CLINICAL NUTRITION

VITAMIN C TOXICITY
Pharmacologic doses of vitamin C increase uric acid excretion in urine
and depress blood uric acid. Furthermore, use of vitamin C at high dosage levels
increases susceptibility of red cells to hemolysis and,
in one instance, was apparently involved as a causative
factor producing death in a patient with
glucose-6-phosphate dehydrogenase deficiency.

Key Words: toxicity, megavitamin therapy, uric acid, Chronic administration of 8 g of ascorbic
hemolysis, glucose-6-phosphate dehydrogenase acid daily to three subjects resulted in an in-
deficiency creased clearance of uric acid to 174 percent of
control values. The increased loss of uric acid
The toxicity of vitamins A and D is well known. was maintained throughout the study and for
The water-soluble vitamins are relatively non- one or two days thereafter. Serum uric acid
toxic but all materials are toxic to some degree declined in all three subjects by 1.5, 3.1 and
if consumed in sufficiently large amounts. The 1.2 mg per 100 ml while they were receiving
widespread consumption of large doses of vita- ascorbic acid. These data may be relevant to
min C is thus a matter of some concern. Three the formation of uric acid stones or in the man-
reports have recently been published indicating agement of gouty individuals.
possible untoward effects, at least in some in- A second study was concerned with the phar-
dividuals. macologic effects of ascorbic acid on the
One paper’ is concerned with the effects of hemolysis of red cells.2 These studies were
ascorbic acid on uric acid metabolism. Ten men suggested by previous work indicating a hemo-
and five women were studied. Five of the sub- lytic effect of ascorbic acid in mice. The lytic
jects had gout, three had asymptomatic hyper- sensitivity of erythrocytes to hydrogen perox-
uricemia and six had normal levels of uric acid. ide was tested in 14 healthy volunteers with no
The subjects were maintained on a purine-free previous history of hemolysis and who were
diet which provided about 2600 kcal and 70 taking no drugs. Five grams of ascorbic acid
g of protein. Drugs known to interfere with uric were given daily, 1 g at breakfast and 2 g after
acid metabolism or excretion were not taken. the noon and evening meals. The percent lysis
In nine fasting subjects the administration of was approximately 3 percent prior to the admin-
4 g of ascorbic acid caused a significant in- istration of ascorbic acid and rose to approxi-
crease (approximately 200 percent of control mately 9 percent. None of the subjects showed
values) in the clearance of uric acid. Single any evidence of hemolysis in vivo. The investi-
doses of 0.5 or 2 g did not increase the clear- gators speculate that ascorbic acid might in-
ance. The authors conclude that the change in crease hemolysis in patients who have de-
clearance with the large dose of ascorbic acid pressed mechanisms for handling oxidant
was not due to changes in urate binding to stress, such as glucose-6-phosphate dehy-
serum proteins since in vitro studies did not drogenase deficiency.
show a change in binding. Ascorbic acid did The final paper is concerned with a patient
not change the creatinine clearance and thus who may represent the first reported death in
the glomerular filtration rate was not changed. which megadoses of ascorbic acid were a
A change in tubular function was finally pro- contributing f a ~ t o rThe
. ~ patient was a 60-year-
posed to explain the results since three of four old black man admitted for treatment of acute
patients demonstrated a complete inhibition of renal failure. Six days prior to admission he
the ascorbic acid induced uricosuria when ace- suffered second degree burns of the hand.
tylsalicylic acid and pyrazinamide were given. He received 80 g of ascorbic acid intravenously
236 NUTRITION REVIEWS I VOL. 34, NO. 8 I AUGUST 1976
on each of two consecutive days. Before treat- less than 5 percent). The patient was dialyzed
ment, urinalysis and hemoglobin concentra- with little change in clinical status. Platelet lev-
tions were normal but on the third day the els returned to normal suggesting that the dis-
patient became oliguric. The urine was dark in seminated intravascular coagulation had
color and the serum was red. Creatinine con- abated. The neurological status deteriorated,
centration was 4 mg per 100 ml and the hemo- however, and the patient died on the twenty-
globin concentration was 6 g per 100 ml. He second day.
was first transferred to a regional hospital and Thus while ascorbic acid obviously has a low
given two units of blood and corticosteroids toxicity in most individuals, and this is an un-
and then transferred to a university hospital. usual case, patients with G-6-PD deficiency
Upon admission the patient was comatose and appear to be unusually sensitive. Excessive
in respiratory distress. Physical examination re- doses of anything should be viewed with sus-
vealed right-sided hemiparesis. The liver and picion until evidence of the utility and safety is
spleen were not enlarged and there was no firmly established. 0
purpura. At this time the hemoglobin concentra-
tion was 12 g per 100 ml, the platelet count ~~

45,000 per mm3, an abnormal bone marrow

was noted and the serum creatinine concentra- 1. H.B. Stein, A. Hasan and I.H. Fox: Ascorbic
tion was 14 mg per 100 ml. The patient was Acid-Induced Uricosuria. A Consequence of
anuric. The erythrocyte glucose-6-phosphate Megavitamin Therapy. Ann. lnt. Med. 84: 385-
388, 1976
dehydrogenase (G-6-PD) was only 1.76 IU per
2. C.E. Mengel and H.L. Greene, Jr.: Ascorbic
gram of hemoglobin (normal values 8.4 k
Acid Effects on Erythrocytes. Ann. Int. Med.
1.3 IU). Electrophoresis revealed the isoen- 84: 490, 1976
zyme GdA- which is relevant since individuals 3. G.D. Campbell, Jr., M.H. Steinberg and J.D.
of African descent with G-6-PD deficiency Bower: Ascorbic Acid-Induced Hemolysis in
show this isoenzyme. About 50 percent of the G-6-PD Deficiency. Ann. Int. Med. 82: 810,
patient’s erythrocytes lacked G-6-PD (normal 1975

MALNUTRITION AND DRUG METABOLISM IN MAN

Protein-calorie malnutrition in children diminished the biotransformation
of chloramphenicol. Malnutrition in adults lowered the half-life
of tetracycline, sulfadiazine and antipyrine.

Key Words: protein-calorie malnutrition, drug me- rives from animals. Changes in the biological
tabolism, chloramphenicol, tetracycline, sulfadia- half-life of a drug should be an important con-
zine, antipyrine, half-life sideration in establishing its dose and its sched-
ule of administration. Recently two groups of
The therapeutic response of a drug depends on workers in India examined the effects of mal-
a variety of factors such as absorption, tissue nutrition in humans on the metabolism and/or
uptake, tissue response and rate of elimination biological half-life of some of the commonly
of the drug from the body. The process of elimi- used drugs. Strangely, they arrived at divergent
nation in turn depends on factors such as bio- conclusions with regard to the dose schedules
transformation of the drug (in the case of drugs to be adopted in m a l n ~ t r i t i o n . ~ - ~
which are metabolized to inactive derivatives), Mehta and colleagues2 from Chandigarh,
binding to plasma and tissue proteins, and India, examined chloramphenicol metabolism
renal clearance. The literature is replete with in ten children suffering from protein-calorie
reports on the effects of malnutrition on these malnutrition (PCM) and in four healthy chil-
factors, particularly on hepatic drug-metaboliz- dren of the same age group. None of the chil-
ing enzymes,’ but most of the information de- dren suffered from infection or dehydration
NUTRITION REVIEWS / VOL. 34, NO. 8 I AUGUST 1976 237