An increasing proportion of the population is not covered by the current RDA for vitamin C - interrogation of EPIC-Norfolk and NHANES 2017/2018 cohorts.

With the rising prevalence of obesity globally, increasing proportions of the population may not be covered by current recommended daily allowances (RDAs) that are supposed to provide 97.5% of the population with a sufficient nutrient status but are typically based on a healthy young 70 kg male reference person. Using the EPIC-Norfolk (UK) and the NHANES (US) cohorts, we estimated the effect of body weight on the dose-concentration relationship to derive weight-based requirements to achieve an 'adequate' plasma concentration of vitamin C estimated to be 50 µmol/L. Inverse correlations between body weight and vitamin C were observed in both cohorts (p < 0.0001). Moreover, only about 2/3 of the cohorts achieved an adequate plasma vitamin C status by consuming the RDA or above, while only 1/3 to 1/2 of the cohorts achieved adequacy by an intake of the local RDA ± 10%. Using vitamin C as an example, the present data demonstrate that a considerable and expectedly increasing proportion of the world population is unable to achieve an adequate target plasma concentration with the current recommended daily intakes of vitamin C. This needs to be considered in future public health recommendations.

In this paper, we highlight the inverse association between body weight and vitamin C status. Our study strongly suggests that a large proportion of the population is not covered by the current recommended intakes of vitamin C.

Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial.

BACKGROUND: Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C's enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock. METHODS: This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations. RESULTS: Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35-62) hours and in the placebo group was 54 (95% CI 41-62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05). CONCLUSIONS: Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence. TRIAL REGISTRATION: ACTRN12617001184369 (11/8/2017).

Discrepancies in global vitamin C recommendations: a review of RDA criteria and underlying health perspectives.

The concept of a 'recommended dietary allowance' (RDA) and similar terms describing the daily intake of essential nutrients recommended for healthy individuals is widely used by various health authorities around the world. For vitamin C, however, there remain significant discrepancies in the criteria used to establish dietary recommendations and consequently, global recommendations for daily vitamin C intake vary by more than five fold. While it appears that the scientific data underlying the recommendations are more or less the same, the interpretation differs considerably. Moreover, although a number of the assumptions used in e.g. the body pool estimates of the 1960s and 1970s have later been proven wrong and give rise to significant underestimations, these data are still used as the main support of several recommendations. Aspects that modify vitamin C requirements, such as gender, age, pregnancy, lactation, and smoking, have been taken into consideration by many but not all regulatory authorities, and are thus subject of debate. In contrast, body weight, a significant predictor of vitamin C status and requirement, has not been taken into consideration with respect to vitamin C recommendations, even in the face of the looming global obesity pandemic. The present review examines the discrepancies in vitamin C dietary recommendations of international authorities and critically discusses representative examples of criteria and the underlying health perspectives used to derive current recommended intakes of vitamin C. New biological signatures of vitamin C nutriture are also explored with regard to their potential use for future updates of dietary recommendations.

Harm of IV High-Dose Vitamin C Therapy in Adult Patients: A Scoping Review.

OBJECTIVES: The potential harm associated with the use of IV vitamin C has not been systematically assessed. We aimed to review the available evidence on harm related to such treatment. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Library, National Institute of Health Clinical Trials Register, and World Health Organization International Clinical Trials Registry Platform. STUDY SELECTION: We included studies in adult population that reported harm related to IV high-dose vitamin C which we defined as greater than or equal to 6 g/d, greater than or equal to 75 mg/kg/d, or greater than or equal to 3 g/m/d. DATA EXTRACTION: Two independent investigators screened records and extracted data. DATA SYNTHESIS: We identified 8,149 reports, of which 650 full text were assessed for eligibility, leaving 74 eligible studies. In these studies, 2,801 participants received high-dose vitamin C at a median (interquartile range) dose of 22.5 g/d (8.25-63.75 g/d), 455 mg/kg/d (260-925 mg/kg/d), or 70 g/m/d (50-90 g/m/d); and 932 or more adverse events were reported. Among nine double-blind randomized controlled trials (2,310 patients), adverse events were reported in three studies with an event rate per patient for high-dose vitamin C identical to placebo group in one study (0.1 [1/10] vs 0.1 [1/10]), numerically lower in one study (0.80 [672/839] vs 0.82 [709/869]), and numerically higher in one study (0.33 [24/73] vs 0.23 [17/74]). Six double-blind randomized controlled trials reported no adverse event in either group. Five cases of oxalate nephropathy, five cases of hypernatremia, three cases of hemolysis in glucose-6-phosphate dehydrogenase deficiency patients, two cases of glucometer error, and one case of kidney stones were also reported overall. CONCLUSIONS: There is no consistent evidence that IV high-dose vitamin C therapy is more harmful than placebo in double-blind randomized controlled trials. However, reports of oxalate nephropathy, hypernatremia, glucometer error, and hemolysis in glucose-6-phosphate dehydrogenase deficiency patients warrant specific monitoring.

The role of vitamin C in the treatment of pain: new insights.

The vitamin C deficiency disease scurvy is characterised by musculoskeletal pain and recent epidemiological evidence has indicated an association between suboptimal vitamin C status and spinal pain. Furthermore, accumulating evidence indicates that vitamin C administration can exhibit analgesic properties in some clinical conditions. The prevalence of hypovitaminosis C and vitamin C deficiency is high in various patient groups, such as surgical/trauma, infectious diseases and cancer patients. A number of recent clinical studies have shown that vitamin C administration to patients with chronic regional pain syndrome decreases their symptoms. Acute herpetic and post-herpetic neuralgia is also diminished with high dose vitamin C administration. Furthermore, cancer-related pain is decreased with high dose vitamin C, contributing to enhanced patient quality of life. A number of mechanisms have been proposed for vitamin C's analgesic properties. Herein we propose a novel analgesic mechanism for vitamin C; as a cofactor for the biosynthesis of amidated opioid peptides. It is well established that vitamin C participates in the amidation of peptides, through acting as a cofactor for peptidyl-glycine α-amidating monooxygenase, the only enzyme known to amidate the carboxy terminal residue of neuropeptides and peptide hormones. Support for our proposed mechanism comes from studies which show a decreased requirement for opioid analgesics in surgical and cancer patients administered high dose vitamin C. Overall, vitamin C appears to be a safe and effective adjunctive therapy for acute and chronic pain relief in specific patient groups.

Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes.

BACKGROUND: Vitamin C is an essential water-soluble nutrient which cannot be synthesised or stored by humans. It is a potent antioxidant with anti-inflammatory and immune-supportive roles. Previous research has indicated that vitamin C levels are depleted in critically ill patients. In this study we have assessed plasma vitamin C concentrations in critically ill patients relative to infection status (septic shock or non-septic) and level of inflammation (C-reactive protein concentrations). Vitamin C status was also assessed relative to daily enteral and parenteral intakes to determine if standard intensive care unit (ICU) nutritional support is adequate to meet the vitamin C needs of critically ill patients. METHODS: Forty-four critically ill patients (24 with septic shock, 17 non-septic, 3 uncategorised) were recruited from the Christchurch Hospital Intensive Care Unit. We measured concentrations of plasma vitamin C and a pro-inflammatory biomarker (C-reactive protein) daily over 4 days and calculated patients' daily vitamin C intake from the enteral or total parenteral nutrition they received. We compared plasma vitamin C and C-reactive protein concentrations between septic shock and non-septic patients over 4 days using a mixed effects statistical model, and we compared the vitamin C status of the critically ill patients with known vitamin C bioavailability data using a four-parameter log-logistic response model. RESULTS: Overall, the critically ill patients exhibited hypovitaminosis C (i.e., < 23 µmol/L), with a mean plasma vitamin C concentration of 17.8 ± 8.7 µmol/L; of these, one-third had vitamin C deficiency (i.e., < 11 µmol/L). Patients with hypovitaminosis C had elevated inflammation (C-reactive protein levels; P < 0.05). The patients with septic shock had lower vitamin C concentrations and higher C-reactive protein concentrations than the non-septic patients (P < 0.05). Nearly 40% of the septic shock patients were deficient in vitamin C, compared with 25% of the non-septic patients. These low vitamin C levels were apparent despite receiving recommended intakes via enteral and/or parenteral nutritional therapy (mean 125 mg/d). CONCLUSIONS: Critically ill patients have low vitamin C concentrations despite receiving standard ICU nutrition. Septic shock patients have significantly depleted vitamin C levels compared with non-septic patients, likely resulting from increased metabolism due to the enhanced inflammatory response observed in septic shock.

The development and effectiveness of an ecological momentary intervention to increase daily fruit and vegetable consumption in low-consuming young adults.

OBJECTIVES: To develop and test the effectiveness of a mobile-phone based ecological momentary intervention (EMI) to increase fruit and vegetable (FV) consumption in low-consuming young adults. METHODS: A two-week randomised controlled trial of low-FV consuming young adults ages 18-25 years (n = 171) compared three conditions: ecological momentary intervention (EMI), fruit and vegetable intervention (FVI), and a diet-as-usual control (ANZCTRN12615000183583). Participants in the EMI condition were sent two targeted text messages a day for 13 days and were asked to increase daily FV consumption to at least five servings. These messages were designed, using the Health Action Process Approach, to address salient beliefs identified as effective in a preliminary focus group investigation. Participants in the FVI condition were provided two servings of FV a day (carrots, kiwifruit or oranges, and apples) to eat in addition to their current diet. Control participants ate their normal diet. Participants reported their daily servings of FV each evening during the study using a smartphone-delivered survey. Blood samples testing plasma vitamin C and total carotenoids were taken pre- and post-intervention as an objective biomarker of FV intake. RESULTS: Participants in the EMI and FVI conditions reported higher daily servings of FV - approximately +1 serving per day more compared to control (EMI = 3.7 servings/day; FVI = 3.7 servings/day; Control = 2.8 servings/day) and approximately +1.2 servings compared to baseline. Increases in objective biomarkers for the experimental conditions supported the validity of self-reported FV consumption. CONCLUSIONS: Our results provide initial proof of concept that EMI strategies (with minor financial assistance) are as effective as giving FV in increasing FV consumption in educated, low-consuming young adults.

Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock?

Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine ß-hydroxylase and peptidylglycine α-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock.

Understanding the additional impact of prediabetes and type 2 diabetes mellitus on vitamin C requirements in people living with obesity.

Obesity and diabetes are known to negatively affect vitamin C status. However, whether the presence of diabetes, in addition to obesity, contributes an additional impact on vitamin C status is currently uncertain. In a cohort of 152 adults living with obesity, we assessed metabolic and nutrient parameters in participants without diabetes (n = 92), and with prediabetes (n = 22) and type 2 diabetes mellitus (T2DM; n = 35). Vitamin C concentrations were measured in plasma and leukocytes using HPLC and vitamin C intakes were assessed using 24-hour dietary recall. Metabolic severity scores were derived using gender, ethnicity, height, weight, waist circumference, systolic blood pressure, fasting glucose, HDL, and triglyceride values. In people living with obesity, those with prediabetes and T2DM had increased metabolic dysregulation and decreased vitamin C status relative to those without diabetes (P < .05). Vitamin C deficiency was observed in a high proportion (23%-32%) of participants with prediabetes and T2DM and ≥50% had hypovitaminosis C. However, there was no difference in vitamin C intake between those without diabetes and those with prediabetes or T2DM (P > .05). There was a significant inverse correlation between plasma vitamin C status and metabolic severity score (r = -0.290, P < .001). Linear regression indicated that for every 1-unit increase in metabolic severity score, there was a 6.5 µmol/L decrease in vitamin C status. Thus, the enhanced metabolic dysregulation observed with prediabetes and T2DM is associated with an increased demand for vitamin C in people living with obesity.

A High Vitamin C Micronutrient Supplement Is Unable to Attenuate Inflammation in People with Metabolic Syndrome but May Improve Metabolic Health Indices: A Randomised Controlled Trial.

Chronic low-grade inflammation is a characteristic of people with metabolic syndrome and is thought to contribute to the condition progressing to the more severe type 2 diabetes and cardiovascular disease (CVD). The aim was to carry out a double-blind randomised placebo-controlled trial in people with metabolic syndrome to determine if supplementation with a micronutrient formula containing 1000 mg/d vitamin C could attenuate inflammation in people with metabolic syndrome. We recruited 72 adults aged a median of 52 years with metabolic syndrome, defined as obesity (based on waist circumference or BMI), and at least two of hyperglycaemia, raised triglycerides, lowered HDL cholesterol, hypertension, or taking medications for these conditions. A further inclusion criteria comprised C-reactive protein (CRP) concentrations ≥ 3 mg/L, i.e., high risk of CVD. The participants were randomised to daily micronutrient formula (n = 37) or matched placebo control (n = 35) for 12 weeks. The primary outcome was change in CRP concentrations and secondary outcomes included changes in vitamin C concentrations, pro-inflammatory cytokines (IL-6, TNFα), oxidative stress marker (F2isoprostanes), glycaemic indices (glucose, insulin, HbA1c), lipid markers (triglycerides, LDL and HDL cholesterol), anthropometric parameters (weight, BMI), insulin resistance and insulin sensitivity, and metabolic severity score. The participants had a low median (Q1, Q3) vitamin C status of 29 (15, 41) µmol/L and a high proportion of hypovitaminosis C (38%) and outright deficiency (19%). Following 12 weeks of micronutrient supplementation, at least 70% of the participants reached adequate vitamin C status (≥50 µmol/L), however, there was no change in CRP concentrations relative to the placebo group (Δ-0.3 [95%CI -2.7, 2.1] mg/L, p = 0.8). Similar trends were observed for IL-6, TNFα and F2isoprostanes (p > 0.05). Instead, there were small improvements in BMI, fasting glucose and HbA1c concentrations, insulin sensitivity and metabolic severity score in the micronutrient group relative to placebo (p < 0.05). Overall, 12-week micronutrient supplementation was unable to mitigate systemic inflammation in people with metabolic syndrome but may improve several metabolic health indices.

SunGold Kiwifruit Consumption Restores Adequate to Optimal Vitamin C Status in People with a History of Severe Respiratory Infections.

Severe respiratory infections are characterised by depleted vitamin C and elevated inflammation and oxidative stress. The aim of this study was to recruit people with a history of severe respiratory infections to undergo a six-week intervention with SunGold kiwifruit to determine if this could restore adequate vitamin C status. Secondary outcomes included changes in inflammatory and oxidative stress biomarkers, self-reported fatigue and subjective mood, and the incidence, duration and severity of respiratory symptoms. The total cohort comprised 20 adults (65% female, age range 31-84 years). The participants had a low median fruit and vegetable intake of 2.3 servings/day and a correspondingly low vitamin C intake of 46 mg/day. Circulating vitamin C status was a median of 45 µmol/L and was in the hypovitaminosis range in 25% of the cohort. Following intervention with two SunGold kiwifruit/day (equivalent to ~300 mg vitamin C), there was an increase in plasma vitamin C concentrations to >60 µmol/L (p < 0.05). Approximately 20% of the participants were unable to reach adequate vitamin C status (≥50 µmol/L), possibly due to current smoking, which enhances vitamin C turnover, and a strong inverse correlation between body weight and vitamin C status (r = -0.734, p < 0.05). Following the intervention, there were indications towards decreases in the inflammatory biomarkers C-reactive protein and TNFα (p > 0.05), but no changes in oxidative stress biomarkers (F2isoprostanes, protein carbonyls). There were decreases in fatigue and depression (p < 0.05) and a lower number of individual respiratory symptoms reported during the kiwifruit intervention phase (8.5 vs. 10, p = 0.05). Overall, the consumption of two SunGold kiwifruit per day for six weeks was able to restore adequate to saturating vitamin C status in ~80% of the participants. Smokers and people with higher body weight may need larger doses and/or longer duration of supplementation. The contribution of vitamin C to reducing fatigue, depression, and number of respiratory symptoms warrants further investigation.

Does Aging Affect Vitamin C Status Relative to Intake? Findings from NHANES 2017-2018.

The aging population is growing and fueling a global increase in chronic diseases and healthcare expenditure. In this study, we examine vitamin C dose-concentration relationships based on data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 to identify a possible age-dependent change in intake vs. concentration relationship among non-supplemented individuals (n = 2828). The vitamin C intake was similar between the younger (18-36 years), middle (37-58 years) and older (59-80+ years) age groups; however, circulating vitamin C concentrations were significantly lower in the middle and older age groups (p < 0.001). For intakes above 75 mg/day, no significant difference in the intake vs. serum concentration relationship was identified between younger and older individuals. However, for intakes below 75 mg/day, we found significantly lower serum concentrations relative to intake for the older compared to younger individuals, despite smoking being more prevalent in the younger compared to older adults (p < 0.001). This effect persisted among non-smokers and was further exacerbated by smoking in older people. Collectively, the present study suggests that healthy aging in non-institutionalized individuals does not increase requirements for vitamin C. In contrast, the lower serum concentrations relative to intake observed in older individuals at intakes < 75 mg/day may suggest that older individuals are more sensitive to a low vitamin C intake, perhaps due to the increased impact of long-term smoking and increased chronic disease prevalence in older adults. This finding may have implications for future intake guidelines in countries with low RDAs and for WHO/FAO, but requires further investigation.

Does Aging Have an Impact on Vitamin C Status and Requirements? A Scoping Review of Comparative Studies of Aging and Institutionalisation.

The global healthcare burden of an aging population continues to increase, with nearly a quarter of the total global burden of disease attributable to people aged ≥60 years. Older people are at greater risk of micronutrient deficiencies, including immune-supportive vitamin C, which is both a contributor to and a consequence of acute and chronic illnesses. However, whether healthy aging, per se, is associated with depleted vitamin C status and increased requirements for the vitamin is less certain. A systematic scoping review was carried out to assess comparative studies that reported the vitamin C status and prevalence of deficiency in older versus younger people and in older people relative to residential status. Furthermore, vitamin C requirements were assessed through comparative studies reporting vitamin C status and pharmacokinetics in older people relative to younger people. Overall, there was limited evidence to suggest that healthy aging, per se, is related to lower vitamin C status or higher requirements for the vitamin. However, institutionalised elderly had lower vitamin C status and enhanced vitamin C requirements, primarily as a result of low intakes and/or chronic illnesses, which were not being met by hospital or residential diets. Because institutionalised elderly are vulnerable to malnutrition and micronutrient deficiencies, it is imperative that appropriate nutritional interventions are instigated to provide optimal micronutrient intake to support healthy aging.

Factors Affecting the Vitamin C Dose-Concentration Relationship: Implications for Global Vitamin C Dietary Recommendations.

Vitamin C status is known to be associated with several demographic and lifestyle factors. These include gender, age, ethnicity, pregnancy/lactation, body weight, smoking status and dietary habits. In the present study, our aim was to investigate the National Health and Nutrition Examination Survey (NHANES) 2017-2018 datasets to assess the impact of these factors on vitamin C dose-concentration relationships to establish if there are higher requirements for vitamin C in certain subpopulations, and the possible extent of these additional requirements. The final cohort comprised 2828 non-supplementing adult males and females (aged 18-80+ years) with both vitamin C serum concentrations and dietary intake data available. The data were subsequently stratified by gender, age tertiles (≤36, 37-58, ≥59 years), ethnicity (non-Hispanic white, non-Hispanic black, and total Hispanic), socioeconomic tertiles (poverty income ratios: ≤1.35, 1.36-3.0, >3.0), weight tertiles (<72, 72-91, >91 kg), BMI tertiles (<26, 26-32, >32 kg/m2) and smoking status. Sigmoidal (four parameter logistic) curves with asymmetrical 95% confidence intervals were fitted to the dose-concentration data. We found that males required vitamin C intakes ~1.2-fold higher than females to reach 'adequate' serum vitamin C concentrations of 50 µmol/L. Males had both higher body weight and a higher prevalence of smoking than females. Smokers required vitamin C intakes ~2.0-fold higher than non-smokers to reach adequate vitamin C concentrations. Relative to adults in the lighter weight tertile, adults in the heavier weight tertile required ~2.0-fold higher dietary intakes of vitamin C to reach adequate serum concentrations. We did not observe any impact of ethnicity or socioeconomic status on the vitamin C dose-concentration relationship, and although no significant difference between younger and older adults was observed at vitamin C intakes > 75 mg/day, at intakes < 75 mg/day, older adults had an attenuated serum response to vitamin C intake. In conclusion, certain demographic and lifestyle factors, specifically gender, smoking and body weight, have a significant impact on vitamin C requirements. Overall, the data indicate that the general population should consume ~110 mg/day of vitamin C to attain adequate serum concentrations, smokers require ~165 mg/day relative to non-smokers, and heavier people (100+ kg) require ~155 mg/day to reach comparable vitamin C concentrations. These findings have important implications for global vitamin C dietary recommendations.