Tocopherol Excess in Man CREATINURIA ASSOCIATED WITH PROLONGED INGESTION By Ronexr W, Hituatan, x0." A BSsti8 role for vitamin in aman metabolism has yet to be established, However, its well documented indispensability to certain functions in experimental animals, and its seeming relationship to metabolic ab- normalities described in patients apparently depleted of this substance suggest that vitamin probably also required by man, Although tocopherol therapy generally fails, to benefit patients with muscular dystrophy, the ereatinuria that accompanies the reversible muscular disorders characteristic of vitamin E deficiency in other species may have a clinical counterpart. In a recently reported case of fatal biliary cirrhosis," creatinuria and pento- suria were associated with an absence of meas- turable tocopherols in the blood serum, and were temporarily alleyiated by tocopherol ad- ministration. Similarly, vitamin E therapy has inhibited creatinuria in infants with eystie fibrosis of the pasicreas and biliary atresia.? ‘The present report describes an instance in which the experimental ingestion of an excess of tocopherol over a period of three months by an apparently normal subject was associated with a transitory creatinuria in the absence of other significant adverse clinical or laboratory effects, ‘CASE REPORT. A Al-year old physigian ingested @ total of 296 g of alpha tocopherol aver a peri of 8 days, in the follow From the Department of Environmental Medicine and Community Health, State University of New York Collegeof Medicine at Sew York City, Brooklyn ‘Associate Professor of Environmental Medicine sand Community Health, State University. of New York, College of Medicine at New York C) chansia-Charge, Associate Attending Physician, The Brovklsn Hos. pita ing dosage: 2 g daily for 87 days; 4 g daily for 58 days: ‘and 2 g on the final day. Two preparations were cewiployed: phynal Acetate? for the first 80 days; and Aquasol E¥ for the last 13 days. Usually the vitamin was taken in two daly doses about eight hours apart, but there was no rigid adherence to this routine or tony fixed dietary regimen, There was no apprec able change in physical activity during the test period, ror were any significant intercurrent infections ine curred, EsuLTs ‘The principal laboratory findings are cated in the accompanying table and figure. Fig. 1, Blood plasma tonopheral response to ingested vitamin B: 296 g pt-alpha tocophery] acetate in 93 days ‘The plasma tocopherol concentration, meas- ured by a macro adaptation of the method of Quaife et al.,* showed a rapid initial rise fol- lowed by a variable plateau without overall in- crement, which was maintained throughout ‘most of the test period at approximately twice FEphynal Acetate, Roche, supplied in part through the courtesy of Dr. 8, Evert Svenson, Hofiman-La Roche, Ine, Nutley, N. J. 4} Aquasol E, U.S, Vitamin Corporationns THE AMERICAN JOURNAL OF CLINIC. TABLE T Plasma Tocopherol Concentration and 24-hour Urinary Excretion of Creatine and Creatinine Before, During ‘and Following Excess Tocopherol Ingestion ° 1708 1 0 | ase 0 | 1,878 * Mg per 100 ml 1 Mg per 24 hours, ‘the usual concentration." It returned rapidly to the pretest range when the tocopherol was discontinued. The mean fasting concentra- tion of 2.26 + 0.84 mg per 100: differed signifi- cantly (P less than 0,001) from the mean level Repeated absorption tests showed considerable variation, with mo consistent plasma response patter. I general following ingestion of amounts up to4 gina single dose, plasma tocopherol Levesshoved only small gradual changes, Apart from the single fasting level of 15.39 mig per 100 ml, & concentration in excess of 4.0 mg per 100 ml was noted in only one instance, six hours after te ingestion of 4g of tocopherol J] Asigniicant creatinoria ws | test period) On the day before initiation of the SUTRITION Wot. 5 of 1.15 + 0.36 per 100 ml before and after the test period,f The fasting concentration was not appreciably higher on the daily dose of 4 than of 2 g, nor did the substitution of the aqueous dispersion for the nonwater- miscible preparation have any apparent added effect. ‘Tocopherol could not be detected in the urine at times of maximum plasma concentration or over spans of several hours following ingestion of this substance. s noted during the vitamin regimen, creatine was absent from a 24- hhour specimen, On the Sith and 9Ist days cof the experiment, the 24-hour excretion totals were 151.5 and 143 mg respectively. Twelve, and again, 27 days after the tocopherol was withheld, creatine could not be detected in 24: hour samples. Creatinine excretion was questionably al- tered by the tocopherol ingestion, The output in the 24-hour period before the start of the test was greater by approximately 20 to 25 per cent than quantities measured on two oc- casions during, and two following, the experi ‘mental period, Except for a slight increase 27 days after the preparation was discontinued, these four readings were virtually identical. lethe excretion of 17-ketosteroids seemed un- ‘affected by the tocopherol administration be- ing 11.3 mg per 24 hours on the day before, ‘and 11.9 mg on the Sith day of the tocopherol regimen. Blood cholesterol, carotene and vita- min A levels, the serum bilirubin level, cephalin flocculation, thymiol turbidity, and the prothom- bin, bleeding and coagulation times showed no significant changes during the test period. ‘The Harvard two-step test for physical fitness, Master two-step test, electrocardiogram and ballistocardiogram were likewise unaffected. Biopsy of the deltoid muscle at the end of the 4 The mean plasma level of 1.16 0.99 mg per 100 mt toefore that period did not dilfersiguifieanty from the evel of L12“t 0.20 mg per 100 ml following the experi- neat. Hoorever, the mean fasting level for this subjert (G62 readings before and after the test period) of 1.15 © (0.37 me differed significantly (P tess than 020001) from the mean fasting level of 30 other subjects (72 readings) of 081 + 0.28 ing.Novent December 1957) experimental period revealed no deviation from the normal. Clinically, no abnormalities were noted that could be attributed unequivocally to the large dozes of tocopherol consumed. However, chapping cheilosis and angular stomatitis ap- peared early and persisted variably, but with- out, progression, throughout the’ ingestion period. Gastrointestinal disturbances were frequent, especially during the final month, ‘when abdominal. distress and diarrhea with tenesmus were pronounced. Vague gen- eralized muscle weakness and increased fatiga- bility were experienced toward the end of the test period, but these wholly subjective com- plaints could not easily be evaluated. The un- toward clinical manifestations disappeared Within two weeks after the tocopherol was dis- continued. DISCUSSION ‘The average plasma concentration main- tained in this case exceeded the usually ac- cepted range of normal, but was lower than maximum, levels reported with much smaller doses.t?/ Higher levels have also been noted ‘in the fast trimester of pregnancy," and in cer- tain pathologic states without apparent excess ingestion of this substance." The type of reparations employed may have been a limit- ing factor, and large amounts may have been lost in the stool." Nevertheless, the lack of progressive increment in the blood, and, as in most other reported instances,'*!\* ‘the absence of vitamin E from the urine, suggest that mechanisms other than those of absorption and elimination are involved in regulating plasma tocopherol concentration. Blood levels are temporarily depresced in a number of con- ditions not affecting intestinal fat trans- fer". and so-called ceiling effects have also been noted by other observers. Creatinuria, as a phenomenon of tocopherol excess, is unexpected and not readily ex- plained. Vitamin F reportedly influences tuitary-adrenal funetion and quéstionably af- fects the production .of 17-ketostervids.!¥~* Yet the unchanged steroid excretion in the present instance, although based on limited data, suggests that altered creatine metabolism HILLMAN 599 does nt result fom moied adrenal or tee tka actity.+ Tocopherol toxsty is readily produced in experiental “anima. Aitough ums stated ott oct man untoward yap toms have been repr doses of 50 to 30g per tay eo) While» iret donage andor diferesi: subject ght. have ice higher plasma levels, wih oF without nial toni, the absences dete adverse ebangs in tie case sugests an apprecable tolerance for tocphercl Crease, con ccivably, say reprecea an ealy subsides ofinduced metabolic matnction SUMMARY Ingestion of 296g of alpha tocopheral by & normal adult male over a period of 03 days re- sulted ina sustained average plasma tocopheral concentration of 2.20 © 0.86 mg per 100 This was statistically sigufcant and approx rately twice the control level of 115. 0.37 img per 100 ml. A significant tranetory crea tinuria occurred during the test period, but there was no apparent change in the exeretion of ereatinine o of 17-ketostroids, There were no unequivocal sigos of clinical toxicity. "Exercise tolerance seemed tnal- fected. The electrocardiogeam, ballistocardio ram, serum cholesterol, liver funetion and ‘Blood coagulation studies, and a muscle biopsy showed no deviation from the normal. Creatinuria may be an carly masifetation of an adverse metabolic effect induced by vita- tin ence ACKNOWLEDGMENTS Appreciation is expressed to Dr. Philip Cabaud for the creatine, creatinine, ctesterol, liver funetion and Dlood coagulation studies; to Dr. David Kyi for the T-ketosteroid determinations; (0 Drs. Williams Noble and Helen Pauling fur the Master two-step, electro- cardiogram and ballistocardiograan; to Dr. Joseph Whelan for perrssing, and to Dr. J. Arnold De Veer for interpreting the musele biopsy’; and to Miss Marie LLevgrand, who performed all ofthe vitamin determina ‘This relationship is being investigated further Preliminary observations suggest that a transitory creatinuria may, in some instances, be induced by. single large dose (4) af tacopherol, without prolonged60 7. 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