Ascorbic acid (vitamin C)

General adverse effects and adverse reactions

Hot flushes, headache, fatigue, insomnia, nausea, vomiting, and diarrhea have been observed with large doses, but it is difficult to tell to what extent these are real rather than placebo effects. The best evidence of problems caused by high doses relates to stone formation, mainly in patients with chronic renal insufficiency. Certain hematological and metabolic effects have been reported in premature infants; however, these have not been corroborated [ ]. Several cases of hemolysis have been reported. Respiratory and cutaneous allergies to ascorbic acid have been described [ ]. Tumor-inducing effects have not been reported.

Respiratory

Ascorbic acid 3 g/day for 6 days causes a significant loss of high altitude resistance, persisting for 2 weeks after withdrawal of treatment. High doses may therefore constitute a risk in people who take them under conditions in which the oxygen supply suddenly becomes impaired, and is also undesirable in people with pathological hypoxia, for example due to respiratory diseases [ ].

A trial in 868 children showed that in those with high plasma ascorbic acid concentrations, the duration of upper respiratory infection was greater than in those with low concentrations [ ]. This finding, which contrasted with the optimistic expectations of other workers, requires confirmation.

Metabolism

Dehydroascorbic acid appears to have a diabetogenic effect and ascorbic acid causes increased excretion of glucose. High ascorbic acid concentrations can delay the insulin response to a glucose challenge and prolong postprandial hyperglycemia [ ].

Renal vitamin C is a precursor of oxalate and promotes its absorption, potentially causing hyperoxaluria, the commonest cause being related to enzymic deficiency. Less well recognized is subacute insidious nephropathy from secondary causes, for example excessive vitamin C intake and malabsorption, which causes calcium chelation with fatty acids, producing enteric hyperoxaluria. This can be accentuated by dehydration and hypocitraturia from diarrhea-induced metabolic acidosis [ ].

• A 73-year-old man took an oxalate-rich diet plus vitamin C 680 mg/day and furosemide and developed chronic diarrhea and a serum creatinine of 740 μmol/l (compared with 106 μmol/l 4 months before; reference range 50–120). The cause was postulated as calcium oxalate-induced nephropathy, which was confirmed by hyperoxaluria and diffuse intraluminal crystals and extensive interstitial fibrosis on biopsy. He was hemodialysed six times to remove excess oxalate. Within 2 weeks of stopping vitamin C, his creatinine fell to 273 μmol/l, and 3 months later, on a low oxalate diet and vitamin B6100 mg/day, his urine oxalate-to-creatinine ratio fell from 0.084 to 0.02 (normal less than 0.035), while the creatinine fell and stabilized at 158 μmol/l.

High-dose vitamin C can cause hyperoxaluric nephropathy and progressive renal insufficiency, especially if aggravated by diarrhea, an oxalate-rich diet, metabolic acidosis, and dehydration. The authors concluded that the diagnosis should be suspected in patients with unexplained renal insufficiency when associated with these susceptibility factors and recommended monitoring urinary oxalate in patients taking high-dose vitamin C and renal biopsy if necessary.

An increase in serum cholesterol has been reported in patients with atherosclerosis taking high doses of ascorbic acid [ ].

Metal metabolism

Binding of zinc and copper by high doses of ascorbic acid has been reported [ ].

Hematologic

Under experimental conditions, ascorbic acid 5 g/day increased the lytic sensitivity of erythrocytes to hydrogen peroxide [ ]. Similar doses, given with mandelamine or antibiotics, lower urinary pH and have a small effect on blood pH; in patients with sickle-cell anemia such doses can precipitate a crisis [ ]. The erythrocytes of premature infants can be damaged by ascorbic acid [ ]; reduced glutathione concentrations and increased Heinz-body formation have been seen [ ]. Possible explanations may be higher glucose consumption and increased glycolytic enzyme activities compared with erythrocytes in adults, accompanied by increased sensitivity to hemolysis [ ].

Also at risk of hemolysis are patients with glucose-6-phosphate dehydrogenase deficiency, in whom ascorbic acid can denature hemoglobin and reduce erythrocyte glutathione concentrations; one such case proved fatal [ ]. This was further demonstrated by reports of hemolytic effects [ ]; in two young subjects with glucose-6-phosphate dehydrogenase deficiency hemolysis was induced by excessive intake of “fizzy drinks” fortified with ascorbic acid [ ].

Gastrointestinal

Nausea, abdominal cramps, and diarrhea are not uncommon [ ]. In runners taking daily doses of 1 g of ascorbic acid for reduction of musculoskeletal symptoms, mild diarrhea is common [ ]. Ascorbic acid stones have been found to obstruct the ileocecal valve [ ].

Urinary tract

Ascorbic acid 4 g/day increases uric acid clearance in volunteers [ ], although it does not reduce protein-bound uric acid in blood. Ascorbic acid 4–12 g/day causes acidification of the urine, which can cause precipitation of urate and cystine and consequently formation of urate stones or cystinuria. Ascorbic acid is excreted largely as oxalate, and hyperoxaluria results when large doses are taken. In patients with pre-existing oxalosis, gram doses of ascorbic acid further increase oxalate excretion [ , ].

Whether this increased oxalate excretion has consequences in terms of stone formation depends very much on the dosage and duration of treatment. In a small study in healthy individuals short-term, high-dose ascorbic acid (4 g in 5 days) did not affect the risk factors associated with calcium oxalate kidney stone formation [ ]. A prospective study of the association between doses of pyridoxine and ascorbic acid and the risk of symptomatic kidney stones was undertaken in a large cohort of US nurses. Ascorbic acid was not associated with a higher risk of stone formation [ ].

In a study to determine the biochemical and physicochemical risks of high doses of ascorbic acid a man with no history of nephrolithiasis took ascorbic acid 2 g qds while following his normal diet [ ]. The study was planned to last 9 days. However, he developed significant hematuria on the eighth day. Urinary oxalate and ascorbic acid concentrations were increased. The intestinal absorption of ascorbic acid falls from almost 100% at normal doses to 20% at a dose of 5 g/day [ ], and the high concentrations of ascorbic acid in this study suggest that, irrespective of the quantity converted to oxalate, at least 35% of the ingested ascorbic acid had been absorbed. The relative supersaturation of oxalate and the Tiselius risk index both increased. Increases in the calcium oxalate relative supersaturation [ ] and Tiselius index [ ] are powerful physicochemical indicators of increases in the crystal-forming potential of the urine. In this case the increases in both measures were impressively substantiated by scanning electron microscopy, which showed large crystals and crystal aggregates in the urine. The authors suggested that the passage of these crystals caused irritation and epithelial injury manifesting as hematuria.

Oxalate-induced renal damage has been related to excessive doses of ascorbic acid [ ].

• A 31-year-old man developed a headache, nausea, and vomiting. He had taken ascorbic acid, 2–2.5 g/day and before the onset of symptoms up to 5 g/day. He had a raised serum creatinine (1000 μmol/l). Renal ultrasound showed increased cortical echogenicity, and a renal biopsy showed acute tubular necrosis and massive oxalate deposition. He was given pyridoxine and two sessions of hemodialysis.

Another case involving renal damage from extreme oral vitamin C dosage has been reported [ ].

• A 49-year-old woman, who had taken vitamin C at least 4 g/day for several months, developed acute oliguric renal failure and a creatinine of 400 μmol/l (4.5 mg/dl). She had a history of migraine, for which she had been taking large doses of ibuprofen (up to 2000 mg/day). She also reported nausea and vomiting over the previous 24 hours. She had orthostatic hypotension and dry mucous membranes. There was marked proteinuria. Renal biopsy showed widespread tubular degenerative changes and interstitial edema, typical of acute tubular necrosis, with prominent tubular calcium oxalate deposition. The glomeruli were unremarkable. She became anuric, received four hemodialysis treatments, and began to recover renal function. Nine months later, her creatinine concentration was 97 μmol/l (1.1 mg/dl).

The authors conclude that acute tubular necrosis observed in this patient was most likely related to dehydration and renal hypoperfusion in the setting of nausea, vomiting and the use of high doses of non-steroidal anti-inflammatory drugs. Calcium oxalate deposition was presumably related to the very high vitamin C intake, since oxalate results from its metabolism.

Various forms of renal damage, notably tubulointerstitial nephropathy, have been associated with long-term use of high dosages of ascorbic acid, for example 3 g/day [ ].

Skin

Cutaneous allergy has been described with ascorbic acid [ ].

Contact dermatitis has been attributed to ascorbic acid in a cosmetic anti-ageing cream [ ].

Musculoskeletal

In animal experiments, high doses of ascorbic acid adversely influenced skeleton stability. In chicks, supplementary ascorbic acid 220 mg/kg in the food increased mobilization of calcium and phosphate from the skeleton, as demonstrated by 45Ca studies and determination of acid phosphatase activity in plasma. Increased ascorbic acid also resulted in increased oxygen consumption and decreased lactic acid production by cultured chick tibiae; in growing swine, large doses (about 1 g/day for 32 days) led to a significant increase in the excretion rate of hydroxyproline, indicating an increased rate of collagen breakdown [ ]. The relevance of these old findings to humans has never been confirmed.