Vitamins

H.D. Reuter

40

Vitamins

G E N E R A L TOPICS

Vitamin supplementation in children (1 r) It is generally accepted that the diets of most children contain enough vitamins to prevent deficiency diseases. Full-term babies who are either breast-fed or bottle-fed are not likely to develop vitamin deficiencies. Very premature infants do, however, need supplementary vitamins because they do not have the stores normally laid down during the last trimester of pregnancy; they particularly need vitamin D and folic acid during the first 6 months of life. Vitamin supplementation is also needed in babies of lactating mothers with low vitamin intake, who as well as providing insufficient vitamins in their breast milk are likely to have transferred inadequate amounts of vitamins across the placenta during late pregnancy. Babies of vegetarian mothers may, for example, develop megaloblastic anemia and rickets from deficiency of vitamin Bi2 and D. The heat-labile vitamin C may be destroyed in formula feeds and during the preparation of food. There is thus good reason for all babies and toddlers to receive supplements of vitamins A, C and D as multivitamin drops. A more controversial question is whether subclinical vitamin deficiencies can have various non-specific effects. The provision of 'freedom of choice' for youngsters in meals they buy and the growth of the 'junk food' industry have led to concern that school-age children may not be getting enough vitamins. A doubleblind placebo-controlled trial showed that nonverbal intelligence was improved by supplements of vitamins and minerals. This finding would have wide implications if correct, but it has been criticized on methodological and statistical grounds. Unfortunately, the study included both vitamins and minerals in the sup-

plement, so the effect of either alone is unknown. There are considerable attractions for both parents and health professionals in ascribing often intractable and worrying problems to causes that might be amenable to simple dietary solutions and that carry no pejorative implications. It should however be kept in mind that treatment with high doses of vitamins, particularly with the fat-soluble vitamins A and D, may have side effects. Though watersoluble vitamins are safer, they can also have undesired effects. Thus, huge of doses of ascorbic acid may cause hematuria and a massive intake of pyridoxine has been associated with peripheral neuropathy.

Vulval pruritus caused by oral vitamin preparations Vulval pruritus can be caused by a wide variety of conditions aud provocative factors. Among others it can be induced by oral vitamin preparations (2c).

9 1990 Elsevier Science Publishers B.V. (Biomedical Division)

Side Effects of Drugs Annual 14 M.N.G, Dukes and L, Beeley, editors

329

V I T A M I N A (RETINOL) (SED-11, 799;

SEDA-12, 327; SEDA-13, 346) Even moderate amounts of vitamin A, when ingested over a prolonged period of time, can cause significant hepatocellular injury. This is emphasized by a report of vitamin A hepatotoxicity in several members of a family. Three out of 5 family members experienced symptoms and biochemical evidence of hepatitis that could not be explained on the basis of infectious, metabolic or immunological disorders of the liver. A history of prolonged ingestion of 20000--45000 IU per dag for 7-10 years was obtained in each of the 3 family members (father, 62 years old; mother, 63 years old; son 33 years old) and was absent in the remaining 2 unaffected individuals. Vitamin A toxicity in one family member was confirmed by liver biopsy (3c). An update of vitamin A toxicology is summarized by Biesalski and Seelert (4a). Accord-

330 ing to the review by Bauernfeind (5c), symptoms of toxicity develop more quickly when very high daily doses are ingested. With daily intake of 1 000 000 IU toxicity develops within days or weeks. Intake of 400 000-700 000 IU per day produces symptoms of hypervitaminosis after 1-36 months and daily doses of 150 000-200 000 IU produce toxicity only after 6-85 months. The frequency and severity of toxicity in general depend on the vitamin status of the individual. Thus, in persons with low hepatic vitamin stores, high daily doses are tolerated much better than in persons with normal stores. Because the development of toxic symptoms depends on various factors such as liver stores, age, protein intake and underlying diseases, an absolute real therapeutic range cannot be defined. Goodman et al (6 c) found that daily intake of 200 000 IU vitamin A per m 2 body surface corresponding to about 330000 IU per patient for up to 4 months did not result in important side effects. Precautions have however to be taken in pregnant women and in women capable of childbearing. In animals both deficiency and massive overdose with vitamin A can be teratogenic. In humans only a few cases of teratogenicity associated with vitamin A (in the form of retinol or retinylester) have been observed. Rosa and colleagues from the Food and Drug Administration (FDA) have reported 18 cases of malformations correlated with high doses of vitamin A taken long before and during pregnancy (7c). They conclude that: 'though the data so far do not provide human dose/risk estimates, findings in laboratory studies and human experience with other vitamin A analogues provide reason for cautioning against long term intake of 25 000 units per day or more in women who may become pregnant.' On the basis of laboratory studies, of experiences with retinoids in man and of the few cases of fetal lesions during 1987 recommendations have been issued by several institutions concerning dosage of vitamin A in pregnant women. The FDA, the Teratology Society and the American College of Obstetricians and Gynecologists recommend that pregnant women and women who may become pregnant limit their daily vitamin A intake for food supplementation to a maximum of 8000 IU. I0000 IU of vitamin A per day is the recommendation issued by the Council of

Chapter 40

H.D. Reuter

Responsible Nutrition and the International Vitamin A Consultative Group (IVACG). The limits of 8000 and 10000 IU per day for pregnant women cannot be substantiated scientifically. They result from the high safety consciousness of all responsible institutions. The hepatic complications of long-term ingestion of vitamin A include hepatomegaly, abnormal biochemical tests, portal hypertension, and even cirrhosis. The role of perisinusoidal cells in the genesis of fibrosis linked to vitamin A ingestion was first suggested when electron microscopy showed collagen deposits in close contact with perisinusoidal ceils in Disse's space in chronic hypervitaminosis A with portal hypertension and ascites. Since then, in several cases of hypervitaminosis A, investigators have stressed that an excessive amount of vitamin A in perisinusoidal cells may stimulate fibrinogenesis but have not given further evidence. There is much evidence showing that perisinusoidal cells (Ito's cells) store vitamin A and are involved in fibrinogenesis. The presence of vimentin attests to their mesenchymal origin and the presence of desmin is in favor of their myoid differentiation. Moreover, perisinusoidal cells acquire certain characteristics of fibroblasts or myofibroblasts, as shown by electron microscopy, in diseases with progressive liver fibrosis (e.g. alcoholic cirrhosis), in diseases with liver cell necrosis (e.g. after CC14 administration) and in miscellaneous conditions (including chronic venous congestion). A report of the chance discovery of hepatic fibrosis in a patient with asymptomatic hypervitaminosis A (8r is the first in which the liver ultrastructure has been investigated before clinical or liver function abnormalities have occurred. A liver biopsy specimen was obtained from a 50-year-old patient who had taken approximately 40 000 IU per day of vitamin A for 4 years (4 times the maximum required). Liver architecture was normal with slightly dilated perisinusoids in zone 2 and numerous and enlarged perisinusoidal cells. On Sirius red staining, there was mild fibrosis of the central veins, portal tracts, and terminal portal venules and perisinusoidal fibrosis in zone 1 of the acinus. Liver vitamin A level was increased. On electron microscopy, perisinusoidal cells filled with numerous lipid droplets had slightly dilated rough endoplasmatic reticulum, numerous minute filament condensations below the plas-

Vitamins Chapter40 ma membrane, and stellate-shaped processes giving them the appearance of fibroblast-myofibroblast-like cells. Numerous collagen bundles, fibrils, amorphous material, and fragments of basement-membrane-like material were identified in Disse's space. Immuno-cytochemistry showed increased amounts of collagen types I, III, IV, laminin, and fibronectin. This observation suggests that vitamin A per se, and not the cellular damage often seen in hypervitaminosis A, is responsible for fibrosis. p-Carotene A transitory dose-dependent carotenodermia was seen in the course of treatment of erythropoietic protoporphyria with r-carotene (100 mg/d by mouth for 20 days) in an 18-year-old male patient (9c).

VITAMIN B (SED-11, 801; SEDA-12, 328;

SEDA-13, 347) Nicotinic acid (SED-11,802)

A case of self-administered intra-arterial injection of nicotinic acid in a patient with dystrophia myotonica is reported (10c). A 27-yearold former male nurse presented 3 hours after accidentally injecting a suspension of several tablets of nicotinic acid (niacin) in tap water into his right ulnar artery. The injection resuited in a continuous blockade of the brachial plexus via the axillary route with severe peripheral ischemia. Severe peripheral ischemia also has been reported following intra-arterial injection of many drugs. The vascular damage is probably the result of a combination of vasospasm, endothelial damage and occlusion of the vessel by embolization or thrombus. Further, the injected drug may crystallize at body pH and a direct toxic effect may result in a vasculitis with further reduction in blood flow. Niacin maculopathy is reported in 4 patients who had been taking daily doses of 3.0~1.5 g niacin as a serum-cholesterol-lowering drug (11 c). Three of the patients with niacin-induced visual symptoms (blurring of central vision, seeing haloes round lights) had cystoid maculopathy without leakage on fluorescein angiography, the 4th patient exhibited no fundus abnormality. In all patients the visual symptoms

331 disappeared upon cessation of niacin therapy. An additional 15 asymptomatic patients who were receiving daily doses of 1.0-1.6 g niacin for the treatment of hypercholesterolemia were evaluated for evidence of subclinical macular disease. None of these patients had cystic or other significant macular changes. Over the last 9 years in the Lipid Disorders Clinic at the Oregon Health Sciences University approximately 300 patients have been treated with niacin for hyperlipidemia. In only 2 cases was definite cystoid maculopathy observed. Thus the incidence of documented niacin maculopathy in these patients is estimated at 0.67 %. Reports in the literature of loss of vision due to high-dose niacin are likewise rare. Folic acid (SED-11, 803; SEDA-13, 348) The existence of a relationship between some anticonvulsant compounds and folic acid is now common knowledge. Phenytoin, primidone and phenobarbital affect folate absorption at the level of the intestinal mucosa, and low levels of folate have been observed in serum, red cells and cerebrospinal fluid of patients on long-term anticonvulsant therapy. It has been suggested that the antiepileptic action of some drugs may be partly mediated by their antifolate action. Though the vast majority of patients with epilepsy are not adversely affected by folic acid supplementation, the apparent deleterious effect of folic acid on individual epileptic patients should not be ignored. Sensitivity to the epileptogenic effect of folic acid may be quite rare, but when present it represents a major therapeutic problem. In a study reported here, 19 epileptic patients (16 on chronic antiepileptic treatment and 3 untreated at the time of observation) and 10 age-matched healthy volunteers were slowly infused with 50 ml saline containing 10 mEq of 5-methyltetrahydrofolate with continuous EEG monitoring to detect a possible increase in epileptic activity. Folate infusion had no clinical effect in healthy volunteers and 16 epileptic patients. Two of 19 patients (with partial seizures secondarily generalized and on carbamazepine and phenobarbital therapy) exhibited a slight increase in spike focal activity in comparison with the baseline recordings. Another patient with secondary generalized seizures and on treatment with carbamazepine and phenobar-

332 bital, 4 min after the beginning of folate intravenous administration showed a marked slowing of the basal EEG activity and the presence of multiple spike and wave generalized discharges, accompanied by diffuse myoclonic jerks and a reduced level of consciousness. This situation was followed by serveral (4-6 per day) elementary partial and partial complex seizures, which lasted for the next 9 days despite intensive treatment with intravenous diazepam. The data confirm the presence of an epileptogenic effect of folic acid. This effect, occurring in a small percentage of patients, may produce early changes on the EEG which can prevent such patients being exposed to the dangerous side effects of folate therapy (10c).

VITAMIN C (ASCORBIC ACID) (SED-11,

803; SEDA-13, 348) A premature infant, born after 27 weeks gestation, developed anemia and jaundice 2 days after receiving a multivitamin preparation. 20 % of the red blood cells contained Heinz bodies. Numerous 'bite cells' and other abnormally shaped erythrocytes were noted in a blood film. When the medication was stopped, the hemolysis ceased and Heinz body numbers decreased to 2%. On rechallenge with the multivitamin preparation (Poly-Vi-Sol) Heinz bodies reappeared in the red blood cells. This observation, together with the fact that ascorbic acid can act as an oxidant, suggested to the authors that vitamin C might have been responsible for the erythrocyte damage. A study was therefore undertaken to investigate the effect of ascorbic acid on erythrocytes obtained from premature infants, full-term infants and adults. In vitro incubation of erythrocytes of premature infants with 0.1 mg/ml sodium ascorbate for 3 hours significantly raised the percentage of Heinz-body-containing cells from 17.6 _ 5.7 to 27.2 + 8.2 (mean + SD). Erythrocytes of term infants and those of adults developed Heinz bodies after exposure to higher sodium ascorbate concentrations (1.0 mg/ml). Erythrocytes of adult and newborn guinea-pigs were similarly affected by sodium ascorbate. Daily intraperitoneal injections of 500 mg of sodium ascorbate, given for 7 days to 4 adult guinea pigs, caused significant Heinz-body formation. These studies indicate that the erythrocytes of

Chapter 40 H.D. Reuter premature infants are uniquely sensitive to the development of Heinz bodies after exposure to sodium ascorbate. The levels required to produce Heinz bodies in vitro are in the range of those found in vivo after routine administration of vitamin C to premature infants. The significance of these observations for the development of hyperbilirubinemia in premature infants and the safety of vitamin C remains to be determined (13c).

V I T A M I N D (CALCIFEROL) A N D A N A L O G S (SED-11,805; SEDA-12, 334)

Hypervitaminosis D with hyperealcemia and acute renal failure developed in 4 female patients with osteoporosis or osteomalacia. All patients were given pharmacological doses for 6 weeks to 5 years. 25-Hydroxyvitamin D levels were elevated in 3 patients (mean 247 ng/ml; range 142-322). Levels were not determined in the 4th patient who became normocalcemic when vitamin D was discontinued (14C'R). The hypothesis that reversal of the negative calcium balance associated with senile, postmenopausal and glucocorticoid-induced osteoporosis with vitamin D metabolites could lead to skeletal stabilization or healing has been extensively tested. The use of pharmacological doses of vitamin D has become common clinical therapy, despite lack of clearcut efficacy and safety. Hypervitaminosis D reported in patients with osteoporosis suggests that pharmacological doses of vitamin D should be avoided in patients suffering from any form of osteoporosis. Published data on the use of vitamin D for prophylaxis or treatment of osteoporosis fail to document benefits superior to those of calcium alone or calcium with estrogens and fluoride. Data on the use of 25-hydroxyvitamin D show no greater benefit than for vitamin D. The use of 1,25-dihydroxyvitamin D plus calcium may be superior to the use of calcium alone in some forms of osteoporosis (14R).

V I T A M I N E (ct-TOCOPHEROL) (SED-11,

723; SEDA-12, 330; SEDA-13, 349) Postrhinoplasty epistaxis occurred in 2 patients who had been ingesting megadoses of vitamin E ( > 400 mg/d). The rate of vitamin E

Vitamins Chapter40 consumption in a population of 100 uncomplicated nasal operations during the same period was 16 %. Seven patients ingested daily doses of 100 g, 9 patients 400 mg (15~,r). Although vitamin E does not have significant effects on the coagulation factors of healthy humans and animals (16 g) vitamin E therapy in vitamin-K-deficient subjects and subjects on anticoagulant therapy has a marked effect on hemostasis by decreasing active plasma prothrombin levels (17c). A statistically significant increase in retinal hemorrhage with parenteral vitamin E was found in premature infants (18c). Investigations on the potential role of vitamin E as an inhibitor of platelet aggregation in healthy volunteers given vitamin E in dosages of 400--1200 mg/d showed a small but sigificant reduction in collagen-induced platelet aggregation. Even more striking was the reduction of platelet adhesion to collagen (19c). These results were recently confirmed using a dynamic flow chamber (20c). An almost complete lack of platelet adhesion was observed at the 400 mg/d dose. This effect was amplified with vitamin E ingestion up to 1200 mg/d. Vitamin E exerts its antiaggregating effect without inhibiting the enzymes of the arachidonic acid cascade in the platelets (21 c). A further side effect of vitamin E supplements in premature infants is necrotizing ente-

333 rocolitis. Determination of the ~t-tocopherol concentrations in 52 preterm infants receiving < 25 mg/kg/d ~t-tocopherol acetate supplements in intravenous hyperalimentation solutions, lipid and oral ~-tocopherol showed concentrations of > 3.5 mg/100 ml at least once in 25 % of the infants. Another 25 % of the infants had concentrations < 0.5 mg/100 ml through the first postnatal week. The highly variable serum tocopherol concentrations correlated with total serum lipid content but not with plasma ~-tocopherol hydrolysis activity (22c). A correlation was found between concentrations of ~t-tocopherol exceeding 3.5 mg/100 ml and necrotizing enterocolitis. VITAMIN K (SED-11, 809; SEDA-13, 349)

Vitamin K (phytomenadione) (SED-11,758, 809; SEDA-12, 330; SEDA-13, 349) Localized pseudoscleroderma ( Texier's syndrome) occurring around the sites of intramuscular injection of phytomenadione in a female with drug-induced liver disease is reported (23c). The patient had been treated with 10 mg phytomenadione daily intramuscularly into the thighs for 13 days. This is the first report on Texier's syndrome to appear in the Britisch literature.

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334 on the use of vitamin D in these disorders. Am. J. Med., 82, 224. 15. Churukian MM, Zemplenyi J, Steiner M et al (1988) Postrhinoplasty epistaxis. Arch. Otolaryngol. Head Neck Surg., 114, 748. 16. Hale WE, Perkins LL, May FE et al (1986) Vitamin E effect on symptoms and laboratory values in the elderly. J. Am. Diet Assoc., 114, 625. 17. Helson L (1984) The effect of intravenous vitamin E and nenadiol sodium diphosphate on vitamin K-dependent dotting factors. Thrombos. Res., 35, 11. 18. Rosenbaum AL, Phelps DL, Isenberg SJ et al (1985) Retinal hemorrhage in retinopathy ofprematurity associated with tocopherol treatment. Ophthalmology, 92, 1012. 19. Steiner M (1983) Effect of alpha tocopherol ad-

Chapter 40 H.D. Reuter ministration on platelet function in man. Thromb. Haemost, 49, 73. 20. Jandok J, Steiner M (1986) An effective inhibitor of platelet adhesion. Blood, 68, 1153. 21. Srivastave KC (1986) Vitamin E exerts antiaggregatory effects without inhibiting the enzymes of the arachidonic acid cascade in platelets. Prostglandins Leukotrienes Med., 21,177. 22. Friedman CA, Wender DF, Temple DM et al (1988) Serum alpha-tocopherol concentrations in preterm infants receiving less than 25 mg/kg/day alpha-tocopherol acetate supplements. Dev. Pharmacol. Ther., 11,273. 23. Brunskill N J, Beth-Jones J, Graham-Brown RAC (1988) Pseudosclerodermatous reaction to phytomenadione injection (Texier's syndrome). Clin. Exp. Dermatol., 13, 276.