsCRP), an inflammatory biomarker that predicts cardiovascular disease. Whether vitamin C deficiency is associated with hsCRP and cardiac events in heart failure (HF) patients has not been examined. PURPOSE: The aim of this study is to determine the relationships among vitamin C intake, serum levels of hsCRP, and cardiac events. METHODS: A total of 200 HF patients completed a 3-day food diary to determine vitamin C deficiency and provided blood to measure serum levels of hsCRP. Patients were followed for 2 years to obtain data on cardiac event-free survival. Moderation analyses with hierarchical logistic and Cox regressions were used for the data analysis. RESULTS: Seventy-eight patients (39%) had vitamin C deficiency and 100 (50%) had an hsCRP level higher than 3 mg/L. Vitamin C deficiency was associated with an hsCRP level higher than 3 mg/L in the hierarchical logistic regression (odds ratio, 2.40; 95% confidence interval, [1.13-5.10]; P = .023). Vitamin C deficiency (hazard ratio, 1.68; 95% CI, 1.05-2.69, P = .029) and hsCRP level higher than 3 mg/L (hazard ratio, 1.79; 95% CI, 1.07-3.01; P = .027) predicted shorter cardiac event-free survival in hierarchical Cox regression. The interaction of hsCRP level higher than 3 mg/L and vitamin C deficiency produced a 2.3-fold higher risk for cardiac events (P = .002) in moderation analysis. Higher level of hsCRP predicted shorter cardiac event-free survival only in patients with vitamin C deficiency (P = .027), but not in those with vitamin C adequacy. CONCLUSION: Vitamin C deficiency moderated the relationship between inflammation and cardiac events in patients with HF. Future study is required to determine whether adequate intake of vitamin C could play a protective role against the impact of inflammation on cardiac events in HF patients.

Vitamin C is not the Missing Link Between Cigarette Smoking and Spinal Pain.

STUDY DESIGN: A nationwide cross-sectional study. OBJECTIVES: To measure the associations between cigarette smoking (defined as serum cotinine concentration >15 ng/mL) and the 3-month prevalence of spinal pain (neck pain, low back pain, low back pain with pain below knee, and self-reported diagnosis of arthritis/rheumatism) and related limitations, and to verify whether these associations are mediated by serum concentrations of vitamin C. SUMMARY OF BACKGROUND DATA: Cigarette smoking has been consistently associated with back pain, but this association has never been explained. Because vitamin C has recently been reported to be associated with spinal pain and related functional limitations, and the metabolism of vitamin C differs between smokers and nonsmokers, we hypothesized that the prevalence of spinal pain and related limitations might be greater among smokers because they are more susceptible to be in a state of hypovitaminosis C. METHODS: We conducted secondary analyses of National Health and Nutrition Examination Survey (NHANES) 2003 to 2004 data on 4438 individuals aged ≥20 years. RESULTS: Serum concentrations of vitamin C and cotinine were strongly and inversely correlated (r = -0.35, P < 0.0001). Smoking was statistically associated with the prevalence of neck pain [adjusted odds ratio: aOR: 1.25; 95% confidence interval (95% CI): 1.06-1.47], low back pain (aOR: 1.20; 95% CI: 1.04-1.39), and low back pain with pain below knee (aOR: 1.58; 95% CI: 1.13-2.22) and related limitations, with a dose-response relationship (P < 0.05). However, the associations between smoking and spinal pain were not mediated by concentrations of vitamin C. CONCLUSION: These results confirm the relationship between smoking and spinal pain, but they do not support a mediating effect of vitamin C on this relationship. LEVEL OF EVIDENCE: 2.

Inadequate Vitamin C Status in Prediabetes and Type 2 Diabetes Mellitus: Associations with Glycaemic Control, Obesity, and Smoking.

Vitamin C (ascorbate) is an essential micronutrient in humans, being required for a number of important biological functions via acting as an enzymatic cofactor and reducing agent. There is some evidence to suggest that people with type 2 diabetes mellitus (T2DM) have lower plasma vitamin C concentrations compared to those with normal glucose tolerance (NGT). The aim of this study was to investigate plasma vitamin C concentrations across the glycaemic spectrum and to explore correlations with indices of metabolic health. This is a cross-sectional observational pilot study in adults across the glycaemic spectrum from NGT to T2DM. Demographic and anthropometric data along with information on physical activity were collected and participants were asked to complete a four-day weighed food diary. Venous blood samples were collected and glycaemic indices, plasma vitamin C concentrations, hormone tests, lipid profiles, and high-sensitivity C-reactive protein (hs-CRP) were analysed. A total of 89 participants completed the study, including individuals with NGT (n = 35), prediabetes (n = 25), and T2DM managed by diet alone or on a regimen of Metformin only (n = 29). Plasma vitamin C concentrations were significantly lower in individuals with T2DM compared to those with NGT (41.2 µmol/L versus 57.4 µmol/L, p < 0.05) and a higher proportion of vitamin C deficiency (i.e. <11.0 µmol/L) was observed in both the prediabetes and T2DM groups. The results showed fasting glucose (p = 0.001), BMI (p = 0.001), smoking history (p = 0.003), and dietary vitamin C intake (p = 0.032) to be significant independent predictors of plasma vitamin C concentrations. In conclusion, these results suggest that adults with a history of smoking, prediabetes or T2DM, and/or obesity, have greater vitamin C requirements. Future research is required to investigate whether eating more vitamin C rich foods and/or taking vitamin C supplements may reduce the risk of progression to, and/or complications associated with, T2DM.

Vitamin C Status Correlates with Markers of Metabolic and Cognitive Health in 50-Year-Olds: Findings of the CHALICE Cohort Study.

A cohort of 50-year-olds from Canterbury, New Zealand (N = 404), representative of midlife adults, undertook comprehensive health and dietary assessments. Fasting plasma vitamin C concentrations (N = 369) and dietary vitamin C intake (N = 250) were determined. The mean plasma vitamin C concentration was 44.2 µmol/L (95% CI 42.4, 46.0); 62% of the cohort had inadequate plasma vitamin C concentrations (i.e., <50 µmol/L), 13% of the cohort had hypovitaminosis C (i.e., <23 µmol/L), and 2.4% had plasma vitamin C concentrations indicating deficiency (i.e., <11 µmol/L). Men had a lower mean plasma vitamin C concentration than women, and a higher percentage of vitamin C inadequacy and deficiency. A higher prevalence of hypovitaminosis C and deficiency was observed in those of lower socio-economic status and in current smokers. Adults with higher vitamin C levels exhibited lower weight, BMI and waist circumference, and better measures of metabolic health, including HbA1c, insulin and triglycerides, all risk factors for type 2 diabetes. Lower levels of mild cognitive impairment were observed in those with the highest plasma vitamin C concentrations. Plasma vitamin C showed a stronger correlation with markers of metabolic health and cognitive impairment than dietary vitamin C.

Poor Vitamin C Status Late in Pregnancy Is Associated with Increased Risk of Complications in Type 1 Diabetic Women: A Cross-Sectional Study.

Vitamin C (vitC) is essential for normal pregnancy and fetal development and poor vitC status has been related to complications of pregnancy. We have previously shown lower vitC status in diabetic women throughout pregnancy compared to that of non-diabetic controls. Here, we evaluate the relationship between vitC status late in diabetic pregnancy in relation to fetal outcome, complications of pregnancy, diabetic characteristics, and glycemic control based on data of 47 women from the same cohort. We found a significant relationship between the maternal vitC level > or ≤ the 50% percentile of 26.6 µmol/L, respectively, and the umbilical cord blood vitC level (mean (SD)): 101.0 µmol/L (16.6) versus 78.5 µmol/L (27.8), p = 0.02; n = 12/16), while no relation to birth weight or Apgar score was observed. Diabetic women with complications of pregnancy had significantly lower vitC levels compared to the women without complications (mean (SD): 24.2 µmol/L (10.6) vs. 34.6 µmol/L (14.4), p = 0.01; n = 19 and 28, respectively) and the subgroup of women (about 28%) characterized by hypovitaminosis C (<23 µmol/L) had an increased relative risk of complications of pregnancy that was 2.4 fold higher than the one found in the group of women with a vitC status above this level (p = 0.02, 95% confidence interval 1.2-4.4). No correlation between diabetic characteristics of the pregnant women and vitC status was observed, while a negative association of maternal vitC with HbA1c at delivery was found at regression analysis (r = -0.39, p < 0.01, n = 46). In conclusion, our results may suggest that hypovitaminosis C in diabetic women is associated with increased risk of complications of pregnancy.

Marginal Ascorbate Status (Hypovitaminosis C) Results in an Attenuated Response to Vitamin C Supplementation.

Inadequate dietary intake of vitamin C results in hypovitaminosis C, defined as a plasma ascorbate concentration ≤23 µmol/L. Our objective was to carry out a retrospective analysis of two vitamin C supplementation studies to determine whether supplementation with 50 mg/day vitamin C is sufficient to restore adequate ascorbate status (≥50 µmol/L) in individuals with hypovitaminosis C. Plasma ascorbate data from 70 young adult males, supplemented with 50 or 200 mg/day vitamin C for up to six weeks, was analyzed. Hypovitaminosis C status was identified based on plasma ascorbate being ≤23 µmol/L and the response of these individuals to vitamin C supplementation was examined. Of the participants consuming 50 mg/day vitamin C for up to six weeks, those with hypovitaminosis C at baseline achieved plasma concentrations of only ~30 µmol/L, whereas the remainder reached ~50 µmol/L. Participants who consumed 200 mg/day vitamin C typically reached saturating concentrations (>65 µmol/L) within one week, while those with hypovitaminosis C required two weeks to reach saturation. Regression modelling indicated that the participants' initial ascorbate status and body weight explained ~30% of the variability in the final ascorbate concentration. Overall, our analysis revealed that supplementation with 50 mg/day vitamin C, which resulted in a total dietary vitamin C intake of 75 mg/day, was insufficient to achieve adequate plasma ascorbate concentrations in individuals with hypovitaminosis C. Furthermore, increased body weight had a negative impact on ascorbate status.

Maternal vitamin C deficiency does not reduce hippocampal volume and ß-tubulin III intensity in prenatal Guinea pigs.

Marginal vitamin C (vitC) deficiency affects 5% to 10% of adults including subpopulations such as pregnant women and newborns. Animal studies link vitC deficiency to deleterious effects on the developing brain, but exactly how the brain adapts to vitC deficiency and the mechanisms behind the observed deficits remain largely unknown. We hypothesized that vitC deficiency in utero may lead to a decreased neuronal maturation and increased cellular death giving rise to alterations of the hippocampal morphology in a guinea pig model. Brains from prenatal guinea pig pups (n=9-10 in each group) subjected to either a sufficient (918mg vitC/kg feed) or deficient (100mg vitC/kg feed) maternal dietary regimen were assessed with regards to hippocampal volume and ß-tubulin isotype III staining intensity at 2 gestational time points (45 and 56). We found a distinct differential regional growth pattern of the hippocampus with a clear effect of gestational age, whereas vitC status did not affect either investigated parameters. Within hippocampal subdivisions, the overall expansion of the hippocampus from gestational day 45 to 56 was found to reside in the dentate gyrus. In conclusion, the present study found that hippocampal volume and ß-tubulin isotype III intensity in the prenatal guinea pig were influenced by gestational day but not by maternal vitC intake.