Vitamin Biomarkers: Vitamin C

Optimal Takeaways

Vitamin C must be obtained in the diet of humans as they are one of the few mammals that can’t produce it endogenously. It has far-reaching effects as an antioxidant and as a cofactor in several metabolic functions, including collagen synthesis. Vitamin C insufficiency leads to impairment of blood vessel integrity, bruising, poor wound healing, excess bleeding, infection, inflammation, joint pain, mood changes, and scurvy. Severe deficiency can lead to sudden cardiac death.

Elevated levels of vitamin C are usually associated with high-dose intravenous administration although excess vitamin C may be contraindicated in those with G6PD deficiency, oxalate kidney stones, and iron overload disorders.

Standard Range: 0.20 – 2.70 mg/dL (11.36 – 153.31 umol/L)

The ODX Range: 1.30 – 4.00 mg/dL (73.81 – 227.12 umol/L)

Low serum vitamin C is associated with atherosclerosis, oxidized LDL, compromised blood vessel integrity, musculoskeletal complaints, arthralgia, myalgia, fatigue, weakness (Amisha 2022), scurvy, bleeding gums, bruising, perifollicular hemorrhage, excess bleeding, impaired collagen production, hair and nail malformation, poor wound healing, bone fractures, NAFLD, iron overload, gastrointestinal inflammation, malabsorption, alcoholism, smoking, eating disorders, restrictive diets, and low fruit and vegetable intake (Maxfield 2020).

Low vitamin C is also associated with oxidative stress, inflammation, lower extremity edema, back pain, joint pain, syncope (Klimant 2018), pancreatitis, myocardial infarction, diabetes, sepsis, critical illness (Levine 2011), and diabetic retinopathy (Xiong 2022), and compromised physical functional health (Tardy 2020). Vitamin C deficiency and scurvy are also associated with decreased B12 and alkaline phosphatase levels (Pagana 2022).

High serum vitamin C is associated with high-dose intake, especially intravenous administration (Levine 2011, Klimant 2018), increased renal oxalate excretion, and potential calcium oxalate crystal and stone formation (Maxfield 2020). Excess vitamin C may cause a false-negative guaiac stool test, increased uric acid and total bilirubin, and decreased triglycerides and LDH (Pagana 2021).

Overview

Vitamin C is known as the “antiscorbutic vitamin” called ascorbic acid, or ascorbate in its active form. It is an essential nutrient for humans, one of the few mammals unable to synthesize vitamin C due to a lack of the enzyme L-gulonolactone oxidase. The consumption of fresh fruits and vegetables, including citrus, berries, melon, broccoli, cauliflower, Brussels sprouts, cabbage, peppers, spinach, tomatoes, and potatoes, provides 90% of the vitamin C consumed by humans. (Maxfield 2020). However, vitamin C is easily destroyed by heat, light, cooking, alkaline solutions, and oxidation, reducing its availability in the diet (Gropper 2021).

The four main mechanisms controlling blood vitamin C levels include gastrointestinal absorption, renal regulation, tissue accumulation, and utilization rate (Levine 2011). The highest tissue concentrations of vitamin C are found in the adrenal and pituitary glands. Substantial amounts are also found in the brain, neurons, white blood cells, eyes, liver, kidneys, heart, lungs, pancreas, and muscle, including approximately 1,000-1,500 mg in skeletal muscle specifically. The total body pool of vitamin C is estimated to be 2-5 grams (Gropper 2021).

Insufficient intake can quickly lead to the depletion of normal body stores. Clinical signs of deficiency occur when body stores drop below 350 mg and include impaired collagen synthesis in the skin, blood vessels, tendons, bone, and other tissues. Other signs of insufficiency include irritability, loss of appetite, poor wound healing, swollen bleeding gums, loss of teeth, soft malformed nails, corkscrew hairs, petechiae, bruising, capillary fragility, dry eyes, alopecia, nonalcoholic fatty liver disease (NAFLD), excess bleeding, and rheumatological disorders. Repletion with up to 2,000 mg per day loading dose for three days and then 500-1,000 mg/day can help correct a deficiency and restore serum levels. A serum level below 0.2 mg/dL (11.36 umol/L) is associated with scurvy and severe vitamin C deficiency (Maxfield 2020).

Since scurvy affects the skin and soft tissue, symptoms are wide-ranging and include musculoskeletal complaints such as fatigue, weakness, arthralgia, and myalgia; bruising, hemarthrosis, and bleeding throughout the body; significant collagen disruption with weakened leaking blood vessels; infection; and sudden cardiac death. Clinical signs of scurvy can occur within 30 days without sufficient vitamin C intake. While white blood cell concentration of vitamin C reflects long-term body stores, plasma vitamin C reflects recent intake, and clinical signs manifest as levels drop below 0.20 mg/dL (11.36 umol/L). One case study of a 72-year-old woman with a highly-processed diet, insufficient vitamin C intake, and 16-pound weight loss over 90 days revealed a plasma vitamin C below 0.05 mg/dL (2.84 umol/L). The patient presented with fatigue, malaise, weakness, falls, bruising, petechial rash, gingival inflammation and bleeding, painful ecchymosis, and low plasma vitamin A, E, B1, folate, iron, and hemoglobin. Some symptoms began to improve within 24 hours following supplementation with vitamin C and multivitamins, though musculoskeletal symptoms may take two weeks to resolve (Amisha 2022).

Evaluation of plasma vitamin C levels in a large population study comprising more than 15,000 subjects observed that those with vitamin C levels below 0.72 mg/dL (41 umol/L), a level within the conventional range, had significantly increased risk of poor physical functional health and vitality scores compared to levels above 1.16 mg/dL (66 umol/L). Vitamin C supplementation was associated with improved physical functional health (Tardy 2020).

Vitamin C is also a cofactor in several metabolic enzymes, including those involved in the metabolism of norepinephrine, collagen, carnitine, DNA, and hypothalamic, gastrointestinal hormones, and other hormones. Vitamin C also supports (nonheme) iron absorption, prevents the formation of nitroso compounds, increases endothelium-dependent vasodilation, decreases neutrophil-induced oxidation, and quenches metabolic free radicals (Padayatty 2016).

Vitamin C also appears to be involved in the metabolism of the cytochrome P450 enzymes that are responsible for breaking down and detoxifying drugs, food additives, pollutants, pesticides, and other carcinogens. Regeneration of other antioxidants including glutathione and vitamin E is another important role of vitamin C. Unfortunately, the current adult RDA of 75-90 mg/day may be inadequate as it underestimated the total body pool of vitamin C and was based on preventing overt deficiency instead of promoting health. The Tolerable Upper Intake Level of 2,000 mg is set to avoid osmotic diarrhea that larger oral doses of vitamin C may cause, although it is a level commonly consumed without adverse effects. Higher doses may be contraindicated in those with renal complications or iron overload disorders. However, higher doses of 6-16 grams administered intravenously in the critically ill help reduce vascular permeability, improve hemodynamic stability and vasopressor sensitivity, preserve endothelial function, and maintain circulation (Gropper 2021).

Insufficient levels of vitamin C compromise enzyme activity and metabolism and lead to overt scurvy at levels below 0.2 mg/dL (11.4 umol/L). Vitamin C also appears to play a protective role in stress. The adrenal glands maintain some of the highest concentrations of vitamin C in the body and release it quickly upon ACTH stimulation and before cortisol release. Taking oral doses of 1-3 grams of vitamin C daily may maintain plasma levels at concentrations close to those seen in the adrenal vein during ACTH stimulation. Consuming five servings of fresh fruits and vegetables daily can provide 200-250 mg of vitamin C. Depletion/repletion studies indicate that an intake of 100 mg of vitamin C per day increased plasma levels to 0.99 mg/dL (56 umol/L)… and 400 mg/day increased levels to 1.23 mg/dL (70 umol/L) (Padayatty 2016).

Individuals with diabetes tend to have lower vitamin C levels than non-diabetics, likely partly due to oxidative stress and increased antioxidant requirements. One cross-sectional study of 89 individuals revealed significantly lower vitamin C levels in those with T2DM and prediabetes compared to those with normal glucose tolerance, i.e., 0.74 mg/dL (41.2 umol/L) and 0,85 mg/dL (48 umol/L) versus 1.01 mg/dL (57.4 umol/L). Those with T2DM and prediabetes had a higher incidence of overt vitamin C deficiency with levels below 0.19 mg/dL (11 umol/L), and far fewer had saturating levels of 1.3 mg/dL (74 umol/L) or above. An inverse relationship was observed between vitamin C levels in the blood and fasting glucose, hs-CRP, BMI, and smoking (Wilson 2017).

Vitamin C is used therapeutically to improve blood lipid profiles, including the reduction of total cholesterol. Meta-analysis of 13 studies involving hypercholesterolemic subjects revealed that supplementation with at least 500 mg/day of vitamin C for at least four weeks significantly reduced LDL cholesterol and triglycerides and increased HDL cholesterol though not significantly. Analysis of 9 studies found a 25% reduction in coronary artery disease incidence in those taking at least 700 mg of vitamin C daily. The role of vitamin C in cholesterol metabolism includes preventing the oxidation of LDL, protecting HDL from oxidation, and enabling reverse cholesterol transport. Vitamin C’s additional roles as an antioxidant and cofactor in collagen synthesis further extend its protective role in cardiovascular health (McRae 2008).

Although oral intake of vitamin C via diet or supplementation does not increase plasma levels above 4.4 mg/dL (250 umol/L), intravenous administration can increase plasma vitamin C to pharmacological levels of 440 mg/dL (25 umol/L) and above, generating hydrogen peroxide and cytotoxic effects on cancer cells. Researchers suggest that the pro-oxidant effects of high-dose vitamin C may also be effective in fighting pathogens such as bacteria and viruses (Levine 2011).

Inflammation and oxidative stress—commonly seen in cancer patients—deplete vitamin C and contribute to insufficiency if not replaced. Clinical studies combining intravenous and oral vitamin C in cancer patients were found to be safe and effective in reducing inflammation and improving quality of life. In one observational retrospective study, the provision of 7.5 grams of IV vitamin C in addition to standard treatment in breast cancer patients significantly improved appetite, depression, fatigue, and sleep disorders (Klimant 2018). A prospective interventional study of 60 newly diagnosed advanced cancer patients found that high-dose IV vitamin C (12.5-100 grams) twice weekly and oral vitamin C 2-4 grams daily, significantly improved emotional, social, and physical function and decreased constipation, fatigue, and insomnia in two weeks. Significant cognitive function and pain improvement occurred after four weeks, with no observed adverse reactions despite 55% of subjects receiving concurrent chemotherapy. However, potential contraindications to IV vitamin C include G6PD deficiency, renal failure, history of kidney stones, oxaluria, anuria, severe pulmonary edema, low cardiac output, and dehydration. Researchers also suggest it may be prudent to allow clearance of IV vitamin C before administering chemotherapy. Pro-oxidant effects can occur at doses of IV vitamin C above 15 grams given over a short period and when blood levels exceed 53-70 mg/dL (3000-4000 umol/L) (Klimant 2018).

References

Amisha, Fnu et al. “Scurvy in the Modern World: Extinct or Not?.” Cureus vol. 14,2 e22622. 26 Feb. 2022, doi:10.7759/cureus.22622

Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P. Advanced Nutrition and Human Metabolism. 8^th edition. Wadsworth Publishing Co Inc. 2021.

Klimant, E et al. “Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach.” Current oncology (Toronto, Ont.) vol. 25,2 (2018): 139-148. doi:10.3747/co.25.3790

Levine, Mark et al. “Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries.” Advances in nutrition (Bethesda, Md.) vol. 2,2 (2011): 78-88. doi:10.3945/an.110.000109

Maxfield, Luke. and Jonathan S. Crane. “Vitamin C Deficiency.” StatPearls, StatPearls Publishing, 4 July 2022.

McRae, Marc P. “Vitamin C supplementation lowers serum low-density lipoprotein cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials.” Journal of chiropractic medicine vol. 7,2 (2008): 48-58. doi:10.1016/j.jcme.2008.01.002

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Padayatty, S J, and M Levine. “Vitamin C: the known and the unknown and Goldilocks.” Oral diseases vol. 22,6 (2016): 463-93. doi:10.1111/odi.12446

Tardy, Anne-Laure et al. “Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence.” Nutrients vol. 12,1 228. 16 Jan. 2020, doi:10.3390/nu12010228

Wilson, Renée et al. “Inadequate Vitamin C Status in Prediabetes and Type 2 Diabetes Mellitus: Associations with Glycaemic Control, Obesity, and Smoking.” Nutrients vol. 9,9 997. 9 Sep. 2017, doi:10.3390/nu9090997

Xiong, Ruilin et al. “Micronutrients and Diabetic Retinopathy: Evidence From The National Health and Nutrition Examination Survey and a Meta-analysis.” American journal of ophthalmology vol. 238 (2022): 141-156. doi:10.1016/j.ajo.2022.01.005