Factors Contributing to the High Prevalence of Vitamin B6 Deficiency in US: A Systematic Review
Based on the "Second National Report on Biochemical Indicators of Diet and Nutrition in the US Population" from CDC in 2012, 10.5% of the population over 1-year-old were vitamin B6 deficient (plasma pyridoxal 5'-phosphate < 20 nM). We hypothesize that gender, age, food preparation, and disease conditions could affect the intake and/or the availability of vitamin B6.
Literature review was performed to test the hypothesis. MEDLINE, PubMed, Web of Science and Google were used. Only papers that reported biochemical indicators of B6 status were used in analyzing B6 deficiency.
Most studies collected B6 intake information through the dietary recall method. Among healthy populations over 1-year-old from different countries, women (especially those with restricted energy intake) and older adults tended to have lower intake than RDA and thus experienced a higher incidence of deficiency. About half of the nursing home residents showed B6 deficiency. Even in the populations with mean intake higher than RDA, deficiency persisted in up to 20% of the individuals. Lower functional bioavailability of B6 from plant origins or the loss of functional B6 during storage and cooking could negatively affect B6 status. B6 deficiency was also studied among patients with chronic diseases. Patients with type 2 diabetes, colorectal cancer, rheumatoid arthritis, renal disease and renal transplant showed various degrees of B6 deficiency. Renal dialysis likely led to increased B6 depletion through reduced renal reabsorption and thus a 100% B6 deficiency was observed in patients before B6 supplementation. B6 deficiency in Type 2 diabetes could also be due to a higher renal loss. In addition, increased catabolism and intracellular retention may contribute to the low plasma pyridoxal 5'-phosphate levels among patients with inflammatory conditions.
Intake below requirement (due to lower energy intake) and disease conditions (especially renal diseases) are risk factors for B6 deficiency. Screening for B6 deficiency and B6 supplementation may be necessary for these at-risk populations.
Vitamin B6 has a wide range of nutritional importance. The active coenzyme form of vitamin B6, pyridoxal-phosphate (PLP), is associated with more than one hundred enzymes. It participates in biochemical reactions including the amino acid and homocysteine metabolism, cellular multiplication, glucose and lipid metabolism, neurotransmitter production, DNA/RNA synthesis and gene expression modulation [1-3].
The metabolism, absorption and intracellular trafficking of vitamin B6 have been reviewed [4,5]. Major biological forms of vitamin B6 are pyridoxine (PN), pyridoxal (PL) and pyridoxamine (PM). After passively absorbed in the intestine, vitamin B6 is converted to PLP for function. Plasma PLP is a convenient and most frequently used biomarker of vitamin B6 status [3,4,6]. Vitamin B6 deficiency is diagnosed when plasma PLP level is lower than 20 nmol/L. Suboptimal vitamin B6 status may be considered when plasma PLP concentrations are at 20-30 nmol/L .
The hepatic catabolic product of B6, 4-pyridoxic acid (PA), is excreted in the urine and has also been used as an indicator of recent vitamin intake . Urinary PA excretion of ≤ 3.0 μmol/day is thought to indicate deficiency. In addition, plasma PL plus PLP, and plasma ratio of PA to PL plus PLP have been used as indicators of B6 status as reviewed before . Because PLP is needed for various biochemical reactions, B6 functional status can also been determined through the activity of PLP-dependent enzymes, for example, aminotransferase activities in the erythrocyte and plasma kynurenine metabolites .
When plasma level of PLP was used by The Centers for Disease Control and Prevention (CDC) in the analysis of data from 2003-2006 National Health and Nutrition Examination Survey (NHANES), over 10% of US population over 1 year old was found to be vitamin B6 deficient (plasma PLP < 20 nmol/L) (http://www.cdc.gov/nutritionreport). This "Second National Report on Biochemical Indicators of Diet and Nutrition in the US Population" issued by CDC in 2012 actually found B6 deficiency to be the most common nutrient deficiency. Using various indicators of B6 status as mentioned above, chronic suboptimal B6 status has been linked to increased risks for cardiovascular diseases [8,9], and cancers [6,10-12].
While low vitamin B6 intake can lead to deficiency, plasma level of PLP did not always strongly correlate to the estimated vitamin B6 intake in population studies . Other factors may also affect the metabolism of vitamin B6 and increase the incidence of vitamin B6 deficiency. Compared to other micronutrients that were also identified in the CDC report as showing deficiency in US, vitamin B6 has not been studied as much. This review summarizes the available observations on vitamin B6 status. We hypothesize that gender, age, food preparation, and disease conditions could affect the availability and/or the metabolism of vitamin B6. The identification of risk factors for vitamin B6 deficiency is an essential step in promoting proper vitamin B6 nutrition.
Literature review was performed to test the hypothesis. MEDLINE, PubMed, Web of Science and Google were used to identify articles published from 1971 to 2017 using the keywords "vitamin B6 deficiency", "vitamin B6 deficiency diseases", "PLP deficiency", and "plasma PLP level", "vitamin B6 food sources and /or storage". Only papers that reported biochemical indicators of B6 status were used in analyzing B6 deficiency.
Results and Discussion
The literature review uncovered several possible causes of vitamin B6 deficiency in the population as described below.
Lower B6 intake than the Recommended Dietary Allowance (RDA)
A good correlation between B6 intake and plasma PLP was reported in some studies . We summarized studies on the relationship between B6 intake and B6 status among healthy individuals in Table 1.
Vitamin B6 is present in almost all foods. Low overall food intake is a risk factor for poor B6 status. In addition, the RDA of vitamin B6 ranges from 0.1 mg (newborns) to 2 mg (lactating women) depending on age, gender and health status. Some groups may have a higher risk for vitamin B6 deficiency because of a higher requirement. For example, the high B6 deficiency among nursing home residence may be a combined result of poor food intake and higher requirement [19,21]. Low vitamin intake in elderly increased the risk for frailty . Among different groups, the prevalence of low vitamin B6 intakes were in general higher among women as compared to men [13-15] as shown in Table 1. A recent study in US found lower B6 intake in women compared to men but the use of B6 supplement led to sufficient total vitamin B6 intake in both gender groups .
Different populations with similar mean vitamin B6 intake do not always have the same prevalence of vitamin B6 deficiency. For example, despite similar B6 intake, B6 deficiency rate was only 1.5% among pregnant Vancouver women  yet 15.7% Korean adults showed deficiency . The women in Metro Vancouver women study in general had higher socioeconomic status . B6 deficiency reached 11% among Puerto Rican adults although the mean intake was higher than their requirement . It is possible that in some populations, such as Puerto Ricans, there were a wider range of B6 intake and thus the mean intake cannot reflect the population B6 status. It is also possible that the bioavailability of vitamin B6 depends on the food type as discussed below. Other factors may also change B6 metabolism. This will explain why the correlation between B6 intake and B6 status is not always strong .
B6 availability depends on the food type: plant versus animal source
All forms of B6 are found in the food but their bioavailability varies. Plant foods have mostly the structure analogs of PN (the most stable form of B6) . Glycosylated forms of PN found in some plant foods are poorly available for functional phosphorylation [24-26]. Also, dietary fiber in the plant causes incomplete digestion, which further reduce the bioavailability of PN . The pre-cecal digestibility of vitamin B6 from plant products is on the average 10% lower than that of animal products and B6 in brown rice is only 16% digestible . In contrast, animal products have mostly bioavailable PL, PM and their phosphorylated forms. Sirloin steak, salmon, and the light meat of chicken are rich sources of bioavailable B6 . Thus, similar amount of total B6 intake may lead to different B6 status because of the difference in the bioavailability. Few studies considered the bioavailability of vitamin B6 from different food sources. PN found in the supplement or fortification improves vitamin B6 status  but the information on supplement usage or food B6 fortification is not always available.
A loss of vitamin B6 during the food storage and processing
The effect of cooking method on B6 stability also should be considered [26,27]. Most vitamins will suffer from some loss during storage and cooking based on the exposed temperature, sunlight, PH, moisture, oxygen and size of portions [28,29]. Thermal degradation of vitamin B6 increases as pH rises. Aldehyde group in PL and PLP can react with the epsilon-amino group of protein-bound lysine [24,30,31]. Because of this Schiff base reaction, the stability of the vitamin during processing of plant products, which contain predominantly PN, may be higher than that of vitamin B6 in animal products, which contain mainly PLP and PMP. Vitamin B6 is water-soluble and thus is at a higher risk of losing in liquid food. The loss of vitamins from vegetable is mainly through escaping into the cooking liquid . In dehydrated food systems at 180 ℃ for 25 minutes, the loss of 50 - 70% of PN, PM and PLP added in experimental fortification was also observed . Storage will also lead to the loss of vitamin B6. Storage at higher temperature or longer duration will increase the extent of loss [32-34]. The vitamin B6 content of baked cod has been reported to decline by 20% after 3 days of cold storage [29,35]. Large losses, ranging from 20 to 70%, can happen to both vegetables and animal products even in frozen foods [29,36].
Effect of exercise and weight control
Several population studies listed in Table 1 found women at a higher risk for low B6 intake and low plasma PLP level [13,16,18]. Compared to sedentary women, many female athletes consumed more energy. As a result, they had higher B6 intake that reduced the chance of B6 deficiency . Nevertheless, low B6 intake was found in young women participating in sports where weight restriction was encouraged, and thus total energy intake was low [37,38]. Low total energy and B6 intake also happened in men intending to lose weight during sport training . Gastric bypass surgery for morbid obesity was linked to general vitamin deficiency including 17.6% B6 deficiency at 2-year after the surgery in an earlier study . However, a recent study showed that at a year after the surgery when diabetic, hypertension and hypercholesterolemia conditions were mostly eliminated, B6 status also improved . The different post-surgery B6 outcome may be due to an improvement in the surgical procedures in the last decade as well as a wider use of vitamin supplement.
Diseases and Inflammation
Data supporting links between various diseases and B6 deficiency have been compiled into Table 2.
Although lower B6 intake could increase the chance of B6 deficiency, other factors such as inflammation likely also influence B6 status. A study simultaneously measuring B6 intake, plasma PLP and inflammatory marker C-reactive protein (CRP) found a gradually higher plasma PLP with gradually higher B6 intake . Interestingly, the highest tertile in B6 intake also had the lowest CRP level [52,54]. An older study found lower mean plasma PLP level among current smokers compared to that of past smokers and non-smokers . All three groups in the study consumed normal western-style diet and sadly all had mean plasma PLP below 20 nmol/L, the cutoff for B6 deficiency.
Disease-specific pathological changes may also have significant effects on the plasma PLP levels. Excessive renal loss of B6 is expected in diabetic and dialysis patients. Indeed, vitamin B6 deficiency is common among these patients [42-45]. Two small trials both found that pharmacological doses of B6 were able to correct the deficiency [44,45].
Patients with inflammation due to various diseases and conditions were found to have lower vitamin B6 status compared to the control subjects. Because vitamin B6 is integrally involved in the white blood cell division and the production of cytokines and other polypeptide mediators during the inflammatory response [1,48,52], the intracellular retention of the active form of B6 as PLP is increased during systemic inflammation . This can lead to a decrease in the plasma PLP pool. More irreversible degradation of PLP to PA can also lead to lower B6 status . Alkaline phosphatase is a key enzyme in the degradation of PLP. Smokers had elevated heat-stable alkaline phosphatase isoenzyme that may result in an increased hydrolysis of PLP [18,46]. Elevated level alkaline phosphatase was also observed during systemic inflammation .
Patients with higher plasma CRP levels tended to have lower PLP levels . In population studies, increased catabolism of vitamin B6, as indicated by the higher ratio of PA:(PL+PLP), can be explained almost exclusively by the inflammatory markers CRP, and white blood cells [3,6,9]. Because inflammation is accompanied by oxidative and aldehyde stress, several aldehyde-degrading enzymes including aldehyde oxidase and aldehyde hydrogenase are also upregulated and may promote the oxidation of PL to PA [44,45]. The deleterious effect of inflammation on B6 can be overcome by supplementation. Pharmacological doses of B6 improved the B6 status of adults after coronary angiography  and prevented B6 deficiency among patients in the intensive care unit .
Inflammation and vitamin C
In our examination of literature on inflammation, a link between inflammation and low vitamin C status was also noticed [56-62]. This link may also have impacted on the vitamin C status in US. Vitamin C intake in US is close to or exceeds the requirement in all age groups based on NHANES . Yet 6% of the population in the same 2012 CDC report showed vitamin C deficiency when plasma ascorbic acid levels were analyzed. Vitamin B6 and C are the top 2 most deficient water-soluble vitamins in the CDC report.
Vitamin B6 coenzyme has a wide range of functional importance. Lower intake of vitamin B6 can contribute to B6 deficiency among vulnerable populations such as elderly and individuals with restricted energy intake or systemic inflammation. Although there is no sufficient information, vegetarians could also have an increased risk of deficiency because of the lower B6 bioavailability from plant sources. Renal diseases and elevated systemic inflammatory responses also changed B6 metabolism and increase the need of vitamin B6. Inflammation may have also increased vitamin C deficiency in US.
B6 supplementation appears to be effective in alleviating B6 deficiency although pharmacological doses may be needed in some cases. The use of vitamin C supplement is also known to increase plasma ascorbic acid level . However, vitamin B6 and vitamin C are known to show toxicity upon prolonged high-level supplementation and both have Upper Levels established. Despite the possible link between inflammation and their deficiencies, high-level supplementation of these two water-soluble vitamins should only be considered under medical supervision.
- Paul L, Ueland PM, Selhub J (2013) Mechanistic perspective on the relationship between pyridoxal 5'-phosphate and inflammation. Nutr Rev 71: 239-244.
- Woolf K, Hahn NL, Christensen MM, et al. (2017) Nutrition Assessment of B-Vitamins in Highly Active and Sedentary Women. Nutrients 9.
- Ulvik A, Midttun O, Pedersen ER, et al. (2014) Evidence for increased catabolism of vitamin B-6 during systemic inflammation. Am J Clin Nutr 100: 250-255.
- Ueland P, Ulvik A, Rios-Avila L, et al. (2015) Direct and Functional Biomarkers of Vitamin B6 Status. Annu Rev Nutr 35: 33-70.
- Whittaker J (2016) Intracellular trafficking of the pyridoxal cofactor. Implications for health and metabolic disease. Arch Biochem Biophys 592: 20-26.
- Gylling B, Myte R, Schneede J, et al. (2017) Vitamin B-6 and colorectal cancer risk: a prospective population-based study using 3 distinct plasma markers of vitamin B-6 status. Am J Clin Nutr 105: 897-904.
- Kim YN, Cho YO (2014) Evaluation of vitamin B6 intake and status of 20- to 64-year-old Koreans. Nutr Res Pract 8: 688-694.
- Ulvik A, Pedersen E, Svingen G, et al. (2016) Vitamin B-6 catabolism and long-term mortality risk in patients with coronary artery disease. Am J Clin Nutr 103: 1417-1425.
- Zuo H, Tell G, Ueland P, et al. (2018) The PAr index, an indicator reflecting altered vitamin B-6 homeostasis, is associated with long-term risk of stroke in the general population: the Hordaland Health Study (HUSK). Am J Clin Nutr 107: 105-112.
- Zuo H, Ueland PM, Eussen SJ, et al. (2015) Markers of vitamin B6 status and metabolism as predictors of incident cancer: the Hordaland Health Study. Int J Cancer 136: 2932-2939.
- Huang J, Butler L, Midttun Ø, et al. (2018) A prospective evaluation of serum kynurenine metabolites and risk of pancreatic cancer. PLoS One 13: e0196465.
- Zuo H, Ueland P, Midttun Ø, et al. (2018) Results from the European Prospective Investigation into Cancer and Nutrition Link Vitamin B6 Catabolism and Lung Cancer Risk. Cancer Res 78: 302-308.
- Brants HA, Brussaard JH, Bouman M, et al. (1997) Dietary intake among adults with special reference to vitamin B6. Eur J Clin Nutr 51: S25-S31.
- Brussaard JH, Lowik MR, van den Berg H, et al. (1997) Dietary and other determinants of vitamin B6 parameters. Eur J Clin Nutr 51: S39-S45.
- Brussaard JH, Lowik MR, van den Berg H, et al. (1997) Micronutrient status, with special reference to vitamin B6. Eur J Clin Nutr 51: S32-S38.
- Chang SJ, Hsiao LJ, Hsuen SY (2003) Assessment of vitamin B-6 estimated average requirement and recommended dietary allowance for adolescents aged 13-15 years using vitamin B-6 intake, nutritional status and anthropometry. J Nutr 133: 3191-3194.
- Morris MS, Picciano MF, Jacques PF, et al. (2008) Plasma pyridoxal 5'-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004. Am J Clin Nutr 87: 1446-1454.
- Ye X, Maras JE, Bakun PJ, et al. (2010) Dietary intake of vitamin B-6, plasma pyridoxal 5'-phosphate, and homocysteine in Puerto Rican adults. J Am Diet Assoc 110: 1660-1668.
- Kjeldby IK, Fosnes GS, Ligaarden SC, et al. (2013) Vitamin B6 deficiency and diseases in elderly people--a study in nursing homes. BMC Geriatr 13: 13.
- Ho CL, Quay TA, Devlin AM, et al. (2016) Prevalence and Predictors of Low Vitamin B6 Status in Healthy Young Adult Women in Metro Vancouver. Nutrients 8.
- Yannakoulia M, Mamalaki E, Anastasiou C, et al. (2018) Eating habits and behaviors of older people: Where are we now and where should we go? Maturitas 114: 14-21.
- Balboa-Castillo T, Struijk E, Lopez-Garcia E, et al. (2018) Low vitamin intake is associated with risk of frailty in older adults. Age Ageing 47: 872-879.
- Dhana A, Yen H, Li T, et al. (2018) Intake of folate and other nutrients related to one-carbon metabolism and risk of cutaneous melanoma among US women and men. Cancer Epidemiol Biomarkers Prev 55: 176-183.
- Reynolds RD (1988) Bioavailability of vitamin B-6 from plant foods. Am J Clin Nutr 48: 863-867.
- Gregory JF (1998) Nutritional Properties and significance of vitamin glycosides. Annu Rev Nutr 18: 277-296.
- Steluti J, Martini LA, Peters BS, et al. (2011) Folate, vitamin B6 and vitamin B12 in adolescence: serum concentrations, prevalence of inadequate intakes and sources in food. J Pediatr (Rio J) 87: 43-49.
- Roth-Maier DA, Kettler SI, Kirchgessner M (2002) Availability of vitamin B6 from different food sources. Int J Food Sci Nutr 53: 171-179.
- Ford JE, Hurrell RF, Finot PA (1983) Storage of milk powders under adverse conditions. 2.Influence on the content of water-soluble vitamins. Br J Nutr 49: 355-364.
- Severi S, Bedogni G, Manzieri AM, et al. (1997) Effects of cooking and storage methods on the micronutrient content of foods. Eur J Cancer Prev 6: 21-24.
- Lešková E, Kubíková J, Kováčiková E, et al. (2006) Vitamin losses: Retention during heat treatment and continual changes expressed by mathematical models. J Food Comp analysis 19: 252-276.
- Gregory J, Kirk J (1978) Assessment of roasting effects on vitamin B6 stability and bioavailability in dehydrated food systems. J Food Sci 43: 1585-1589.
- Perera AD, Leklem JE, Miller LT (1979) Stability of vitamin B6 during bread making and storage of bread and flour. Cereal Chem 56: 577-580.
- Augustin J, Marousek G, Tholen L, et al. (1980) Vitamin retention in cooked, chilled, and reheated potatoes. J Food Sci 45: 814-816.
- Williams P (1996) Vitamin retention in cook/chill and cook/hot-hold hospital foodservices. J Am Diet Assoc 96: 490-498.
- Jonsson L, Danielsson K (1981) Vitamin retention in foods handled in foodservice systems. Lebensmittel-Wissenschaft und Technologie 14: 94-96.
- Schroeder H (1971) Losses of vitamins and trace minerals resulting from processing and preservation of foods. Am J Clin Nutr 24: 562-573.
- Leydon MA, Wall C (2002) New Zealand jockeys' dietary habits and their potential impact on health. Int J Sport Nutr Exerc Metab 12: 220-237.
- Ziegler PJ, Kannan S, Jonnalagadda SS, et al. (2005) Dietary intake, body image perceptions, and weight concerns of female US International Synchronized Figure Skating Teams. Int J Sport Nutr Exerc Metab 15: 550-566.
- Durguerian A, Bougard C, Drogou C, et al. (2016) Weight Loss, Performance and Psychological Related States in High-level Weightlifters. Int J Sports Med 37: 230-238.
- Clements R, Katasani V, Palepu R, et al. (2006) Incidence of vitamin deficiency after laparoscopic Roux-en-Y gastric bypass in a university hospital setting. Am Surg 72: 1196-1202.
- Christensen M, Fadnes D, Røst T, et al. (2018) Inflammatory markers, the tryptophan-kynurenine pathway, and vitamin B status after bariatric surgery. PLoS One 13: e0192169.
- Iwakawa H, Nakamura Y, Fukui T, et al. (2016) Concentrations of Water-Soluble Vitamins in Blood and Urinary Excretion in Patients with Diabetes Mellitus. Nutr Metab Insights 9: 85-92.
- Minovic I, Riphagen IJ, van den Berg E, et al. (2017) Vitamin B-6 deficiency is common and associated with poor long-term outcome in renal transplant recipients. Am J Clin Nutr 105: 1344-1350.
- Okada H, Moriwaki K, Kanno Y, et al. (2000) Vitamin B6 supplementation can improve peripheral polyneuropathy in patients with chronic renal failure on high‐flux haemodialysis and human recombinant erythropoietin. Nephrol Dial Transplant 15: 1410-1413.
- Ross E, Shah G, Reynolds R, et al. (1989) Vitamin B6 requirements of patients on chronic peritoneal dialysis. Kidney Inter 36: 702-706.
- Vermaak WJ, Ubbink JB, Barnard HC, et al. (1990) Vitamin B-6 nutrition status and cigarette smoking. Am J Clin Nutr 51: 1058-1061.
- Huang YC, Lan PH, Cheng CH, et al. (2002) Vitamin B6 intakes and status of mechanically ventilated critically ill patients in Taiwan. Eur J Clin Nutr 56: 387-392.
- Friso S, Jacques PF, Wilson PW, et al. (2001) Low circulating vitamin B 6 is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation 103: 2788-2791.
- Van Guelpen B, Hultdin J, Johansson I, et al. (2009) Plasma folate and total homocysteine levels are associated with the risk of myocardial infarction, independently of each other and of renal function. J Intern Med 266: 182-195.
- Chiang EP, Bagley PJ, Roubenoff R, et al. (2003) Plasma pyridoxal 5'-phosphate concentration is correlated with functional vitamin B-6 indices in patients with rheumatoid arthritis and marginal vitamin B-6 status. J Nutr 133: 1056-1059.
- Chiang EP, Smith DE, Selhub J, et al. (2005) Inflammation causes tissue-specific depletion of vitamin B6. Arthritis Res Ther 7: 1254-1262.
- Sakakeeny L, Roubenoff R, Obin M, et al. (2012) Plasma pyridoxal-5-phosphate is inversely associated with systemic markers of inflammation in a population of U.S. adults. J Nutr 142: 1280-1285.
- Ebbing M, Bleie O, Ueland PM, et al. (2008) Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA 300: 795-804.
- Mazidi M, Kengne A, Mikhailidis D, et al. (2018) Effects of selected dietary constituents on high-sensitivity C-reactive protein levels in U.S. adults. Ann Med 50: 1-6.
- Ueland P, McCann A, Midttun Ø, et al. (2017) Inflammation, vitamin B6 and related pathways. Mol Aspects Med 53: 10-27.
- Dherani M, Murthy GV, Gupta SK, et al. (2008) Blood levels of vitamin C, carotenoids and retinol are inversely associated with cataract in a North Indian population. Invest Ophthalmol Vis Sci 49: 3328-3335.
- Dietrich M, Block G, Norkus EP, et al. (2003) Smoking and exposure to environmental tobacco smoke decrease some plasma antioxidants and increase gamma-tocopherol in vivo after adjustment for dietary antioxidant intakes. Am J Clin Nutr 77: 160-166.
- Nourmohammadi I, Modarress M, Khanaki K, et al. (2008) Association of serum alpha-tocopherol, retinol and ascorbic acid with the risk of cataract development. Ann Nutr Metab 52: 296-298.
- Gao X, Curhan G, Forman JP, et al. (2008) Vitamin C intake and serum uric acid concentration in men. J Rheumatol 35: 1853-1858.
- Johnston CS, Meyer CG, Srilakshmi JC (1993) Vitamin C elevates red blood cell glutathione in healthy adults. Am J Clin Nutr 58: 103-105.
- Wannamethee SG, Lowe GD, Rumley A, et al. (2006) Associations of vitamin C status, fruit and vegetable intakes, and markers of inflammation and hemostasis. Am J Clin Nutr 83: 567-574.
- Carr A, Rosengrave P, Bayer S, et al. (2017) Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care 21: 300.
- Bailey R, Akabas S, Paxson E, et al. (2017) Total Usual Intake of Shortfall Nutrients Varies With Poverty Among US Adults. J Nutr Educ Behav 49: 639-646.
- Langlois K, Cooper M, Colapinto C (2016) Vitamin C status of Canadian adults: Findings from the 2012/2013 Canadian Health Measures Survey. Health Rep 27: 3-10.
Shiu-Ming Kuo, Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, NY 14214, USA.
© 2018 Tang Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.