Investigative algorithm for disorders affecting plasma vitamin C: a narrative review

Introduction

Vitamin C (ascorbic acid, ascorbate, C₆H₈O₆) and its metabolite dehydroascorbic acid (DHA) are essential micronutrients that play a significant role in numerous physiological processes, including collagen stabilisation, catecholamine synthesis, antioxidant defence, and immune regulation (1). Unlike most mammals, humans lack the terminal enzyme gulonolactone oxidase and therefore depend entirely on dietary intake and supplementation to maintain adequate vitamin C levels; serum concentrations vary between 50–80 µmol/L (2). Ascorbate is very labile and easily destroyed in food preparation and DHA is destroyed over 6–20 minutes in an aqueous solution at body temperature (3).

Disorders affecting vitamin C status range from overt deficiency to subclinical insufficiency, and include rare inherited defects (4). Although scurvy is often regarded as historic, it continues to occur in high-risk groups include the elderly, persons with alcohol dependence or following restrictive diets (5). The prevalence of vitamin C deficiency in the United States is reported to be 7.1%, and as high at 73.9% in northern India (6-8). Excessive vitamin C supplementation has also raised safety concerns, including possible risk of nephrolithiasis in men (9,10).

This review aims to outline a practical investigative pathway to approach biochemical disorders of vitamin C in humans, if the cause is not clinically apparent. The proposed algorithm is not intended to replace established national or international guidelines but to assist clinicians in systematically approaching abnormal vitamin C results when there is uncertainty about the clinical relevance. To our knowledge, previous reviews have focused on the narrative review. We present this article in accordance with the Narrative Review reporting checklist (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-73/rc).

Methods

A targeted literature search for this narrative review was conducted between September to November 2025; using PubMed/MEDLINE, Google Scholar, OMIM and seminal texts from database inception to 1 November 2025. Search terms included key words such as: vitamin C/ascorbate deficiency/excess, scurvy, prevalence, diagnostic algorithm and homeostasis. We included English language human and animal studies, prioritising systematic reviews and guidelines. Titles/abstracts were screened for relevance, with full texts assessed against inclusion criteria. The diagnostic algorithms were then created using the information gathered for the literature review (Table 1).

Discussion

Homeostasis

Vitamin C is water soluble and is abundant in fresh fruits and vegetables, especially guava, kiwifruit, citrus, strawberries, peppers, and kale, and lower in apples, carrots, celery, asparagus, and onions (11-13). Substantial degradation occurs during preservation, processing, storage, and cooking, making diet composition and meal preparation important determinants of intake (14). In healthy adults, 60 mg a day is enough to prevent clinically symptomatic deficiency and daily intakes of 200–400 mg ensure plasma saturation (15,16). Doses up to 200mg per day are almost fully absorbed by the sodium-dependent vitamin C transporter 1 (14). Higher intake results in some passive diffusion but once the transporters are saturated any additional vitamin C taken orally will not be absorbed and so bioavailability can drop from 100% under 200 mg to less than 50% at much higher doses while intakes exceeding 500 mg are largely excreted by the kidneys in individuals with adequate plasma saturation and bowel absorption (14,17).

There is little evidence that the bioavailability of supplemental vitamin C differs significantly from that of food-derived vitamin C (14,18). Evidence on formulation type is mixed: some studies report no difference between plain and slow-release preparations, whereas others found a two-fold increase in bioavailability with sustained-release forms (19,20). Salts and tablets appear equivalent (21). Liposomal formulations show enhanced bioavailability ranging from 35% to 150%, likely due to improved stability and absorption (22-25).

Vitamin C is well absorbed predominantly throughout the intestine (14). Ascorbate uptake in the proximal small intestine occurs predominantly through sodium-dependent vitamin C transporters SVCT1 (apical gut membrane and renal proximal tubules) and SVCT2 (basolateral gut membrane and metabolically active cells), encoded by the SLC23A1 and SLC23A2 genes respectively (26). Animal models demonstrate the essential nature of both vitamin C transporters: deletion of SLC23A1 causes urinary wasting and systemic depletion, whereas complete loss of SLC23A2 results in perinatal lethality due to the inability of tissues to retain ascorbate (2). DHA is absorbed by glucose transporters (GLUT) (27). In addition, a passive transfer of ascorbate occurs across the phospholipid bilayer, although likely to be small in comparison to active transfer (28). Some ascorbate is biochemically destroyed in the gut or metabolised by gut bacteria (29). Vitamin C is filtered and reabsorbed in the glomeruli and proximal tubules (30) (Figure 1).

Figure 1 Vitamin C homeostasis in humans (31). Created in BioRender. Shipman AR. [2026] (https://BioRender.com/qpmj1ea).

Once absorbed, the water-soluble ascorbate circulates freely in plasma and is actively concentrated in leukocytes with the highest concentrations in metabolically active tissues such as the adrenal glands, pituitary, and brain (16,32). Within cells, DHA is recycled to ascorbate via glutathione-dependent enzymatic reduction, maintaining redox equilibrium (33). Despite extensive research, many of the proposed mechanisms of vitamin C pharmacology remain speculative due to limited pharmacodynamic data (14). As a reducing agent, ascorbate donates electrons in hydroxylation reactions and maintains other antioxidants such as vitamin E and glutathione in their reduced states (34,35).

Homeostasis is tightly regulated through coordinated intestinal absorption, tissue uptake, and renal reabsorption (36). When intake is low, renal conservation increases through sodium-dependent reabsorption via SVCT1 (SLC23A1) in the proximal tubule (2,16). Once plasma concentrations exceed 70–80 µmol/L (renal threshold), excess ascorbate is renally excreted (16). Urinary excretion is minimal with intake below 40–50 mg/day (37,38).

Parenteral administration bypasses the saturable intestinal SVCT1 transport mechanism and achieves plasma concentrations nearly 100-fold higher than those attainable orally (16,39-43). It provides faster and more predictable replenishment in severe deficiency (14).

Laboratory investigations

The assessment of vitamin C status is most commonly performed using plasma samples; deficiency begins at plasma levels <11 mmol/L, whereas suboptimal status ranges from 11–28 mmol/L (44). Plasma samples are analysed by high-performance liquid chromatography with electrochemical detection or, increasingly, by liquid chromatography tandem mass spectrometry (36,45). Plasma concentrations are responsive to recent intake, but accurate measurement requires strict pre-analytical precautions given the instability of ascorbate. Plasma samples should be collected in ethylenediaminetetraacetic acid (EDTA) or heparin tubes, protected from light, rapidly acidified (for example with metaphosphoric acid) or frozen rapidly and shipped and stored frozen to prevent oxidative degradation. Despite these challenges, plasma measurement remains the most widely available clinical test (45,46).

Measurement of leukocyte vitamin C provides a more reliable reflection of tissue stores because intracellular concentrations are maintained even when plasma values fluctuate. Leukocytes accumulate vitamin C via active transport, and their levels change more slowly than plasma concentrations, thereby offering a longer-term indicator of vitamin C status. However, leukocyte assays require cell isolation and specialised analytical platforms, limiting their routine clinical use (1,47).

Urinary vitamin C excretion has also been studied as a marker of renal handling and excretion but is not used clinically as a substitute to plasma levels. Elevated urinary ascorbate could reflect high supplementation or conditions such as diabetes; and is a risk factor for kidney stone formation in men (14,48).

Various biomarkers have been discussed in the context of oxidative damage, but they are presented as indicators of oxidative stress rather than as validated diagnostic tools for vitamin C status and are not commonly used in laboratories (14). In fact, in clinical practice, it is usually simpler, cheaper, and safer to treat suspected scurvy than to await a vitamin C concentration in those with risk factors, symptoms and signs of hypovitaminosis.

Vitamin C deficiency

Clinical manifestations of vitamin C deficiency cause a clinical syndrome of scurvy (with ascorbate plasma concentration <10 µmol/L, but rarely is a test is required as the diagnosis is usually made clinically) and typically arise after several weeks of inadequate intake and include fatigue, gingival swelling, petechiae, ecchymoses, cork screw hairs, pedal oedema, joint swelling, anaemia, haemorrhage and delayed wound healing, reflecting impaired collagen synthesis and microvascular integrity and even death (49).

Vitamin C will become deficient if intake is inadequate or demand, degradation and loss outstrip intake. Historically scurvy was seen in those on long ship voyages with inadequate intake of fresh fruit and vegetables, but modern cases include those whose daily intake avoids fruit and vegetables or cannot afford them and included those who rely on alcohol or have disordered eating. Therefore, poor dietary intake remains the leading cause of true vitamin C deficiency (2,5).

Smoking and obesity increase oxidative stress and elevate DHA, accelerating vitamin C degradation (14,50,51). Smokers may in addition have lower dietary fruit and vegetable intake and therefore reduced vitamin C status (52-54). Tobacco smoking increases oxidative stress in a dose-dependent manner: as few as one cigarette every five days can lower plasma vitamin C, and fewer than ten cigarettes per day may double daily requirements (14,55-57). Since 2023, Nordic guidelines recommend an additional 40 mg/day of vitamin C for smokers (55,58). Increased visceral fat promotes chronic inflammation and oxidative stress, accelerating antioxidant turnover (14,59,60). Approximately 10–22 mg of additional vitamin C is required per 10kg of weight gained, and note patients with obesity may be eating very little fresh fruit and vegetables (57).

In chronic kidney disease and among haemodialysis patients, reduced conservation and dialytic losses result in low plasma ascorbate, as it’s water soluble and easily transfers across dialysis membranes (61). However, scurvy is more likely if patients on dialysis are avoiding fruit and vegetables (to avoid high potassium loads) and not complying with recommended supplementation (62).

Patients with type 2 diabetes mellitus exhibit lower vitamin C status and higher deficiency rates despite comparable dietary intake, reflecting increased oxidative and inflammatory burden (63,64). They may require 40–60% higher intakes to maintain normal levels (65). Diabetic kidney dysfunction can further reduce renal reuptake and enhance vitamin C excretion (66,67).

Vitamin C depletion is also common in cancer, infection, and inflammatory states. Patients with high-grade tumours or undergoing chemo/radiotherapy often have significantly reduced plasma vitamin C concentrations (68). Intravenous supplementation does not fully normalise these concentrations compared with healthy controls (69,70). Severe deficiency is linked with respiratory infections such as pneumonia, a major cause of death in scurvy (71). Critically ill patients with sepsis or pneumonia show markedly reduced vitamin C concentrations despite enteral or parenteral supplementation (1,72-74). Doses of 2–3 g/day may be required to normalise plasma concentrations in this population (75,76). In a 2014 clinical trial, intravenous ascorbic acid administration reduced Sequential Organ Failure Assessment scores and pro-inflammatory biomarkers, including C-reactive protein (CRP) and procalcitonin, without altering thrombomodulin concentrations (77). However, subsequent studies found that vitamin C infusions did not significantly improve organ dysfunction scores or modify markers of inflammation and vascular injury in patients with sepsis or acute respiratory distress syndrome (78). Therefore, there is a strong possibility that measuring vitamin C during an acute illness, or immediately post-surgery, will give the clinician a falsely low reading and not a true biochemical reflection of clinically significant vitamin C deficiency, i.e., a negative acute phase reactant (see Table 2) (79,80). Evidence also supports that vitamin C deficiency picked up in acute and sub-acute settings does not affect morbidity and mortality rates (81).

Damage and loss of the proximal small intestine can potentially reduce the absorption of vitamin C. In a bariatric surgery cohort of almost 6,000 patients, only 3% of the patients have vitamin C measured (perhaps because they were the only people who have clinical signs of potential vitamin deficiency) and a third had vitamin C deficiency (82). However, there were no data on clinical symptoms of scurvy nor presence/absence of disordered eating. In inflammatory bowel disease, a study demonstrated vitamin C deficiency, but the deficiency was related to the CRP concentration and there was no difference in scurvy symptoms between those measured as vitamin C deficient or not, again supporting that low plasma ascorbate does not reflect true deficiency but will be a risk if someone has significant bowel pathology (83).

Recent clinical literature supports that the relationship between inflammation and vitamin C status is bidirectional: inflammation can depress plasma vitamin C, risking overdiagnosis of deficiency, while true deficiency may exacerbate inflammatory phenotypes in select patient groups (80,84,85). Case-based evidence describes normalisation of markedly elevated CRP after vitamin C repletion in a patient with very low levels (86). Interventional evidence also suggests that supplementation can reduce CRP and high-sensitivity CRP (hs-CRP) in some contexts and observational work demonstrates inverse associations between vitamin C status and inflammatory markers consistent with acute-phase behaviour and/or causal contribution; furthermore, there are reports of diagnostic delay in scurvy-associated pulmonary arterial hypertension (80,87,88).

Medications, particularly when used chronically, can affect nutrient intake. The acid state of the stomach will affect absorption and so the taking proton pump inhibitors, particularly with active H. pylori infections, can potentially impair vitamin C absorption (89,90). Non-steroidal anti-inflammatory drugs (NSAIDs) were thought to decrease vitamin C absorption, but the data were not replicable as the low plasma vitamin C was probably due to the concomitant inflammatory illness (91). However, NSAIDs may reduce storage of vitamin C in leucocytes (92). Oral contraceptive drugs do not drop vitamin C despite early concerns (93). There are no reports of diuretics causing vitamin C deficiency despite increased diuresis as the active reabsorption of ascorbate continues unaffected.

Vitamin C is so labile that if the blood sample is not treated and tested rapidly the test will be spuriously low (one has less than 4 hours to process the sample) and so liaising with your local laboratory is essential to prevent diagnostic inaccuracy (94). Spuriously low concentrations can be produced by pre-analytic degradation, such as light-exposure, delayed centrifugation, failure to acidify or freeze, and transport at ambient temperature (95). In the face of low plasma vitamin C on testing, with no obvious cause, then an algorithm is presented (Figure 2) of standard laboratory tests to help point at the cause of the result, bearing in mind that most if not all will have low intake as part of the problem (if the measurement is true) and aetiology might be multifactorial. The algorithm does not replace advice from your local experts and guidelines, particularly in complicated cases, nor is it validated in clinical practice.

Figure 2 Diagnostic algorithm for possible causes of low plasma vitamin C in humans, when the clinical cause is not immediately apparent. Created in BioRender. Shipman A. [2026] (https://BioRender.com/k5zol8p). CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HbA1c, hemoglobin A1c.

High vitamin C

Vitamin C excess is rarely toxic, in part because it is labile and once the renal reabsorption pathway is exceeded the rest of the water-soluble ascorbate is excreted in urine. Those in renal failure therefore may run the risk of toxicity but probably only in the setting of excess intake (61). Vitamin C toxicity can lead to further kidney problems with stone formation, as oxalate is one of the metabolites of ascorbate.

High-dose vitamin C supplementation (>1 g/day) is widely practised as it marketed as a health providing antioxidant, with plasma concentrations often exceeding physiological norms. While generally considered safe as the kidneys promptly excrete it, high intake has been linked to gastrointestinal upset and renal stone formation in susceptible individuals (9). It should be noted that regular consumption of antioxidants may actually increase mortality rate and should not be recommended (96).

Patients in renal failure may avoid potassium-containing fruit and vegetables, their kidneys may stop reabsorbing vitamin C and dialysis may remove too much of it. Therefore, they may take vitamin supplements including intravenous ascorbate. If not balanced correctly, this can lead to vitamin C toxicity in the form of raising oxalate, which deposits in blood vessels and kidneys (97).

An investigative algorithm is not required for hypervitaminosis C, as the cause is most likely to be high intake plus or minus some reduced renal handling. In routine practice, very high vitamin C levels are rarely encountered, and vitamin C testing itself is infrequently requested outside suspected scurvy or specialist nutrition pathways, unless directed by patients on health checks (81,98).

Special states

During pregnancy, vitamin C progressively declines due to haemodilution, weight gain, and active placental transfer, reaching its lowest concentrations in the third trimester (99-102). Maternal and neonatal vitamin C concentrations are closely correlated; infants typically have 2–3 times higher concentrations, suggesting preferential foetal transport (14,99,100,103-106). Animal studies show that during sustained deficiency, maternal stores are maintained at the expense of the offspring; and deficiency is associated with placental and foetal growth retardation (107,108). Vitamin C is actively transferred into breast milk, with concentrations dependent on infant age (109-114). This process follows saturation kinetics (38). Preterm and newborn infants require higher vitamin C intake, milk and colostrum contain high concentrations (115-117). Vitamin C is heat-sensitive, and its content in expressed breast milk declines rapidly during storage (118-120). Smoking during pregnancy reduces maternal and neonatal vitamin C status (112).

Strengths and weaknesses

Strengths of this review include its clinically oriented diagnostic approach and its emphasis on common interpretive pitfalls. Limitations include the narrative design and the potential for incomplete capture of all relevant studies. Future research could review the frequency of use and effectiveness of the diagnostic algorithm in clinical practice.

Conclusions

In conclusion, our view would be an isolated low plasma vitamin C result should not be interpreted as clinical deficiency, especially in a patient with elevated CRP or recent surgery/sepsis. Instead, it should be interpreted in conjunction with dietary history, risk factors (such as restrictive diets, alcohol dependence, malabsorption), and physical signs of scurvy. Where laboratory conditions are uncertain or inflammation is present, clinicians should consider either repeating measurement when clinically stable with strict handling precautions, using a tissue-oriented measurement such as leukocyte vitamin C, or proceeding with a pragmatic therapeutic trial when suspicion for scurvy is moderate-to-high.

We would recommend against routine measurement in unselected patients, where the pre-test probability is low and false-low results are possible. However, low clinical suspicion and limited testing may also contribute to missed or delayed diagnoses in atypical presentations, and a targeted approach is warranted in high-risk dietary states or unexplained compatible syndromes.

Overall, a practical approach is therefore to prioritise dietary history, risk factors, and examination findings, supported by a diagnostic algorithm to identify likely causes of low vitamin C. Plasma levels should not be measured unless clinical symptoms are present, and it should be reserved for cases where the result will change management and where sampling integrity and inflammatory context can be taken into account. In many suspected cases, measurement is sufficiently challenging that empirical replacement may be a safer and quicker way to confirm scurvy, with symptom resolution providing clinically meaningful confirmation while avoiding overinterpretation of isolated plasma results.

Acknowledgments

All figures were created with BioRender.com.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Sukhbinda Kaur) for the series “Trace Elements and Vitamins” published in Journal of Laboratory and Precision Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-73/rc

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-73/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-73/coif). The series “Trace Elements and Vitamins” was commissioned by the editorial office without any funding or sponsorship. K.E.S. serves as an unpaid editorial board member of Journal of Laboratory and Precision Medicine from September 2024 to December 2026. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients 2017;9:1211. [Crossref] [PubMed]
2. Corpe CP, Tu H, Eck P, et al. Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. J Clin Invest 2010;120:1069-83. [Crossref] [PubMed]
3. Rumsey S, Levine M. Absorption, transport, and disposition of ascorbic acid in humans. The Journal of Nutritional Biochemistry 1998;9:116-30.
4. May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal 2013;19:2068-83. [Crossref] [PubMed]
5. Olmedo JM, Yiannias JA, Windgassen EB, et al. Scurvy: a disease almost forgotten. Int J Dermatol 2006;45:909-13. [Crossref] [PubMed]
6. Baluch A, Landsberg D. Scurvy in the Intensive Care Unit. J Investig Med High Impact Case Rep 2021;9:23247096211067970. [Crossref] [PubMed]
7. Schleicher RL, Carroll MD, Ford ES, et al. Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES). Am J Clin Nutr 2009;90:1252-63. [Crossref] [PubMed]
8. Ravindran RD, Vashist P, Gupta SK, et al. Prevalence and risk factors for vitamin C deficiency in north and south India: a two centre population based study in people aged 60 years and over. PLoS One 2011;6:e28588. [Crossref] [PubMed]
9. Thomas LD, Elinder CG, Tiselius HG, et al. Ascorbic acid supplements and kidney stone incidence among men: a prospective study. JAMA Intern Med 2013;173:386-8. [Crossref] [PubMed]
10. Jiang K, Tang K, Liu H, et al. Ascorbic Acid Supplements and Kidney Stones Incidence Among Men and Women: A systematic review and meta-analysis. Urol J 2019;16:115-20. [Crossref] [PubMed]
11. Szeto YT, Tomlinson B, Benzie IF. Total antioxidant and ascorbic acid content of fresh fruits and vegetables: implications for dietary planning and food preservation. Br J Nutr 2002;87:55-9. [Crossref] [PubMed]
12. Carr AC, Rowe S. Factors Affecting Vitamin C Status and Prevalence of Deficiency: A Global Health Perspective. Nutrients 2020;12:1963. [Crossref] [PubMed]
13. Maurya VK, Shakya A, McClements DJ, et al. Vitamin C fortification: need and recent trends in encapsulation technologies. Front Nutr 2023;10:1229243. [Crossref] [PubMed]
14. Lykkesfeldt J, Carr AC, Tveden-Nyborg P. The pharmacology of vitamin C. Pharmacol Rev 2025;77:100043. [Crossref] [PubMed]
15. Frei B, Birlouez-Aragon I, Lykkesfeldt J. Authors' perspective: What is the optimum intake of vitamin C in humans? Crit Rev Food Sci Nutr 2012;52:815-29. [Crossref] [PubMed]
16. Lykkesfeldt J, Tveden-Nyborg P. The Pharmacokinetics of Vitamin C. Nutrients 2019;11:2412. [Crossref] [PubMed]
17. Dhotre T, Thanawala S, Shah R. Optimizing Oral Vitamin C Supplementation: Addressing Pharmacokinetic Challenges with Nutraceutical Formulation Approaches-A Mini Review. Pharmaceutics 2025;17:1458. [Crossref] [PubMed]
18. Carr AC, Vissers MC. Synthetic or food-derived vitamin C--are they equally bioavailable? Nutrients 2013;5:4284-304. [Crossref] [PubMed]
19. Sacharin R, Taylor T, Chasseaud LF. Blood levels and bioavailability of ascorbic acid after administration of a sustained-release formulation to humans. Int J Vitam Nutr Res 1977;47:68-74.
20. Bhagavan HN, Wolkoff BI. Correlation between the disintegration time and the bioavailability of vitamin C tablets. Pharm Res 1993;10:239-42. [Crossref] [PubMed]
21. Johnston CS, Luo B. Comparison of the absorption and excretion of three commercially available sources of vitamin C. J Am Diet Assoc 1994;94:779-81. [Crossref] [PubMed]
22. Davis JL, Paris HL, Beals JW, et al. Liposomal-encapsulated Ascorbic Acid: Influence on Vitamin C Bioavailability and Capacity to Protect Against Ischemia-Reperfusion Injury. Nutr Metab Insights 2016;9:25-30. [Crossref] [PubMed]
23. Łukawski M, Dałek P, Borowik T, et al. New oral liposomal vitamin C formulation: properties and bioavailability. J Liposome Res 2020;30:227-34. [Crossref] [PubMed]
24. Jacob J, Sukumaran NP, Jude S. Fiber-Reinforced-Phospholipid Vehicle-Based Delivery of l-Ascorbic Acid: Development, Characterization, ADMET Profiling, and Efficacy by a Randomized, Single-Dose, Crossover Oral Bioavailability Study. ACS Omega 2021;6:5560-8. [Crossref] [PubMed]
25. Joseph A, Kumar D, Balakrishnan A, et al. Surface-engineered liposomal particles of calcium ascorbate with fenugreek galactomannan enhanced the oral bioavailability of ascorbic acid: a randomized, double-blinded, 3-sequence, crossover study. RSC Adv 2021;11:38161-71. [Crossref] [PubMed]
26. Savini I, Rossi A, Pierro C, et al. SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids 2008;34:347-55. [Crossref] [PubMed]
27. Rivas CI, Zúñiga FA, Salas-Burgos A, et al. Vitamin C transporters. J Physiol Biochem 2008;64:357-75. [Crossref] [PubMed]
28. Hannesschlaeger C, Pohl P. Membrane Permeabilities of Ascorbic Acid and Ascorbate. Biomolecules 2018;8:73. [Crossref] [PubMed]
29. Kallner A, Hornig D, Pellikka R. Formation of carbon dioxide from ascorbate in man. Am J Clin Nutr 1985;41:609-13. [Crossref] [PubMed]
30. Lindblad M, Tveden-Nyborg P, Lykkesfeldt J. Regulation of vitamin C homeostasis during deficiency. Nutrients 2013;5:2860-79. [Crossref] [PubMed]
31. Office of Dietary Supplements. Vitamin C - Health Professional Fact Sheet. National Institutes of Health-Office of Dietary Supplements; 2025.
32. Abdullah M, Jamil RT, Attia FN. Vitamin C (Ascorbic Acid). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available online: https://www.ncbi.nlm.nih.gov/books/NBK499877/
33. Linster CL, Van Schaftingen E, Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J 2007;274:1-22.
34. Padayatty SJ, Katz A, Wang Y, et al. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr 2003;22:18-35. [Crossref] [PubMed]
35. Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999;69:1086-107. [Crossref] [PubMed]
36. Levine M, Padayatty SJ, Espey MG. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr 2011;2:78-88. [Crossref] [PubMed]
37. Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A 1996;93:3704-9. [Crossref] [PubMed]
38. Levine M, Wang Y, Padayatty SJ, et al. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A 2001;98:9842-6. [Crossref] [PubMed]
39. Levine M, Espey MG, Chen Q. Losing and finding a way at C: new promise for pharmacologic ascorbate in cancer treatment. Free Radic Biol Med 2009;47:27-9. [Crossref] [PubMed]
40. Espey MG, Chen P, Chalmers B, et al. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med 2011;50:1610-9. [Crossref] [PubMed]
41. Violet PC, Levine M. Pharmacologic Ascorbate in Myeloma Treatment: Doses Matter. EBioMedicine 2017;18:9-10. [Crossref] [PubMed]
42. Nielsen TK, Højgaard M, Andersen JT, et al. Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharmacokinetic evaluation. Basic Clin Pharmacol Toxicol 2015;116:343-8. [Crossref] [PubMed]
43. Ou J, Zhu X, Lu Y, et al. The safety and pharmacokinetics of high dose intravenous ascorbic acid synergy with modulated electrohyperthermia in Chinese patients with stage III-IV non-small cell lung cancer. Eur J Pharm Sci 2017;109:412-8. [Crossref] [PubMed]
44. McCall SJ, Clark AB, Luben RN, et al. Plasma Vitamin C Levels: Risk Factors for Deficiency and Association with Self-Reported Functional Health in the European Prospective Investigation into Cancer-Norfolk. Nutrients 2019;11:1552. [Crossref] [PubMed]
45. Rozemeijer S, van der Horst FAL, de Man AME. Measuring vitamin C in critically ill patients: clinical importance and practical difficulties-Is it time for a surrogate marker? Crit Care 2021;25:310. [Crossref] [PubMed]
46. Pullar JM, Bayer S, Carr AC. Appropriate Handling, Processing and Analysis of Blood Samples Is Essential to Avoid Oxidation of Vitamin C to Dehydroascorbic Acid. Antioxidants (Basel) 2018;7:29. [Crossref] [PubMed]
47. Mitmesser SH, Ye Q, Evans M, et al. Determination of plasma and leukocyte vitamin C concentrations in a randomized, double-blind, placebo-controlled trial with Ester-C Springerplus 2016;5:1161. [Crossref] [PubMed]
48. Ferraro PM, Curhan GC, Gambaro G, et al. Total, Dietary, and Supplemental Vitamin C Intake and Risk of Incident Kidney Stones. Am J Kidney Dis 2016;67:400-7. [Crossref] [PubMed]
49. Gandhi M, Elfeky O, Ertugrul H, et al. Scurvy: Rediscovering a Forgotten Disease. Diseases 2023;11:78. [Crossref] [PubMed]
50. Lykkesfeldt J, Loft S, Nielsen JB, et al. Ascorbic acid and dehydroascorbic acid as biomarkers of oxidative stress caused by smoking. Am J Clin Nutr 1997;65:959-63. [Crossref] [PubMed]
51. Fernández-Sánchez A, Madrigal-Santillán E, Bautista M, et al. Inflammation, oxidative stress, and obesity. Int J Mol Sci 2011;12:3117-32. [Crossref] [PubMed]
52. Masood S, Cappelli C, Li Y, et al. Cigarette smoking is associated with unhealthy patterns of food consumption, physical activity, sleep impairment, and alcohol drinking in Chinese male adults. Int J Public Health 2015;60:891-9. [Crossref] [PubMed]
53. Kim EK, Kim H, Vijayakumar A, et al. Associations between fruit and vegetable, and antioxidant nutrient intake and age-related macular degeneration by smoking status in elderly Korean men. Nutr J 2017;16:77. [Crossref] [PubMed]
54. Lykkesfeldt J, Christen S, Wallock LM, et al. Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am J Clin Nutr 2000;71:530-6. [Crossref] [PubMed]
55. Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med 1995;332:1198-203.
56. Lykkesfeldt J, Viscovich M, Poulsen HE. Plasma malondialdehyde is induced by smoking: a study with balanced antioxidant profiles. Br J Nutr 2004;92:203-6. [Crossref] [PubMed]
57. Carr AC, Lykkesfeldt J. Factors Affecting the Vitamin C Dose-Concentration Relationship: Implications for Global Vitamin C Dietary Recommendations. Nutrients 2023;15:1657. [Crossref] [PubMed]
58. Lykkesfeldt J, Carr AC. Vitamin C - a scoping review for Nordic Nutrition Recommendations 2023. Food Nutr Res 2023;67: [Crossref]
59. Mallick R, Basak S, Das RK, et al. Fatty Acids and their Proteins in Adipose Tissue Inflammation. Cell Biochem Biophys 2024;82:35-51. [Crossref] [PubMed]
60. Varra FN, Varras M, Varra VK, et al. Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options Mol Med Rep 2024;29:95. (Review). [Crossref] [PubMed]
61. Doshida Y, Itabashi M, Takei T, et al. Reduced Plasma Ascorbate and Increased Proportion of Dehydroascorbic Acid Levels in Patients Undergoing Hemodialysis. Life (Basel) 2021;11:1023. [Crossref] [PubMed]
62. Zhou JQ, Velimirovic M, Chang LL, et al. Spontaneous haematomas and haematochezia due to vitamin C deficiency in a haemodialysis patient. BMJ Case Rep 2022;15:e249711. [Crossref] [PubMed]
63. Jha JC, Ho F, Dan C, et al. A causal link between oxidative stress and inflammation in cardiovascular and renal complications of diabetes. Clin Sci (Lond) 2018;132:1811-36. [Crossref] [PubMed]
64. Andreadi A, Bellia A, Di Daniele N, et al. The molecular link between oxidative stress, insulin resistance, and type 2 diabetes: A target for new therapies against cardiovascular diseases. Curr Opin Pharmacol 2022;62:85-96. [Crossref] [PubMed]
65. Carr AC, Lunt H, Wareham NJ, et al. Estimating Vitamin C Intake Requirements in Diabetes Mellitus: Analysis of NHANES 2017-2018 and EPIC-Norfolk Cohorts. Antioxidants (Basel) 2023;12:1863. [Crossref] [PubMed]
66. Ebenuwa I, Violet PC, Padayatty S, et al. Abnormal urinary loss of vitamin C in diabetes: prevalence and clinical characteristics of a vitamin C renal leak. Am J Clin Nutr 2022;116:274-84. [Crossref] [PubMed]
67. Lunt H, Carr AC, Heenan HF, et al. People with diabetes and hypovitaminosis C fail to conserve urinary vitamin C. J Clin Transl Endocrinol 2023;31:100316. [Crossref] [PubMed]
68. Carr AC, Cook J. Intravenous Vitamin C for Cancer Therapy - Identifying the Current Gaps in Our Knowledge. Front Physiol 2018;9:1182. [Crossref] [PubMed]
69. Gillberg L, Ørskov AD, Nasif A, et al. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes. Clin Epigenetics 2019;11:143. [Crossref] [PubMed]
70. Mikkelsen SU, Gillberg L, Lykkesfeldt J, et al. The role of vitamin C in epigenetic cancer therapy. Free Radic Biol Med 2021;170:179-93. [Crossref] [PubMed]
71. Hemilä H. Vitamin C and Infections. Nutrients 2017;9:339. [Crossref] [PubMed]
72. Rogers M, Greenacre T, Dalla-Pozza L. Neutrophilic dermatosis of myeloproliferative disease in a 10-year-old. Pediatr Dermatol 1987;4:305-12. [Crossref] [PubMed]
73. Spencer E, Rosengrave P, Williman J, et al. Circulating protein carbonyls are specifically elevated in critically ill patients with pneumonia relative to other sources of sepsis. Free Radic Biol Med 2022;179:208-12. [Crossref] [PubMed]
74. Vlasiuk E, Rosengrave P, Roberts E, et al. Critically ill septic patients have elevated oxidative stress biomarkers: lack of attenuation by parenteral vitamin C. Nutr Res 2022;108:53-9. [Crossref] [PubMed]
75. Long CL, Maull KI, Krishnan RS, et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res 2003;109:144-8. [Crossref] [PubMed]
76. de Grooth HJ, Manubulu-Choo WP, Zandvliet AS, et al. Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens. Chest 2018;153:1368-77. [Crossref] [PubMed]
77. Fowler AA 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 2014;12:32. [Crossref] [PubMed]
78. Fowler AA 3rd, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA 2019;322:1261-70. [Crossref] [PubMed]
79. Conway FJ, Talwar D, McMillan DC. The relationship between acute changes in the systemic inflammatory response and plasma ascorbic acid, alpha-tocopherol and lipid peroxidation after elective hip arthroplasty. Clin Nutr 2015;34:642-6. [Crossref] [PubMed]
80. Duncan A, Talwar D, McMillan DC, et al. Quantitative data on the magnitude of the systemic inflammatory response and its effect on micronutrient status based on plasma measurements. Am J Clin Nutr 2012;95:64-71. [Crossref] [PubMed]
81. Golder J, Bauer J, Barker LA, et al. The Prevalence, Risk Factors, and Clinical Outcomes of Vitamin C Deficiency in Adult Hospitalised Patients: A Retrospective Observational Study. Nutrients 2025;17:1131. [Crossref] [PubMed]
82. Parrott JM, Parrott AJ, Rouhi AD, et al. What We Are Missing: Using Machine Learning Models to Predict Vitamin C Deficiency in Patients with Metabolic and Bariatric Surgery. Obes Surg 2023;33:1710-9. [Crossref] [PubMed]
83. Gordon BL, Galati JS, Yang S, et al. Prevalence and factors associated with vitamin C deficiency in inflammatory bowel disease. World J Gastroenterol 2022;28:4834-45. [Crossref] [PubMed]
84. Block G, Jensen CD, Dalvi TB, et al. Vitamin C treatment reduces elevated C-reactive protein. Free Radic Biol Med 2009;46:70-7. [Crossref] [PubMed]
85. Crook JM, Horgas AL, Yoon SL, et al. Vitamin C Plasma Levels Associated with Inflammatory Biomarkers, CRP and RDW: Results from the NHANES 2003-2006 Surveys. Nutrients 2022;14:1254. [Crossref] [PubMed]
86. Ayyad M, Tran L, Ansari S, et al. Forgotten Deficiency: A Case Series Highlighting Atypical Presentations of Scurvy in the 21st Century. Case Rep Med 2025;2025:2118907. [Crossref] [PubMed]
87. Jafarnejad S, Boccardi V, Hosseini B, et al. A Meta-analysis of Randomized Control Trials: The Impact of Vitamin C Supplementation on Serum CRP and Serum hs-CRP Concentrations. Curr Pharm Des 2018;24:3520-8. [Crossref] [PubMed]
88. Azar J, Ayyad M, Jaber Y, et al. Scurvy-induced pulmonary arterial hypertension. BMJ Case Rep 2023;16:e254730. [Crossref] [PubMed]
89. Mowat C, Williams C, Gillen D, et al. Omeprazole, Helicobacter pylori status, and alterations in the intragastric milieu facilitating bacterial N-nitrosation. Gastroenterology 2000;119:339-47. [Crossref] [PubMed]
90. McColl KE. Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol 2009;104:S5-9. [Crossref] [PubMed]
91. Mohn ES, Kern HJ, Saltzman E, et al. Evidence of Drug-Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018;10:36. [Crossref] [PubMed]
92. Schulz HU, Schürer M, Krupp S, et al. Effects of acetylsalicylic acid on ascorbic acid concentrations in plasma, gastric mucosa, gastric juice and urine--a double-blind study in healthy subjects. Int J Clin Pharmacol Ther 2004;42:481-7. [Crossref] [PubMed]
93. Pincemail J, Vanbelle S, Gaspard U, et al. Effect of different contraceptive methods on the oxidative stress status in women aged 40 48 years from the ELAN study in the province of Liege, Belgium. Hum Reprod 2007;22:2335-43. [Crossref] [PubMed]
94. NHS. Vitamin C - Scottish Trace Element and Micronutrient Diagnostic and Research Laboratory 2004-2025. Available online: https://www.trace-elements.co.uk/vitamin-c.asp
95. Karlsen A, Blomhoff R, Gundersen TE. Stability of whole blood and plasma ascorbic acid. Eur J Clin Nutr 2007;61:1233-6. [Crossref] [PubMed]
96. Bjelakovic G, Nikolova D, Gluud LL, et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 2008;CD007176.
97. Canavese C, Petrarulo M, Massarenti P, et al. Long-term, low-dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients. Am J Kidney Dis 2005;45:540-9. [Crossref] [PubMed]
98. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 2004;140:533-7. [Crossref] [PubMed]
99. Scaife AR, McNeill G, Campbell DM, et al. Maternal intake of antioxidant vitamins in pregnancy in relation to maternal and fetal plasma levels at delivery. Br J Nutr 2006;95:771-8. [Crossref] [PubMed]
100. Juhl B, Lauszus FF, Lykkesfeldt J. Is Diabetes Associated with Lower Vitamin C Status in Pregnant Women? A Prospective Study. Int J Vitam Nutr Res 2016;86:184-9.
101. Carr AC, Bradley HA, Vlasiuk E, et al. Inflammation and Vitamin C in Women with Prenatal Depression and Anxiety: Effect of Multinutrient Supplementation. Antioxidants (Basel) 2023;12:941. [Crossref] [PubMed]
102. Morse EH, Clarke RP, Keyser DE, et al. Comparison of the nutritional status of pregnant adolescents with adult pregnant women. I. Biochemical findings. The American Journal of Clinical Nutrition 1975;28:1000-13.
103. Madruga de Oliveira A, Rondó PH, Barros SB. Concentrations of ascorbic acid in the plasma of pregnant smokers and nonsmokers and their newborns. Int J Vitam Nutr Res 2004;74:193-8. [Crossref] [PubMed]
104. Madruga de Oliveira A, Rondó PH, Oliveira JM. Maternal alcohol consumption may influence cord blood ascorbic acid concentration: findings from a study of Brazilian mothers and their newborns. Br J Nutr 2009;102:895-8. [Crossref] [PubMed]
105. Jain SK, Wise R, Yanamandra K, et al. The effect of maternal and cord-blood vitamin C, vitamin E and lipid peroxide levels on newborn birth weight. Mol Cell Biochem 2008;309:217-21. [Crossref] [PubMed]
106. Moya-Alvarez V, Koyembi JJ, Kayé LM, et al. Vitamin C levels in a Central-African mother-infant cohort: Does hypovitaminosis C increase the risk of enteric infections? Matern Child Nutr 2021;17:e13215. [Crossref] [PubMed]
107. Schjoldager JG, Tveden-Nyborg P, Lykkesfeldt J. Prolonged maternal vitamin C deficiency overrides preferential fetal ascorbate transport but does not influence perinatal survival in guinea pigs. Br J Nutr 2013;110:1573-9. [Crossref] [PubMed]
108. Schjoldager JG, Paidi MD, Lindblad MM, et al. Maternal vitamin C deficiency during pregnancy results in transient fetal and placental growth retardation in guinea pigs. Eur J Nutr 2015;54:667-76. [Crossref] [PubMed]
109. Bates CJ, Prentice AM, Prentice A, et al. The effect of vitamin C supplementation on lactating women in Keneba, a West African rural community. Int J Vitam Nutr Res 1983;53:68-76.
110. Bates CJ, Prentice AM, Paul AA. Seasonal variations in vitamins A, C, riboflavin and folate intakes and status of pregnant and lactating women in a rural Gambian community: some possible implications. Eur J Clin Nutr 1994;48:660-8.
111. Salmenperä L. Vitamin C nutrition during prolonged lactation: optimal in infants while marginal in some mothers. Am J Clin Nutr 1984;40:1050-6. [Crossref] [PubMed]
112. Ortega RM, Quintas ME, Andrés P, et al. Ascorbic acid levels in maternal milk: differences with respect to ascorbic acid status during the third trimester of pregnancy. Br J Nutr 1998;79:431-7. [Crossref] [PubMed]
113. Tawfeek HI, Muhyaddin OM, al-Sanwi HI, et al. Effect of maternal dietary vitamin C intake on the level of vitamin C in breastmilk among nursing mothers in Baghdad, Iraq. Food Nutr Bull 2002;23:244-7. [Crossref] [PubMed]
114. Martysiak-Żurowska D, Zagierski M, Woś-Wasilewska E, et al. Higher Absorption of Vitamin C from Food than from Supplements by Breastfeeding Mothers at Early Stages of Lactation. Int J Vitam Nutr Res 2016;86:81-7. [Crossref] [PubMed]
115. Bank MR, Kirksey A, West K, et al. Effect of storage time and temperature on folacin and vitamin C levels in term and preterm human milk. Am J Clin Nutr 1985;41:235-42. [Crossref] [PubMed]
116. Udipi SA, Kirksey A, West K, et al. Vitamin B6, vitamin C and folacin levels in milk from mothers of term and preterm infants during the neonatal period. Am J Clin Nutr 1985;42:522-30. [Crossref] [PubMed]
117. Ahmed L Jr, Islam S, Khan N, et al. Vitamin C content in human milk (colostrum, transitional and mature) and serum of a sample of bangladeshi mothers. Malays J Nutr 2004;10:1-4.
118. Heinonen K, Mononen I, Mononen T, et al. Plasma vitamin C levels are low in premature infants fed human milk. Am J Clin Nutr 1986;43:923-4. [Crossref] [PubMed]
119. Francis J, Rogers K, Brewer P, et al. Comparative analysis of ascorbic acid in human milk and infant formula using varied milk delivery systems. Int Breastfeed J 2008;3:19. [Crossref] [PubMed]
120. Buss IH, McGill F, Darlow BA, et al. Vitamin C is reduced in human milk after storage. Acta Paediatr 2001;90:813-5.