“Tue Asnateay Jounst o Curent Nero Tocopherol Deficiency in Man" (Ok Hesey J. Bixpen, 360.) ax Howarp M, Srino, 0. ERE ARE sevtnan. distinct syndromes recognized in. tocopheroldeficient x: perimental animals (1-3) and. tocopherol Eepletion not infrequently occurs in us mans. wih, steaorthea(). However, 3 dlearcut deficiency syndrome has not yet been described in man, Tes apparent that Taboratory evidence of tocopherol def: ciency is not equivalent. to biologic 10. opherot defcienes. We plan to describe a survey for evidence of vitamin Ede. ficiency that was recently completed on group of subjects with @ variety of gar Groinvestinal diseases and to delineate the physiologic and pathologic phenomena at foctated with it "The hydrogen peroxide hemolysis test is a good in vitro test that correlates very well wth the serumtocopherol level. (& Oj] The test is performed by incubating athed. erythroches with 2%. hydrogen peroxide for 3 ht. The amount of hemo- Flobin. produced by the hydrogen pero: fhe incubation is compared 10 that pro- duced in disilled water and the result is expressed as a percentage. GyBrgy et al @). Nitowsky etal @), and Horwite et al (©) have all demonstated that clevated ryhvocyte hemolysis tests are invariably thodated with low serumtocopherol Tevels and. conversely subjects with normal serunviocopherol levels usually have Tow hemolysis tests “From the Department of Jia Medi vate Unsenany Soo! of Melee, New Ha Eons Fa nace wae spponted ta part by Grant anrouto tom the Une Sses Public cath Sene Recplene of @ Special Fellwslip (8AM aaity tm the Navona) Ine of is Neole Beco Altogether our study group subjects. Our control group 29 subjects: 19 healthy Tabora nel and 10 subjects with dis mally associated with vitamin ities. Hydrogen peroxide he were performed in 20 control were all below 10%, Serum-to terminations (7) were obtaine jects and ranged between 497 a 100 pl with a mean of 738 pg) serum-tocopherol determina lly performed by Dr. Davi Distillation Products Indu method utilizes a thinday graphic separation of tocopher somewhat lower values. thas tained previously by other met Serum-carotene values wer gross screening test for steat mal values were above 60) Thirty-one subjects with a v: trointestinal diseases were normal serum carotene val eight of the 80 subjects had ess than 20%; 22. less tha serum-tocopherol levels (less 100 yl) were found in only. One of these three had an ele pancreatitis and Whippie’s di “Thirty-five subjects with st low serumearotene levels Their diagnoses represented diseases but included int creatic, and hepatic disorder: ogy of their steatorrhea. Tw jects had hemolysis tests grea AIl of these had ow son Ievels ranging between 44 pi with a mean of 173 ps;Tocopherol Di fring 13 subjects had a hemolysis test tian 20%. OF these, serum-tocopherol 1s were available in 10, Five had levels pter than 400 yg/100 pl and 5 had values than 400 4g/100 pl. Interestingly, in fof these five subjects with serum. ppherol levels of less than 400 yg/100 but normal hemolysis tests, the dura: of the steatorrhea was less dian I ths. pne individual was given parenteral ersoluble vitamin tocopherol acetate, 1U for 5 days a week for 4 weeks, While serum carotene remained unchanged | feeal fat excretion remained high, the rolysis test fell to a normal level and im-tocopherol levels rose. Similatly, two jects with nontropical sprue were stud- before and after the institution of a entree diet. At a time when their rolysis tests fell from 38 10 20 and 45 11%, respectively, their serum-carotene Is rose along with clinical improve- f haerefore, we can conclude that there is excellent correlation betceen serum- pherol levels and the hydrogen perox- hemolysis tests (Fig. 1). Almost every ect with an elevated hydrogen perox- hemolysis test_had a low serumto- erol level and most subjects with aal hemolysis tests had normal serum oherol levels. The false negative hemol- test occurs. primarily in those indi als with steatorrhea of short duration. the hemolysis test presumably is in- ive of erythrocytetocopherol content may presume that there is depletion rum stores prior to erythrocyte stores malabsorption of tocopherol exists. € etiology of the steatorrhea does not 1 determine whether. tocopherol de on will occur. Our group of 27. pa: with low serum-tocopherol levels in: 1 patients with biliary, pancreatic, testinal disease. Thevelore, the only fon denominator is steatorhea, not sease process, However, the duration + disease does appear important for eficiency in Man Contr Subse Hydrogen Pere ‘perimental Sublects (2) Fie. 1, The inverse conrelation between serum tacopherol levels and the hydrogen peroxide he- tnolysis testis demonstrated, Although a few false negative hemolysis tests occurted, no false positive + hemolysis tests were observed. the occurrence of more severe tissue de- pletion, It might be mentioned that one individual whose duration of steatorrhea could be dated to 6 months did not have a Tow serum-tocopherol level, even though he was absorbing less than 50% of his ingested fat. ‘These results are in keeping with sev- eral other investigations, In the United States, nutitional depletion does not seem to occur. However, in Pakistan it hhas been estimated that 206 of the popu- Tation hay low serum-tocopherol levels (8). Tocopherol depletion has been best stud: ied by Nitowsky, Cornblath and Gordon in patients with cystic filvosis (4). In ad: dition, evidence of tocopherol deficiency has been found in several patients with596 Tanplangiectasia (). Tocopherol deple tion is al preent in newborns (b This i> comected by Lreast feeding and Citamins and to a lesser estent by cow's Inilk, This deReiency appears related to the jnability go transport tocopherol actoss th en le ected the results ofobservations of @ group of newborns whove tocopherol and fat intake treve controlled (10). ‘The intake of poly= Timacurated fatty acids without added t- Copherol leads toa group of symptoms and Signs characterized by initaility, pitting tema, and 2 variety” of skin_ changes THhey were all corrected by vitamin E sup plementation. What are the biologic consequences of this Iaboratory tocopherol deficiency? Ate there any human counterparts to the well Aocumented animal syndromes of vitamin E deficiency? Te is not necessary to discuss the animal syndromes (1-8) such as steril- ity in male rats, fetal resorption in female fats, muscular dystrophy in rabbits and tinea pigs, encephalomalacia. in chicks, nl hertatologie disorders in monkeys. ‘First, it is most important to expand fon wune of the suggestions concerning the mechanism of action of tocopherol. Vi tamin Eis an antioxidant and most of its Setion can be ascribed to its antioxidant properties, At times synthetic antioxidants have been found to replace tocopherol in in siteo experiments. Lipid peroxides as emured by the thiobarbituric tet ac Cumulate in erythrocytes from tocoph- froldefcient animals and individuals Siltea exposed to hydrogen peroxide, Al Though theve is evidence to. suggest that the antioxidant effect of tocopherol pre- serves alutathione stability dough its Maintenance of sullhydryl bonds, there is Conficting evidence present. Reduced lotathione content has not been demon- Strated in. tocopheroleficient infants (11) ‘Seents that reduce erythrocyte GSH do not necessarily. cause hemolysis in vivo and ay Binder and Spio agents that cause hemolysis do no essatily reduce GSH. (12). Therefor alternate hypothesis has been post for its action. [It has been suggested hecause sion s found in the chondria of cells, its absence could abnormal cellular respiration, defe lipogenesis, and accumulation of v Tipid products (13). ‘The relationship of tocopherol mal erythropoiesis has not been pletely explained, (Ve found ma shortened erythrocyte chromium 51 life survivals in four of our subjec four individuals had marked deficie tocopherol as evidenced by low levels and elevated hemolysis tests fone significant feature of these fo dividuals was that there was no ev of in vivo hemolysis. Bone marrc aminations were normal. Anemia w present and normal bilirubin, retie counts, and haptoglobin levels were Although we were not able to fin abnormalities in glutathione conten tathione reductase, or glucose 6-phe dehydrogenase in the chromated ce believe that these shortened stirvivals essence a labeling artifact. It is know high concentrations of chromate wil age normal erythrocytes and lead creased methemoglobin levels and body formation. Similarly, it is conc that abnormal erthyrocytes (ie, toco deficient erythrocytes) will be dams normal concentrations of chromate and co-workers (15) have recently de fa family with congenital nonsph hemolytic anemia associated with | cyte-glutathione deficiency. This far resents an interesting parallel to tients, Although the Ashby techni decreased, the 1Cr technique demo: a markedly redueed survival time. fof the curves suggested to the auth there was destruction of older cel Inily, Prins and coacorkers felt th