Historic Perspective on Vitamin C
Vitamin C is an important water-soluble vitamin; a deficiency of vitamin C causes scurvy. Scurvy, a term originating from the Latin word “scorbutus,” French “scorbut,” and German “skorbut,” is a condition thought to have historically affected millions [
1]. Though recognized due to its effect on sailors, scurvy also affected many individuals in the Great Potato Famine in Ireland as well as several large armies in Europe returning from months of intercontinental voyage or warfare [
2]. Those afflicted by scurvy described lethargy, gum rotting, joint ache, and death. Furthermore, those with scurvy have experienced depression, hysteria, and other psychological issues. Historian Stephen Bown described the cure to scurvy as a “vital factor determining the destiny of nations” [
3]. James Lind, a Scottish physician in the eighteenth century is credited with initiating the search for a cure to scurvy. In a first of its kind research study, a controlled trial, he evaluated six different treatments, including sulfuric acid, for 12 different sailors with scurvy, of which oranges and lemons were the only effective treatments for scurvy [
4]. While Lind was able to elucidate that fresh fruits and vegetables cured scurvy, he was not able to identify the specific agent responsible for the cure. In 1928, Hungarian scientist Albert Gyorgyi isolated a reducing agent from the adrenal glands that he named hexuronic acid; later, it was revealed to be the same as vitamin C [
5].
Sources of Vitamin C
In contrast to all plants and most animals, humans cannot synthesize ascorbic acid. In humans, the gulonolactone oxidase gene that is involved in the ascorbic acid synthesis pathways has been mutated such that it is no longer functional [
2,
10,
21]. As a result, humans are entirely dependent to obtain vitamin C from their diet. Vitamin C in the diet primarily comes from fruits and vegetables (Table
2). Since liver and fish eggs are the most vitamin C-heavy contributions from animals and these food sources are less commonly consumed, animal sources do not contribute much to dietary vitamin C. Among fruits that are common in the western diet, guava, kiwi, and strawberry are good sources of vitamin C. Citrus fruits contain a lower but sufficient amount of vitamin C [
10,
22‐
24]. Boiling vegetables decreases the vitamin C content in vegetables since high pH and high temperature environments cause decomposition of vitamin C. Meanwhile, frying vegetables does not cause a similar amount of vitamin C leaching. Steaming can relatively preserve vitamin C levels compared to boiling. To minimize instability, the ideal storage of vitamin C involves rapid thermal inactivation followed by rapid cooling. In children, breast milk provides an adequate source of ascorbic acid for newborns and infants.
Table 2
Dietary Sources of Vitamin C
Kakadu Pluma |
Camu-camua |
Bilimbia |
Acerola |
Star Fruit |
Sea Buckthorn |
Guava |
Cashew Apple |
Emblic |
Rose Hip |
Sauerkraut |
Black Currant |
Red Pepperb |
Kaleb |
Chiveb |
Corianderb |
Broccolib |
Kiwib |
Parsleyb |
Strawberryb |
Orangeb |
Lemonb |
Potatoc |
Vitamin C Deficiency and its Manifestations
Defining optimal vitamin C status has been a challenge amongst the scientific community. The Recommended Dietary Allowance (RDA) for vitamin C has most recently been defined as 90 mg/day for men and 75 mg/day for women [
25]. The pediatric RDA is 15–45 mg for children up to 13 years and 65–75 mg for children of age 14–18 years [
25,
26]. Vitamin C intake and storage can be measured through both plasma and leukocyte levels. There is still significant debate regarding which levels to measure. While plasma ascorbate levels are easier to measure, require a small amount of plasma, and reflect recent vitamin C intake, plasma ascorbate levels may not reflect accurate body stores of ascorbic acid as measured by leukocyte ascorbate levels [
27]. Clinical manifestations of scurvy, a prolonged and severe form of vitamin C deficiency, are seen among those with plasma vitamin C concentrations below 0.2 mg/dL or 11.4 umol/L (reference range: 23–114 umol/L). These patients commonly present with the following: collagen abnormalities that manifest as loss of teeth due to modified dentine production; vessel wall damage and bleeding that manifest through petechiae; ecchymoses and perifollicular hemorrhage; and skin and bone abnormalities due to abnormal keratin production, inability of osteoblasts to produce the osteoid seam, and alterations in the transcriptional profile of the bone [
26,
28]. Skeletal findings among patients with low vitamin C levels include increased bone pain, skeletal fragility, and bone fractures [
28,
29]. In infants, periostitis leads to pseudo paralysis. Radiographic findings of scurvy include the Frankel sign (dense line at the end of metaphyses from increased width at the zone of provisional calcification), Wimberger ring sign (circular calcification at the epiphyseal center of ossification), scorbutic rosary (costochondral junction expansion), and Pelkin spurs (metaphyseal spurs) and fractures [
30]. Since vitamin C is essential to neurotransmitter production and cortical neurons are highly susceptible to oxidative stress, many individuals with scurvy also present with psychological symptoms including depression and cognitive impairment as well as pseudoparalysis [
27,
31]. Additionally, since vitamin C hydroxylation is required for carnitine production, one of the first manifestations that patients with vitamin C deficiency recognize is low energy and muscle ache in the setting of not being able to transport long chain fatty acids into the mitochondrial matrix [
26].
While frequently associated with historical accounts, vitamin C deficiency is a modern concern as well, even in resource-rich nations. In fact, there are several reports of scurvy being either misdiagnosed or delayed in diagnosis in modern literature. Often, there are clues available in the diet history including lack in consumption of fresh fruits and vegetables in their diets [
32]. Additionally, individuals who smoke cigarettes and those with chronic hyperglycemia in the setting of diabetes or high stress conditions, such as sepsis, tend to present with symptoms of vitamin C deficiency [
33]. Others who are commonly affected by deficiency include those who have recently received stem cell transplantation, patients with anorexia nervosa, and patients with chronic conditions who require long-term tube feeds [
34‐
37].
Even among children, scurvy affects certain subsets of the population. Particularly at-risk populations include: critically ill children; asthmatics; children with intestinal failure and short bowel syndrome; autism spectrum disorder; global developmental delays and genetic syndromes associated with feeding difficulties; those requiring enteral/parenteral nutrition; and those with iron overload from repeat transfusions (i.e. sickle cell or thalassemia patients, and those with a history of chemotherapy) [
38]. Critically ill children are particularly at risk of vitamin C deficiency. A recent prospective single-center observational study of children with congenital heart disease demonstrated decreases in vitamin C levels postoperatively following cardiopulmonary bypass [
39]. In a 2022 study comparing vitamin C levels within 24 hours of admission in a group of Pediatric Intensive Care Unit (PICU) patients to vitamin C levels among pediatric patients in an outpatient procedure room, 18% of PICU patients displayed vitamin C deficiency compared to 0% in the noncritical group [
40]. In a 2024 study of critically ill children who were evaluated for sepsis, vitamin C levels and severity of Sequential Organ Failure Assessment (SOFA) score were inversely correlated [
41]. Children with severe asthma and airway obstruction have also been found to have vitamin C deficiency [
42]. A recent case–control study of children with transfusion dependent B- thalassemia demonstrated significantly lower plasma vitamin C levels in participants with transfusion-dependent thalassemia compared to the control group. Higher serum ferritin levels inversely correlated with vitamin C levels in accordance with the hypothesis that vitamin C is destroyed through oxidation by ferric iron. Supplementation of vitamin C in participants with low vitamin C resulted in decreased malondialdehyde (MDA) oxidant levels, further enforcing the antioxidant role of vitamin C [
43]. Children with these risk factors should be considered for periodic screening [
38].
Vitamin C Supplementation
Per the National Institutes of Health (NIH), the recommended daily allowance of vitamin C is 90 mg in adult men and 75 mg in adult women. In pregnant women, the recommended amount is 85 mg per day. In breastfeeding women, the recommended daily intake is 120 mg. For male teens, the recommended daily intake of vitamin C is 75 mg and for female teens, the recommended intake is 65 mg per day. Children 9–13 years of age should receive 45 mg of vitamin C daily, those 4–8 years should receive 25 mg and from 1–3 years of age should receive 15 mg of vitamin C daily. Infants below 6 months should consume 40 mg of vitamin C daily while those between 7 and 12 months should receive 50 mg daily. Individuals who smoke should increase their total daily recommended amount by 35 mg[
25].
There is no good consensus on vitamin C dosing in the setting of significant vitamin C deficiency. The dosing suggestions below are based on our center’s standard of practice formulated after thoughtful considerations. For vitamin C supplementation in the setting of deficiency in high risk infants, we propose that neonates (birth to 28 days) may receive 50 mg of vitamin C orally daily or intravenously (IV) as indicated. Premature infants may receive 25 mg of vitamin C orally daily or IV. Beyond the neonatal/infantile status, patients under 10 kg are advised to receive 125 mg vitamin C orally daily or 75 mg IV vitamin C daily. Those between 10 and 39.9 kg may receive 250 mg vitamin C BID orally or 250 mg IV daily. Individuals above 40 kg should receive 500 mg vitamin C orally twice daily or 500 mg IV vitamin C daily. We recommend that all doses be adjusted based on follow up levels and that levels be rechecked 2–4 weeks after starting supplementation. IV vitamin C can interfere with bedside glucose estimation by finger stick secondary to its oxidative mechanism and thereby falsely elevating sugar reading. Extremely low vitamin C levels may have very poor prognostic implications and we recommend due attention, intervention and follow up of the lab result.
There has been significant debate regarding the negative consequences of excess vitamin C intake; particularly, there are mixed results regarding the association between high vitamin C levels and kidney stone development since one of the metabolites of vitamin C is oxalate [
44,
45].
Conclusion
Vitamin C is a water-soluble vitamin that plays a crucial role as an enzyme cofactor, reducing agent, and antioxidant. Humans must pay close attention to dietary intake of vitamin C as low vitamin C levels can manifest with bleeding, bone fractures, and neuropsychiatric manifestations. Particularly, physicians should have a high index of suspicion for low vitamin C levels in high-risk children. When assessing the pediatric patient, rather than looking solely for clinical signs of deficiencies, their chronic disease state should be considered. While more studies need to be completed on the pediatric patient to define normative distribution data and optimal dosing practices, we call to question the morbidity and mortality for those children with vitamin and mineral compromise. Moving forward, more head-to-head studies must be performed to better reveal the role of vitamin C in boosting immunity and improving cardiovascular disease and cancer management.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.