Vitamins

H.D. Reuter

40 Editorial note From this volume onwards, data on retinoids are dealt with exclusively in Chapter 15. The use of high-dose vitamin supplementation should be reserved for clinical conditions o f primary or secondary vitamin deficiency. However, pharmacological doses of vitamins are claimed to be of value in a wide variety of conditions which have only a superficial resemblance to the classic vitamin deficiency syndromes. The enormous literature on which these claims are based consists mainly of uncontrolled clinical trials or anecdotal reports. Only a few randomized, double-blind studies have been performed. Evidence from such studies reveals a beneficial therapeutic effect of vitamin E in intermittent claudication and fibrocystic breast disease and of vitamin C in pressure sores, but the use of vitamin A in ache vulgaris, vitamin E in angina pectoris or hyperlipidemia or for enhancement of athletic capacity, of vitamin C in advanced cancer and of niacin in schizophrenia has been rejected. One must therefore always consider the risk/benefit ratio before embarking upon the use of high-dose vitamin supplementation for disorders where proof of efficacy is lacking ( 1R). Vitamin A (SED-1 O, 715; SEDA-8, 344) Reported signs of chronic toxicity in over 200 analyzed cases include (in alphabetical order): alopecia, anemia, anorexia,

ataxia, bone pains, bone abnormalities, brittle nails, bulging o f the fontanelle (infants), cheilitis, conjunctivitis, diarrhea, diplopia, dryness o f mucous membranes, dysuria, edema, elevated CSF pressure, epistaxis, exanthema, facial dermatitis, Side Effects of Drugs Annual 9 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1985 ISBN 0 444 90394 l $0.85 per article per page (transactional system) $0.20 per article per page (licensing system)

Vitamins fatigue, fever, headache, hepatomegaly, hepatotoxicity, hypercalcemia, hyperlipemia, hyperostosis, insomnia, irritability, menstrual abnormalities, papilledema, petechiae, polydypsia, premature epiphyseal closure (children], pruritus, pseudotumor cerebri, skin desquamation, skin erythema, skin rash, skin scaliness, splenomegaly, vomiting and weight loss (2R). Acute and chronic vitamin A toxicity is associated with very high levels of lipoprotein-bound retinyl ester in plasma, no particular change in plasma levels of retinolbinding protein but a marked increase in vitamin A concentration in the brain (3 R ). Being amphiphilic, retinol, retinoic acid and many of the retinoids may well be associated with the membranes of the cell and of subcellular organelles such as the lysosomes, and may either disrupt cellular function or cause cellular lysis. In all but extreme cases the toxic effects of vitamin A are reversed simply by eliminating the excessive intake of the vitamin. Liver disease related to chronic hypervitarninosis A has been known for decades. However, the variety of reported cases as well as our increased knowledge of the pathophysiological mechanisms involved suggest that the condition may frequently be overlooked (4R). In 2 patients with bleeding esophageal varices the underlying hepatic cirrhosis was probably due to prolonged intake of large doses of vitamin A (120,000 IU/d) (5 R). In a 35-year-old woman vitamin A intoxication resulted, after sunbathing, in the sudden onset of ascites and hepatosplenomegaly. Percutaneous liver biopsy demonstrated accumulation of fat storage (Ito) cells. The patient made a complete recovery after vitamin A had been withdrawn (6 c). Retinol was administered to 13 cancer patients in daily doses of 1 0 0 , 0 0 0 - 3 5 0 , 0 0 0 U/m 2. Neuropsychiatric changes were the earliest dose-limiting symptomatic toxicities, observed in 3 of 5 patients receiving more than 240,000 U/m 2 for 3 - 4 months. Two patients receiving more than 270,000 U/m 2

323

Vitamins Chapter40 developed hepatomegaly after 3 - 4 months. Three patients receiving 200,000 U/m 2 developed an increase in serum triglyceride levels. Mild dryness of the skin and mucous membrane occurred in most patients after doses of more than 150,000 U/m 2 (7c). Vitamin B6 (pyridoxine) (SED-1 O, 718) Although extremely high doses ( 6 0 0 3000 mg/d) of vitamin B6 have been administered to schizophrenics and autistic children without repotent side effects, other reports demonstrate that serious neurotoxicity may be associated with the pyridoxine megavitamins. In 7 adult patients a gradually progressive sensory ataxia and profound distal limb impairment of position and vibration sense developed after ingestion of daily doses of 2 - 6 g for 2 - 4 0 months. The central nervous system was clinically spared. However, only 2 patients began taking the vitamin in such high doses. The other patients began with 5 0 - 1 0 0 mg/d and steadily increased their intake in an a t t e m p t to achieve a therapeutic level. Three patients took pyridoxine for edema, one for her psychiatric disease and in 2 cases the vitamin was taken as a self-imposed dietary supplement. None of the patients experienced symptoms at doses below 2 g/d. Substantial improvement occurred in all cases in the months after withdrawal of pyridoxine; usually improvement in gait and less discomfort in the extremities were noted within 2 months. Vibratory sense was usually most severely affected, and the patients recorded less of it than other modalities

(8c).

A 30-year-old patient with pancytopenia, severe sensory neuropathy and a 6year history of excessive vitamin intake 8 - 1 2 tablets of vitamin B complex, 500 mg vitamin C, 500 mg pantothenic acid, 800 mg vitamin B6 (total vitamin B 6 intake 2.5 g/d), 200 mg thiamine, 250 mg niacin, 800 IU vitamin E and 60,000 IU vitamin A - showed portal hypertension on evaluation. Besides hypervitaminosis A, as assessed by liver biopsy, the syndrome of sensory neuropathy secondary to megadoses of vitamin B6 was diagnosed. The patient's neuropathy improved upon withdrawal of supplementary vitamins, but his pancytopenia persisted (9 c). It has been suggested that the sensory neuropathy resulting from pyridoxine abuse,

described by Schaumberg (40 t:) can be associated with cutaneous changes. A 36year-old woman who had taken daily doses of 4 g pyridoxine for 4 years for menstrual fluid retention besides her neuropathy developed vesicular and bullous lesions, many on an erythematous b a s e , o n the dorsa of the metacarpal areas and the proximal parts o f the fingers. The bulla formation tended to be more pronounced during the summer months, suggesting that sunlight may play a role. Excessive doses of pyridoxine appear to cause a metabolic defect that impairs the structural integrity of the skin, especially during the summer months (10c). Vitamin C (ascorbic acid) {SED-1 O, 719)

The most commonly discussed adverse health effects attributed to supplemental vitamin C use are: urinary oxalate excretion (with the risk of kidney stone formation), interaction with vitamin B12, impaired iron absorption and gastrointestinal disturbances as well as interaction with various drugs and interference with clinical laboratory tests. Oxalate excretion Because vitamin C is normally metabolized to oxalic acid, one would expect that as the dose of ascorbic acid escalates there would be a proportional increase in excretion of urinary oxalate which in turn might contribute to kidney stone formation. Controlled trials to verify the cause-and-effect relationship of ascorbic acid ingestion and calcium oxalate to urinary stone formation have not yet been conducted, but a relationship can be assumed in individuals who have a proclivity to stone formation (11R). In a patient with acute renal failure on hemodialysis who received daily ascorbic acid (500 mg) via parenteral alimentation, widespread secondary oxalosis developed, which was especially prominent in the kidney and pancreas. The provision of ascorbic acid to patients with renal failure should therefore be carefully monitored to avoid accelerated development of secondary oxalosis ( 12 C ). Interaction with vitamin B12 It has been reported that of the principal cobalamins (including adenosylcobalamin, methylcobalamin, aquocobalamin and its conjunctive base, hydroxycobalamin) only aquocobala-

Chapter 40 H.D.Reuter

324 min is readily reduced (and subsequently destroyed) by ascorbic acid. Destruction of the other cobalamins by ascorbic acid is highly unlikely. From several studies it appears that large doses of vitamin C will not destroy all the cobalamins in the serum of healthy individuals; however, it may precipitate vitamin Bt2 deficiency in some patients who have deficiencies in cobalamin metabolism (1 l a ) .

nausea,

acid regurgitation, and vomiting. Ascorbic acid appeared to precipitate widespread tumor hemorrhage and necrosis with disastrous consequences in patients with very rapidly proliferating and widely disseminating tumors. These observations indicate that ascorbic acid should be prescribed with extreme caution to persons with advanced cancer (11 R). Vitamin D (calc[ferol) (SED-1 O, 721J

Iron absorption On addition of 5 0 - 1 0 0 mg ascorbic acid to the diet a 2 - 5 fold increase in iron absorption was seen in healthy persons. Individuals who suffer from an unusual form o f iron overload should therefore excercise extreme caution if ascorbic acid supplementation is practised. Especially patients with hemochromatosis, polycythemia and leukemia who present with marked iron overload should keep their intake of vitamin C to a minimum (13 R ).

Gastrointestinal

disturbances The most common side effect with consumption o f 3 - 3 0 g/d of ascorbic acid is reported to be diarrhea (42 R). Drug interaction Impaired response to the anticoagulant warfarin, enhanced drug crystaUuria with aspirin, and decreased renal tubular reabsorption of amphetamines and tricyclic antidepressants can be caused by simultaneously ingested vitamin C (11R). Interference with laboratory tests Values obtained in laboratory and clinical tests can be enhanced or depressed by the presence of vitamin C since, as a reducing agent, it interferes with those l a b o r a t o r y assays in which color reactions involve redox reaction, resulting, for example, in false-negative values of occult blood, falsely elevated estimates of uric acid by interfering in the reduction of phosphotungstate, ferricyanide and copper chelate, and falsely elevated plasma glucose readings. Ascorbic acid at concentrations of 1 0 0 - 3 6 0 mg/100 ml gives falsely high creatine and SGOT values, whereas reduced values in serum bilirubin and LDH may result (11R). Serious adverse health effects are reported when oral doses of 10 g/d of vitamin C. Ascorbic acid usually acts as a diuretic. In these cases a high degree of fluid retention and gravitational edema was seen. Many of the patients also experienced heartburn,

Symptomatic and reversible hypercalcemia was seen in 2 elderly patients on apparently safe amounts of vitamin D and thiazide diuretics. The 'hypersensitivity' resulted from an interaction with calcium carbonate which had been ingested simultaneously. In t h e presence o f other predisposing factors, hypercalcemia may develop in patients taking as little as 5 - 1 0 g o f calcium carbonate daily. The cases reported here involved the ingestion of vitamin D and A supplements and a thiazide diuretic, all of which cause hypercalcemia independently, but not in the amounts being taken by either patient (14c). 1a-Hydroxycholecalciferol (1 a-OHD 3) (SEDA child suffering from X-linked hypophosphatemic rickets developed vitamin D intoxication during treatment with lc~-OHD3 and phosphorus. Besides the usual findings in this condition he showed precocious synostosis o f the skull with signs of raised intracranial pressure. In view of earlier reports of coincidence of craniostenosis and X-linked hypophosphatemic rickets the authors conclude that the possibility exists that intoxication with la-OHD3 has been the precipitating factor. In addition, hypersensitivity to lc~-OHD3 was found 2 months after cessation of treatment and normal levels of calcitrol (t,25-(OH)2D3) at the same time (15 r

10, 723)

1,25-Dihydroxycholecalciferol (1,25-(OH)2D3) (SED-10, 723J Hypercalcemia with calcium levels exceeding 11 rag/100 ml was seen in children with disorders of calcium and phosphate metabolism secondary to chronic renal insufficiency, sexlinked dominant hypophosphatemic rickets, hypoparathyroidism and pseudohypoparathyroidism who were treated with 1 0 - 4 0 ng/kg 1,25-(OH)2D3 per day. Patients with renal osteodystrophy manifested hyper-

Vitamins

Chapter40

calcemia on the average once in every 13 months of treatment. Of 3 children with hypophosphatemic rickets who experienced hypercalcemia 2 proved to have tertiary hyperparathyroidism. Among children with hypoparathyroidism and pseudohypoparathyroidism 3 episodes of hypercalcemia were observed during 124.5 patient-months, an incidence o f 1 hypercalcemic episode per 39 treatment months. With one exception hypercalcemia is an occasional concomitant of such treatment and a more rapid deterioration of renal function may occur in some patients treated with 1,25-(OH)2D3. Thus, careful monitoring of concentrations of calcium, phosphate and creatine must accompany 1,25-(OH)2D3 therapy (16 C).

325 Vitamin K1 (SED-I O, 723)

Allergic cutaneous reactions to vitamin K1 injection were observed in 3 patients who developed pruritic erythematous indurated plaques at the sites o f intramuscular injection 1 2 - 2 3 days after intravenous injection. Intradermal tests with vitamin KI and K3 in 145 normal subjects induced an allergic skin reaction in 13 of them 7 - 2 2 days after injection. The results indicate that the index of cutaneous sensitivity lies somewhere between 5.5% and 8.9%. No cross-sensitivity was seen between vitamin Kt and K3 (17 C).

REFERENCES 1. Oresen L (1984) Vitamin A therapy in the absence of obvious deficiency: What is the evidence? Drugs, 27, 148. 2. Bauernfeind JC (1980) The Safe Use o f Vitamin A. International Vitamin A Consult Group, Nutrition Foundation, Washington DC. 3. Olson JA (1983) Adverse effects of large doses of vitamin A and retinoids. Serrt OncoL, 10, 290. 4. Geubel A.P, Rahier J (1983) Hypervitaminose A: physiopathologie et toxicit6 h6patique. Louvain M~d., 102, 281. 5. F~kiaer E, Hertel L (1981) Langvarig Avitamindtagelse og levercirrose. Ugeskr. Laeg., 143/32, 2038. 6. Guarascio P, Portmann B, Visco G, Williams R (1983) Liver damage with reversible hypertension from vitamin A intoxication: demonstration of Ito cells. J. Clin. PathoL, 36, 769. 7. Goodman GE, Alberts DS, Meyskens FL (1983) Phase I trial of retinol in cancer patients. J. Clin. Oncol., 1,394. 8. Schaumburg H, Kaplan J, Windebank A e t al (1983) Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. N. Engl. J. Med., 309, 445. 9. Davidson RA (1984) Complications of megavitamin therapy. South. Med. J., 77, 200. I0. Baer RL (1983) Cutaneous skin changes probably due to pyridoxine abuse. J. Am. Acad.

Dermatol., 10, 527. 11. Sestili MA (1983) Possible adverse effects of vitamin C and ascorbic acid. Sere. Oncol., 10, 299. 12. Friedman AL, Chesney RW, Gilbert EF et al (1983) Secondary oxalosis as a complication of parenteral alimentation in acute renal failure. Am. J. Nephrol., 3, 248. 13. HaUberg L (1981) Effect of vitamin C on the bioavailability of iron from food. In: Counsell JN, Hornig DH (Eds), Vitamin C (Ascorbic Acid], p 49. Applied Science Publishers, New Jersey. 14. Crowe M, Wollner L, Griffiths RA (1984) Hypercalcemia following vitamin D and thiazide therapy in the elderly. Practitioner, 228, 312. 15. Carlsen NLT, Krasilnikoff PA, Eiken M (1984) Premature cranial synostosis in X-linked hypophosphatemic rickets: possible precipitation by 1-alpha-OH-cholecalciferol intoxication. Acta Paediatr. Scand., 73, 149. 16. Chan JCM, Young RB, /don U, Mamunes P (1983) Hypercalcemia in children with disorders of calcium and phosphate metabolism during long-term treatment with 1,25-dihydroxyvitaminD3. Pediatrics, 72, 225. 17. Hwang SW, Kim YP, Chung BS, Kim HK (1983) Vitamin K~ dermatitis. Korean J. Dermatol., 21, 91.