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1.
Estimating Vitamin C Intake Requirements in Diabetes Mellitus: Analysis of NHANES 2017-2018 and EPIC-Norfolk Cohorts.
Carr, AC, Lunt, H, Wareham, NJ, Myint, PK
Antioxidants (Basel, Switzerland). 2023;(10)
Abstract
Vitamin C is an essential enzyme cofactor and antioxidant with pleiotropic roles in human physiology. Circulating vitamin C concentrations are lower in people with diabetes mellitus, suggesting a higher dietary requirement for the vitamin. We interrogated the NHANES 2017-2018 and EPIC-Norfolk datasets to compare vitamin C requirements between those with and without diabetes mellitus using dose-concentration relationships fitted with sigmoidal (four-parameter logistic) curves. The NHANES cohort (n = 2828 non-supplementing adults) comprised 488 (17%) participants with diabetes (self-reported or HbA1c ≥ 6.5%). The participants with diabetes had a lower vitamin C status (median [IQR]) than those without (38 [17, 52] µmol/L vs. 44 [25, 61] µmol/L, p < 0.0001), despite comparable dietary intakes between the two groups (51 [26, 93] mg/d vs. 53 [24, 104] mg/d, p = 0.5). Dose-concentration relationships indicated that the group without diabetes reached adequate vitamin C concentrations (50 µmol/L) with an intake of 81 (72, 93) mg/d, whilst those with diabetes required an intake of 166 (126, NA) mg/d. In the EPIC-Norfolk cohort, comprising 20692 non-supplementing adults, 475 (2.3%) had self-reported diabetes at baseline. The EPIC cohort had a lower BMI than the NHANES cohort (26 [24, 28] kg/m2 vs. 29 [25, 34] kg/m2, p < 0.0001). Correspondingly, the EPIC participants without diabetes required a lower vitamin C intake of 64 (63, 65) mg/d while those with diabetes required 129 (104, NA) mg/d to reach adequate circulating vitamin C status. C-reactive protein concentrations were strongly correlated with body weight and BMI and provided a surrogate biomarker for vitamin C requirements. In conclusion, people with diabetes had 1.4 to 1.6 fold higher requirements for vitamin C than those without diabetes. This corresponds to additional daily vitamin C intake requirements of ~30-40 mg for people with diabetes, equating to a total daily intake of at least 125 mg/d.
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2.
Vitamin C - a scoping review for Nordic Nutrition Recommendations 2023.
Lykkesfeldt, J, Carr, AC
Food & nutrition research. 2023
Abstract
Vitamin C has multiple metabolic functions in the body, but the available information on the exact relationship between these functions and the intake necessary to maintain them is very limited. However, most attempts to objectively measure adequacy of vitamin C status, including, for example, replacement of metabolic turnover, chronic disease prevention, urinary excretion, and saturation of immune cells and body compartment, currently point toward 50 µmol/L as a reasonable target plasma concentration. As a strong correlation between body weight and vitamin C status exists, recommended intakes (RIs) for other age groups may be extrapolated from the adult RI based on weight. However, as body weights above 70 kg are becoming increasingly common - also in the Nordic region - an RI of 140 mg/day for individuals weighing 100 kg or more should be considered to compensate for the larger volume of distribution. Finally, smoking continues to be a common contributor to poor vitamin C status; therefore, it is proposed that people who smoke increase their daily vitamin C intake by 40 mg/day to compensate for the increased metabolic turnover induced by smoking.
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3.
Does Aging Have an Impact on Vitamin C Status and Requirements? A Scoping Review of Comparative Studies of Aging and Institutionalisation.
Carr, AC, Zawari, M
Nutrients. 2023;(4)
Abstract
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.
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4.
Multi-Level Immune Support by Vitamins C and D during the SARS-CoV-2 Pandemic.
Carr, AC, Gombart, AF
Nutrients. 2022;(3)
Abstract
Vitamins C and D have well-known immune supportive roles, with deficiencies in both vitamins predisposing to increased risk and severity of respiratory infections. Numerous studies have indicated that administration of these vitamins, particularly to people who are deficient, can decrease the risk and severity of respiratory infections. This has stimulated an interest in the potential efficacy of these vitamins in people with novel coronavirus (SARS-CoV-2) infection and its more severe disease (COVID-19). In this overview, we highlight the current research evidence around the multiple levels of immune support provided by vitamins C and D in the context of general respiratory infections and with a focus on the current SARS-CoV-2 pandemic. These include: prevention of infection; attenuating infection symptoms and severity; adjunctive therapy for severe disease; attenuating ongoing sequelae (long COVID); and immunisation support. Although some of these topics have not yet been investigated in great depth concerning SARS-CoV-2 and COVID-19, extensive research into the role of these vitamins in general respiratory infections has highlighted directions for future research in the current pandemic.
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5.
Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial.
Rosengrave, P, Spencer, E, Williman, J, Mehrtens, J, Morgan, S, Doyle, T, Van Der Heyden, K, Morris, A, Shaw, G, Carr, AC
Critical care (London, England). 2022;(1):26
Abstract
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).
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6.
Supplementation with Oral Vitamin C Prior to and during Myeloablative Chemotherapy and Autologous Haematopoietic Stem Cell Transplantation: A Pilot Study.
Carr, AC, Vlasiuk, E, Zawari, M, Meijer, N, Lauren, C, MacPherson, S, Williman, J, Chambers, ST
Antioxidants (Basel, Switzerland). 2022;(10)
Abstract
Chemotherapy-related side effects are common in patients undergoing myeloablative chemotherapy and haematopoietic stem cell transplantation. Some, such as oral mucositis, are believed to be due to enhanced oxidative stress and inflammation. Vitamin C, a potent antioxidant with anti-inflammatory properties, becomes severely depleted following myeloablative chemotherapy. The aim of our study was to assess the feasibility and efficacy of oral vitamin C supplementation to restore and maintain adequate vitamin C concentrations in patients undergoing myeloablative chemotherapy and stem cell transplantation. We carried out a pilot randomized controlled trial in 20 patients with myeloma and lymphoma. Placebo or vitamin C tablets (1 g twice daily) were initiated one week prior to transplantation and continued for 4 weeks post-transplantation. Blood samples were collected weekly for analysis of plasma vitamin C concentrations using high-performance liquid chromatography. The patients' symptoms and quality of life parameters were monitored using the World Health Organization oral toxicity scale and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ). Pre-supplementation with oral vitamin C doubled vitamin C concentrations relative to placebo by day 0 (median 61 vs. 31 µmol/L), with 60% of those in the vitamin C group achieving concentrations ≥ 50 µmol/L, compared with only 10% in the placebo group. Following chemotherapy and transplantation, significance between the vitamin C and placebo groups was lost by day 7, with only 30% of the patients in the vitamin C group having plasma concentrations ≥ 50 µmol/L. This was partly due to intolerance of the oral intervention due to nausea/vomiting and diarrhoea (40% of the participants in each group). Oral mucositis was also observed in 40% of the participants at day 7 or 14. Overall, our study showed that whilst short-term oral vitamin C pre-supplementation was able to restore adequate vitamin C status by day 0, ongoing supplementation could not maintain adequate vitamin C concentrations following chemotherapy and transplantation. Thus, intravenous vitamin C should be trialled as this bypasses the gastrointestinal system, negating intolerance issues and improving bioavailability of the vitamin.
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7.
Circulating protein carbonyls are specifically elevated in critically ill patients with pneumonia relative to other sources of sepsis.
Spencer, E, Rosengrave, P, Williman, J, Shaw, G, Carr, AC
Free radical biology & medicine. 2022;:208-212
Abstract
BACKGROUND Septic shock is a life-threatening dysregulated response to severe infection and is associated with elevated oxidative stress. We aimed to assess protein carbonyls in critically ill patients with different sources of sepsis and determine the effect of vitamin C intervention on protein carbonyl concentrations. METHODS Critically ill patients with septic shock (n = 40) were recruited, and sources of sepsis and ICU severity scores were recorded. The patients were randomised to receive either intravenous vitamin C (100 mg/kg body weight/day) or placebo infusions. Blood samples were collected at baseline and daily for up to three days for measurement of cell counts, vitamin C concentrations, protein carbonyls, C-reactive protein, and myeloperoxidase concentrations. RESULTS Protein carbonyl concentrations increased 2.2-fold in the cohort over the duration of the study (from 169 to 369 pmol/mg protein; p = 0.03). There were significant correlations between protein carbonyl concentrations and ICU severity scores (APACHE III r = 0.47 and SOFA r = 0.37; p < 0.05) at baseline. At study admission, the patients with pneumonia had nearly 3-fold higher protein carbonyl concentrations relative to the patients with other sources of sepsis (435 vs 157 pmol/mg protein, p < 0.0001). The septic patients had deficient vitamin C status at baseline (9.8 ± 1.4 μmol/L). This increased to 456 ± 90 μmol/L following three days of intravenous vitamin C intervention. Vitamin C intervention did not attenuate the increase in protein carbonyl concentrations. CONCLUSIONS Circulating protein carbonyls are specifically elevated in critically ill patients with pneumonia relative to other sources of sepsis. The reasons for this are currently unclear and may indicate a mechanism unique to pulmonary sources of sepsis. Intravenous vitamin C administration did not attenuate the increase in protein carbonyls over time.
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8.
Critically ill septic patients have elevated oxidative stress biomarkers: lack of attenuation by parenteral vitamin C.
Vlasiuk, E, Rosengrave, P, Roberts, E, Boden, JM, Shaw, G, Carr, AC
Nutrition research (New York, N.Y.). 2022;:53-59
Abstract
Patients with septic shock are under an intense inflammatory burden, which is closely associated with increased oxidative stress and depletion of antioxidants such as vitamin C. We hypothesized that patients with septic shock would present with elevated oxidative stress (assessed as F2-isoprostanes) and that administration of parenteral vitamin C to these patients would attenuate F2-isoprostane concentrations. We recruited 40 critically ill patients with septic shock into a randomized placebo-controlled trial and assessed the effect of short-term (4-day) parenteral vitamin C administration (100 mg/kg/d) on 8-isoprostane F2α concentrations, which were measured using enzyme-linked immunosorbent assays. Sources of sepsis and intensive care unit severity scores were recorded. Smokers (n = 20) and nonsmoking controls (n = 50) were assessed for comparison. The median baseline 8-isoprostane F2α concentration in the septic patients was 3.95 (interquartile range [Q1, Q3] 2.1, 6.63) ng/mg creatinine; this was higher than smokers 1.61 [1.25, 2.82] P = .007 ng/mg creatinine; P = .005) and nonsmoking controls 1.12 [0.76, 1.57] ng/mg creatinine; P < .0001). The 8-isoprostane F2α concentrations in the placebo group did not vary significantly over the duration of the study. Although parenteral vitamin C administration significantly increased the vitamin C status of the patients within 24 hours, this did not affect their 8-isoprostane F2α concentrations. In conclusion, patients with septic shock have elevated 8-isoprostane F2α excretion, which short-term parenteral vitamin C administration is unable to attenuate. If vitamin C is to work by antioxidant mechanisms, then early administration, before the development of shock, may be required. This trial was registered at anzctr.org.au (ACTRN12617001184369).
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9.
Micronutrients and respiratory infections: the biological rationale and current state of clinical evaluation.
Rowe, S, Collins, PD, Stacey, SE, Carr, AC
British journal of hospital medicine (London, England : 2005). 2021;(4):1-8
Abstract
A range of nutrients has been studied or proposed for use in preventing respiratory tract infections and reducing their severity. This article gives a narrative review of the existing literature, biological rationales and current state of clinical evaluation for micronutrient therapies. The importance of vitamin A, the B vitamins, vitamin C, vitamin D, eicosapentaenoic acid, vitamin E, selenium, zinc and a range of combination therapies are discussed, looking at their effects on reducing rates of infection, reducing severity of infection and improved recovery from infection. Further discussion regarding the level of evidence required for nutritional interventions is included.
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10.
Discrepancies in global vitamin C recommendations: a review of RDA criteria and underlying health perspectives.
Carr, AC, Lykkesfeldt, J
Critical reviews in food science and nutrition. 2021;(5):742-755
Abstract
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.