Vitamin E: Where Do We Stand?

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PEDIATRICS Vol. 63 No. 6 June 1979 933 COMMENTARIES

Vitamin

E: Where

Do We Stand?

Understanding vitamin E (or tocopherol) is a bewildering prospect because of its protean nature. Since this “shady lady” of vitaminology has been recommended for treatment of anemia, impotence, muscular dystrophy, cystic fibrosis, burns, scars, claudication, and aging, an under-standing of its role in human physiology is

urgent-ly needed.’ Current research involving vitamin E

embraces an equally diverse and seemingly disconnected list of subjects, including platelet

aggregation, hepatic injury, pollutant oxidant

injury, sodium warfarin-associated coagulopathy, granulocyte bacterial killing, and, of particular interest to the pediatrician, bronchopulmonary dysplasia (BPD), retrolental fibroplasia (RLF), and iron-induced hemolytic anemia.2 Tocopherol deficiency in animals causes encephalomalacia, muscular dystrophy, testicular atrophy, fetal wastage, and other problems, depending on the species. What, then, should the pediatrician know about vitamin E?

I

propose that clinicians should have a general understanding of what little physiology is known about tocopherol, be able to recognize the circumstances that cause low tocopherol levels, understand when to provide physiologic replace-ment therapy, and accept the responsibility for protecting their patients from uncontrolled experimental use of tocopherols.

TOCOPHEROL PHYSIOLOGY

Tocopherol’s primary biochemical role is that of a free radical scavenger, or antioxidant, protecting unsaturated bonds from peroxidative cleavage. This action allows tocopherol to be used as a preservative, for example, in preventing rancid changes in fat.3 Until recently, it has been difficult to link this action to observed states of tocopherol deficiency or excess. For example, human platelets, in vitro, have enhanced aggrega-tion in states of tocopherol deficiency and depressed aggregation in states of tocopherol excess. The best explanation for this action is that tocopherol suppresses the peroxidization of platelet membrane arachidonate to the prosta-glandin precursors that cause aggregation.4

The antioxidant protection system in an mdi-vidual is derived from tocopherol in the cell

membrane, selenium-dependent glutathione

per-oxidase in the cytosol, and other systems only beginning to be understood.56 The hydrogen

peroxide hemolysis (HPH) test provides a conve-nient measure of the antioxidant status of an

individual since the amount of antioxidant

protec-tion available is reflected in the degree to which red blood cells are hemolyzed when exposed to

hydrogen peroxide.

TOCOPHEROL PHARMACOLOGY

Tocopherol is a viscous oil marketed as an ester

(

generally acetate) in an emulsion to make it miscible in water. It is readily absorbed by normal

individuals in the presence of bile, but not as

easily by premature infants or those with fat

malabsorption. Available intramuscular forms are

absorbed erratically from the injection site, and the use of an unesterified preparation, which is soon to go on the market, will be limited by its

irritating properties upon injection. Normal adult serum levels of tocopherol range from 0.8 to 1.5 mg/dl; in individuals with low serum lipids, however, the levels may be much lower despite

normal tissue levels, since tocopherol is distri-buted throughout the total body lipids. Daily requirements to maintain these levels are propor-tional to the oxidants (iron) and oxidizable substrate (polyunsaturated fatty acids [PUFA]) in the diet, and range from 3 to 30 international units (IU) per day in the adult. Infant formulae are supplemented in proportion to their PUFA content, usually 0.8 IU per gram of PUFA, or 13

IU

per quart in most formulae.

TOCOPHEROL DEFICIENCY

Efforts to induce human tocopherol-deficiency disease with dietary changes have proved futile,7 despite the relative ease with which animal deficiencies can be produced. It appears that

human

tocopherol deficiency occurs only in premature newborns and in patients with severe, prolonged fat malabsorption, such as cystic

fibro-sis and biliary atresia. Oski and Barness,8 Ritchie et al, and others have described a hemolytic

anemia in premature infants associated with

re-ticulocytosis, thrombocytosis, schistocytes, pe-npheral edema, a strikingly increased sensitivity to HPH testing, and serum tocopherol levels less than 0.5 mg/dl. These changes are in proportion to the depression of serum tocopherol and resolve with treatment. Infants with low tocopherol levels generally do not develop the hemolytic

anemia unless their high PUFA diets are supple-mented with the oxidant iron.

A peripheral

neuropathy

associated with

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934 VITAMIN E

ia, which has been described in six patients with biliary atresia’#{176} and in one patient with cystic

fibrosis (Benjamin Kagen, M.D., written

commu-nication, 1978), may represent a second human deficiency disease.

THERAPY IN DEFICIENCY STATES

Ideally, patients should have tissue levels of tocopherol sufficient to protect their cell membranes from oxidative damage. The HPH test is a reasonable indicator of that ideal, and results are generally normal in individuals with

serum tocopherol levels over 0.5 mg/dl. Unfortu-nately, the HPH test is not commonly available clinically; therefore, a tocopherol serum level of 0.5 mg/dl is probably a reasonable therapeutic goal. Higher levels may not be appropriate in the individual with low serum lipids, such as a person with biliary atresia, because this individual will not readily carry tocopherol in the serum.

I

recommend that children with cystic fibrosis and biliary atresia (or other severe, prolonged fat malabsorption) be screened at least once a year to determine tocopherol and hemoglobin levels, red

cell morphology, reticulocyte and platelet levels,

and oxidative damage to cell membranes by an

HPH

test, if readily available. Tocopherol levels of less than 0.5 mg/dl, evidence of a hemolytic

anemia with thrombocytosis, or abnormal find-ings on an HPH test indicate a need for tocoph-erol treatment. Since natural tocopherols (sun-flower oil, wheat germ oil, peanuts, etc) will be poorly absorbed, large doses of the presently available oral form, tocopherol acetate, must be

used. Because massive doses may be required (in

excess of 100 mg/kg/day), serum levels should be

monitored to avoid overdosing in those few patients who will absorb the vitamin.

Premature infants have transiently depressed tocopherol levels that resolve by 36 to 38 weeks of age postconception; hemolytic anemia occurs only if they receive iron. Therefore, those infants whose condition warrants the administration of iron before 36 weeks of age postconception should be supplemented with tocopherol. Cer-tainly it would be safest to do this on the basis of serum levels, but the majority of laboratories want 2 to 3 ml of blood in order to determine tocopherol levels; most pediatricians consider that amount prohibitive in these small anemic infants. Obtaining blood by heel prick, I currently screen all premature infants weekly for hemato-crit, reticulocytes, red cell morphology, and

platelet values and determine serum levels only

on those infants with hemolytic anemia. If

treat-nient is indicated, tocopherol, 25 to 100 IU/

kg/day, is given orally, and therapy is continued

until the infant is 38 weeks of age postconception or until the hemolytic process resolves. Bell et al have shown elsewhere in this issue (p 830) that the premature infant weighing less than 1,500 gm at birth is able to sustain plasma tocopherol levels in the adult range with the daily oral administration of 25 mg of tocopherol acetate or free tocoph-erol.

PHARMACOLOGIC DOSES OF

TOCOPHEROL

Adults have taken amazing quantities of this vitamin for a variety of reasons with no docu-mented beneficial results and surprisingly few complications. Two cases of side effects have been well-documented; one patient had numer-ous subjective complaints and reversible creatinu-na”; the other, who was being treated with

sodium warfarin, developed bleeding when he

started taking 1,200 lU/day of tocopherol.’2 The tocopherol suppression of his vitamin K-depen-dent clotting factors was well-documented and

has been confirmed in dogs.” Oral doses of up to

300 lU/day of tocopherol are generally

consid-ered nontoxic for human adults; oral median lethal doses for animals have not been established. However, parenteral tocopherol preparations are lethal for animals at doses of approximately 440

mg/kg

and, at lower doses, have resulted in hepatic changes in rabbits, rats, and kittens. Impaired wound anti-inflammatory

effects,’ and suppression of platelet

prostaglan-din synthesis4 have also been noted in patients receiving pharmacologic doses of tocopherol.

The pharmacologic use of tocopherol in BPD and RLF are of special interest. Based on the increased susceptibility of the lungs of tocoph-erol-deficient animals to oxygen, ozone, and NO2, a pilot studyl6 was undertaken using high-dose intramuscular, unesterified tocopherol in

prema-ture infants with respiratory distress syndrome. The findings suggest that tocopherol, given intra-muscularly from birth, shortened the time the

infants required oxygen and possibly reduced the incidence of BPD. The study has several limita-tions, however, which are pointed out in an

accompanying editorial’7; the most serious are the

small sample size, the overall mortality rate, and the alternate assignment to study groups. It is

hoped that these questions will be answered

adequately by the authors’ randomized

double-blind study that has been extended from this pilot trial. No side effects have been noted other than

local reactions at the injection sites.

Tocopherol significantly reduces the acute

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PEDIATRICS Vol. 63 No. 6 June 1979 935

nopathy induced by oxygen in newborn kittens,’8 thus supporting the need for clinical trials of tocopherol in preventing RLF. Currently, John-son, Schaeffer, and Boggs’9 are conducting a randomized double-blind clinical trial of paren-terally administered tocopherol in quantities sufficient to raise the serum levels of premature

infants to 3.5 mg/dl. Their preliminary data, obtained at serum levels of 1.5 mg/dl, suggest a lower incidence of acute RLF in infants whose birth weight is under 1,500 gm.

CONCLUSION

Patients with prolonged fat malabsorption and some premature infants receiving iron must be given vitamin E. Use of tocopherol therapy in

BPD

and RLF, while promising, is unproven and should be used only . in a controlled study.

Research on the role of vitamin E in human physiology is entering a rapid-growth phase. I feel certain the near future will see scientifically well

founded uses for this “vitamin without a

disease.”

Los Angeles, CA 90024

DALE

L.

PHELPS,

M.D.

Division of Neonatology, Department of Pediatrics, UCLA School of Medicine

REFERENCES

1. Melhorn DK: Vitamin E: Who needs it? Ohio State Med

I 69:899, 1973.

2. Oski FA: Metabolism and physiologic roles of vitamin E.

Ho Practice 12:79, October 1977.

3. Bieri JG, Farrell PM: Vitamin E. Vitam Horm 34:31,

1976.

4. Stuart MJ, Oski FA: Vitamin E and platelet function.

Ani I Pediatr Hematol/Oncol, in press.

5. Dormandy TL: Free-radical oxidation and antioxidant. Lancet 1:647, 1978

6. Cross 5: The antioxidant relationship between selenium-dependent gltitathione proxidase and tocopherol.

An I Hematol/Oncol, in press.

7. Horwitt MK, Harvey CC, Duncan GD, Wilson WC: Effects of limited tocopherol intake in man with relationships to erythrocyte hemolysis and lipid

oxidations. Ani I Clin Nutr 4:408, 1956.

8. Oski FA, Barness LA: Vitamin E deficiency: A previous-ly unrecognized cause of hemolytic anemia in the premature infant. I Pediatr 70:211, 1967.

9. Ritchie JH, Fish MB, McMasters V, Grossman M: Edema and hemolytic anemia in premature infants: A vitamin E deficiency syndrome. N Engl I Med

279:1185, 1968.

10. Roselil)lt,m JL, Keating JP, Nelson JS, Prensky AL: A progressive neurologic syndrome in six children

with chronic liver disease and alpha-tocopherol deficiency. Pediatr Res 12:555, 1978.

11. Hillman RW: Tocopherol excess in man. Am I Clin Nutr 5:597, 1957.

12. Comgan

JJ,

Marcus Fl: Coagulopathy associated with vitamin E ingestion. IAMA 230: 1300, 1974. 13. Corrigan JJ: Coagulation problems relating to vitamin

E. Am I Pediatr Hematol/Oncol, in press.

14. Ehrlich HP, Tarver H, Hunt TK: Inhibitory effects of vitamin E on collagen synthesis and wound repair.

Ann Surg 175:235, 1972.

15. Levy L: The anti-inflammatory action of some compounds with antioxidant properties. Inflamma-tion 1:333, 1976.

16. Ehrenkranz BA, Bonta BW, Ablow RC, Warshaw JB: Amelioration of bronchopulmonary dysplasia after vitamin E administration: A preliminary report. N

Engl I Med 299:564, 1978.

17. Northway WH Jr: Bronchopulmonary dysplasia and vitamin E. N Engl I Med 299:599, 1978.

18. Phelps DL, Rosenbaum AL: The role of tocopherol in oxygen-induced retinopathy: Kitten model.

Pediat-rics 59:998, 1977.

19. Johnson L, Schaffer D, Boggs TR Jr: The premature infant, vitamin E deficiency and retrolental fibro-plasia. Am I Clin Nutr 27:1158, 1974.

The Task Force Report

The Future of Pediatric Education, ‘ a report by

a special Task Force under Dr. C. Henry Kempe, has been widely circulated to practitioners and academicians since its publication in the spring of

1978. Dr. Kempe summarized its

recommenda-tions in his presidential address to the American Pediatric Society.2 The Task Force consisted of 17 members representing most of the constituent societies responsible for pediatric education, research, and service in the United States. They worked for two years, commissioned two surveys-one of parents and one of 7,000 recent

(

since 1964) graduates of pediatric residencies-and met with numerous consultants.

Of the 1 1 recommendations, most have resulted in little disagreement, perhaps in part because no single group was forced to change its behavior as a result of the study. The recommendations that have been agreed upon would:

1. Require a periodic assessment of the health status and needs of children and adolescents in the United States

2. Base pediatric education upon the health

needs of children rather than on service needs of tertiary care hospitals

3. Require the medical student’s clerkship to

be of equal length in medicine and pediat-rics and that the pediatric experience emphasize growth and development

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1979;63;933

Pediatrics

Dale L. Phelps