EDITORIAL CORRESPONDENCE
Editorial correspondence or letters to the Ed itor relative to articles published in THE JOURNAL or to topics ofcurrent in terest are subject to critica l re view and to current editorial p olicy in respect to publication in part or in full.
Inunction of oil to correct essential fatty acid deficiency To the Editor: I have read with interest the article by Hunt et al ' in which the y reported the failure of the inunction of oil rich in linoleic acid to correct essen tial fatty acid (EFA) de ficiency in newb orn infants. Correct ion of EFA deficien cy by inun ctio n of oil rich in EFAs has been rep orted pre viously in ra ts' and human be ings." " Five of their six patients failed to show biochemical improvement of the EFA deficiency in spite of the in unction of lOa mg/kg /day of linoleic acid, which is the minimal recommended dose requirement of 1% of the tota l daily calories," Although n demonst ration of rapid correcti on of EFA deficiency in an a d ult with only 2 to 3 mg of linoleic acid / k g/ day was reported by Press et al,' we demonstrated' certain difficulties in predicting the absorption rate of linoleic acid following inunction. Even the relatively large quantities used in our patients, \,400 mg/kg/day, failed to replenish tissues deficient in EFA. Our study clearly demonstrated the biochemical changes in plasma phospholipids following the inunction of sunflower-seed oil which incl uded the increase in arachidonic acid and a decrea se in 5,8,II-eicosatrienoic acid. However, the linoleic acid level remained low in the plasma, red blood cells, a n d adipose tissue even after three weeks of the inunction of sunflower-seed oil. We concluded that prolonged inunction of oil rich in linoleic acid may be required to replenish depleted tissue stores in severe EFA deficienc y. Although the final statement of Hunt et al's ar ticle conclud es, "Unless documented by appropriate biochemical mea surements, no patient receiving to pical EFA-rich oil can be assumed to have normal serum and tissue EF A levels irrespecti ve of the dose of linoleic acid applied ," the authors fail to measure tissue levels of EFA and thus demonstrate only the failure of correction of serum EFA upon the inunction of oil rich in linoleic acid, even in a dose as high as 740 to 1,100 mg/kg/d ay. The fai lure to demonstrate biochemical correction of severe EFA-deficiency in the serum of these infants is not entirely surprising, since during fat-free parenteral hyperalimentation the outflow of linoleic acid from adipose tissue is blocked at least ir. part by the high-insulin levels accompanying glucose administration. Moreover, in adults in whom there are enough EFA in tissu e stores to meet the body's requ irements for months or even years, rapid onset of EFAdeficiency in serum was described during fat-free parenteral nutrition. ' Supplementation of small amounts of linoleic acid
]068
The Journal ofPED IATR I CS
during fat-free parenteral alimentation may thus incorporate into tissues without correcting EFA deficiency in the serum. Cu taneous application of sunflow er-seed oil to the forearms of pat ients with EFA deficiency for two weeks showed the level of linoleic acid in their epidermal lecithin to incr ease markedly, with a conco mitant decrease in the tran sep idermal water loss and the disappearance of the skin lesion s.' We recently demonstrateo v " the ability to correct pla telet function and to increase prostaglandin E turnover by the inunction of sunflower-seed oil in newborn infants with EFA deficiency. Improvements of these functions require an app ropria te absorption of EFA. Finally, the authors compared the level of the EFA In the serum of the ir patients to tho se of cord blood derived from term newborn in fants . Our recent study" demonstrated that cord blood values ofEFA vary in neon ates born a t different gestati onal ages. Moreover, when these infan ts were fed diets con taining EFA, blood val ues rap idly changed. including an increase in the level of linoleic acid and decrease in the levels of arachidonic and 5,8, l l-eicosatrinoic acids. We suggest that the foregoing be considered so as to avoid an incorrect interpretation of the effects of inunction. Zvi Friedman, M .D. The Milton S. Hershey Medical Center Department of Pediatric s Hershey, PA 17033
REFERENCES 1.
2.
3.
4.
5.
6.
Hunt CE, Engel RR, Modler S. Hamil ton W. Bissen S, and Holman RT : Essential fatty acid deficiency in neon ate s: In abil ity to reverse deficiency by topical applications of EFA-rich oil, J PEDIATR 92:603, 1978. Bohle s H. Biebe r MA , and He ird WC : Reversal of experimental essent ial fatty acid deficiency by cutaneous administration of sunflower oil. Am J Clin Nutr 29:398, 1976. Press M, Hartop PJ, and Prouey C: Correction of essential nitty acid deficienc y in man by the cutaneous applications of sunflower-seed oil. Lancet 1:597, 1974. Friedman Z, Sh ochat 5J, Maisels MJ, et al : Correction of essential fatt y acid deficien cy in newborn infants by cu taneous application of sunfl ower-seed oil. Pediatrics 58:650. 1976. Prottey C, Harrop PJ. and Press M: Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin. J Clin Invest Dermatol 64:228. 1975. Holman RT, Castor WO, and Wiese HF: The essential fatty
Editorial correspondence
Volume 93
1069
Number 6
acid requirement of infants and the assessment of their dietary intake of linoleate by serum fatty acid analysis, Am 1 Clin Nutr 14:70, 1964. 7. Wene 10, Connor WE, and DenBesten L: The development of essential fatty acid deficiency in healthy man fed fat-free diets intravenously and orally, 1 Clin Invest 56: 127, 1975. 8. Friedman Z, Lamberth El., Stahlman MT, and Oates 1A: Platelet dysfunction in the neonate with essential fatty acid deficiency, 1 PEDIATR 90:439, 1977. 9. Friedman Z, Seyberth H, Lamberth EL, et al: Decreased prostaglandin E turnover in infants with essential fatty acid deficiency, Pediatr Res 12:711, 1978. 10. Friedman Z, Danon A, Lamberth El., and Mann W1: Cord blood fatty acid composition in infants and in their mothers during the third trimester, J PEDIATR 92:461, 1978.
Reply To the Editor: We are pleased to have the opportunity to respond to the thoughtful comments contained in the above letter. We also are aware of the previous data indicating the beneficial effects of inunction and originally initiated our control study to better document these benefits. One of the potential explanations suggested in the letter for our inability to demonstrate biochemical improvement in plasma phospholipids was that our duration of inunction was too brief and, therefore, that a more prolonged interval of inunction would be required to demonstrate replenishment of depleted tissue stores. However, falling far short of replenishment, we were not even able to prevent significant progression of essential fatty acid (EFA) deficiency with our low-dose inunction. Further, if a larger topical dose applied for a prolonged period of time were all that is required to replenish depleted tissue EFA stores, then we should have been able to prevent the severe deficiency state which developed in the four infants receiving high-dose inunction for several weeks. The second potential explanation suggested for our inability to document biochemical improvement in Our EFA-deficient patients is that, in simple terms, we' did not look in the right place. That is, they suggest that incorporation of topically applied linoleic acid into tissues did occur and would have been documented had we obtained any tissue measurements. Although the availability of animal or human data which includes simultaneous tissue and serum levels is quite limited, we have yet to observe an instance in which tissue EFA levels were normal or improving despite persistently abnormal or worsening serum levels. We should thus expect that the lipid in transit to its site of use should be detectable and, in other investigations, it has in fact been measurable. We also are aware of insulin-related suppression of linoleic acid au tflow from adipose tissue. This effect of insulin most likely explains the temporary EFA deficiency that can occur with high-glucose infusions. Nevertheless, the question as to whether or not we have been curing tissue deficiency while not changing serum lipids is irrelevant in that skin signs of EFA deficiency, when present, did not improve, indicating inadequacy of linoleic acid at the site of synthesis of skin lipids,
The final point to be discussed pertains to the validity of our normal values, which were obtained from cord blood samples in ten healthy term infants. Our normal data for early infancy indicate that linoleic acid content of serum phospholipid fatty acids increases to approximately 30%, arachidonic acid falls to about 10%,20:3119 decreases over the first year, total 116 acids increase slightly during infancy, and the triene:tetraene ratio tends to decrease during infancy. Our negative values for the calculated value 18:2S'l6 - 20:3n9 + 20:4116 in our study patients are dramatically different from control values, whether the controls be neonates or young infants. All of the measurements that we have used to evaluate EFA deficiency were thus not restored by inunction, irrespective of whether the control values were derived from cord blood or from young infants. Finally, as discussed in the above letter, when infants are fed diets containing EFA, blood values rapidly change, with increasing serum linoleic acid levels and decreasing arachidonic and 5,8,11eicosatrienoic acids. Since our patients followed an opposite trend in their serum levels, we still have to conclude that linoleic acid was not absorbed in sufficient quantity to affect serum (or tissue) EFA levels, even at the larger topical dose. We believe that the major significance of our data is an awareness that inunction ofEFA-rich oil may not be successful in all patients. To better clarify the reason for our poor results with inunction, additional studies are required in which tissue and serum levels of the major indices of EFA deficiency are measured. Pending such additional studies, however, we do not believe that inunction, whatever the dose of linoleic acid applied, can be assumed to be preventing or reversing deficient tissue stores. In this regard it is of interest that in a recent personal communication Mead and Robinson' have reported their inability to relieve biochemical EFA deficiency in three infants by safflower-seed oil inunction.
Carl E. Hunt, M.D. Rolf R. Engel, M.D. Ralph T. Holman, Ph.D Northwestern University Children's Memorial Hospital 2300 Children's Plaza Chicago, IL 60614 and University of Minnesota, Minneapolis and A listin. MN
REFERENCE I.
Mead 1F and Robinson S: Departments of Biochemistry and Pediatrics, UCLA, Los Angeles, Calif.
Upper airway conductance re neonatal mortality To the Editor: It was with considerable interest that we read the article by North and MacDonald' in which they reported the lower neonatal mortality rates in .small black infants when compared
Editorial correspondence or letters to the Ed itor relative to articles published in THE JOURNAL or to topics ofcurrent in terest are subject to critica l re view and to current editorial p olicy in respect to publication in part or in full.
Inunction of oil to correct essential fatty acid deficiency To the Editor: I have read with interest the article by Hunt et al ' in which the y reported the failure of the inunction of oil rich in linoleic acid to correct essen tial fatty acid (EFA) de ficiency in newb orn infants. Correct ion of EFA deficien cy by inun ctio n of oil rich in EFAs has been rep orted pre viously in ra ts' and human be ings." " Five of their six patients failed to show biochemical improvement of the EFA deficiency in spite of the in unction of lOa mg/kg /day of linoleic acid, which is the minimal recommended dose requirement of 1% of the tota l daily calories," Although n demonst ration of rapid correcti on of EFA deficiency in an a d ult with only 2 to 3 mg of linoleic acid / k g/ day was reported by Press et al,' we demonstrated' certain difficulties in predicting the absorption rate of linoleic acid following inunction. Even the relatively large quantities used in our patients, \,400 mg/kg/day, failed to replenish tissues deficient in EFA. Our study clearly demonstrated the biochemical changes in plasma phospholipids following the inunction of sunflower-seed oil which incl uded the increase in arachidonic acid and a decrea se in 5,8,II-eicosatrienoic acid. However, the linoleic acid level remained low in the plasma, red blood cells, a n d adipose tissue even after three weeks of the inunction of sunflower-seed oil. We concluded that prolonged inunction of oil rich in linoleic acid may be required to replenish depleted tissue stores in severe EFA deficienc y. Although the final statement of Hunt et al's ar ticle conclud es, "Unless documented by appropriate biochemical mea surements, no patient receiving to pical EFA-rich oil can be assumed to have normal serum and tissue EF A levels irrespecti ve of the dose of linoleic acid applied ," the authors fail to measure tissue levels of EFA and thus demonstrate only the failure of correction of serum EFA upon the inunction of oil rich in linoleic acid, even in a dose as high as 740 to 1,100 mg/kg/d ay. The fai lure to demonstrate biochemical correction of severe EFA-deficiency in the serum of these infants is not entirely surprising, since during fat-free parenteral hyperalimentation the outflow of linoleic acid from adipose tissue is blocked at least ir. part by the high-insulin levels accompanying glucose administration. Moreover, in adults in whom there are enough EFA in tissu e stores to meet the body's requ irements for months or even years, rapid onset of EFAdeficiency in serum was described during fat-free parenteral nutrition. ' Supplementation of small amounts of linoleic acid
]068
The Journal ofPED IATR I CS
during fat-free parenteral alimentation may thus incorporate into tissues without correcting EFA deficiency in the serum. Cu taneous application of sunflow er-seed oil to the forearms of pat ients with EFA deficiency for two weeks showed the level of linoleic acid in their epidermal lecithin to incr ease markedly, with a conco mitant decrease in the tran sep idermal water loss and the disappearance of the skin lesion s.' We recently demonstrateo v " the ability to correct pla telet function and to increase prostaglandin E turnover by the inunction of sunflower-seed oil in newborn infants with EFA deficiency. Improvements of these functions require an app ropria te absorption of EFA. Finally, the authors compared the level of the EFA In the serum of the ir patients to tho se of cord blood derived from term newborn in fants . Our recent study" demonstrated that cord blood values ofEFA vary in neon ates born a t different gestati onal ages. Moreover, when these infan ts were fed diets con taining EFA, blood val ues rap idly changed. including an increase in the level of linoleic acid and decrease in the levels of arachidonic and 5,8, l l-eicosatrinoic acids. We suggest that the foregoing be considered so as to avoid an incorrect interpretation of the effects of inunction. Zvi Friedman, M .D. The Milton S. Hershey Medical Center Department of Pediatric s Hershey, PA 17033
REFERENCES 1.
2.
3.
4.
5.
6.
Hunt CE, Engel RR, Modler S. Hamil ton W. Bissen S, and Holman RT : Essential fatty acid deficiency in neon ate s: In abil ity to reverse deficiency by topical applications of EFA-rich oil, J PEDIATR 92:603, 1978. Bohle s H. Biebe r MA , and He ird WC : Reversal of experimental essent ial fatty acid deficiency by cutaneous administration of sunflower oil. Am J Clin Nutr 29:398, 1976. Press M, Hartop PJ, and Prouey C: Correction of essential nitty acid deficienc y in man by the cutaneous applications of sunflower-seed oil. Lancet 1:597, 1974. Friedman Z, Sh ochat 5J, Maisels MJ, et al : Correction of essential fatt y acid deficien cy in newborn infants by cu taneous application of sunfl ower-seed oil. Pediatrics 58:650. 1976. Prottey C, Harrop PJ. and Press M: Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin. J Clin Invest Dermatol 64:228. 1975. Holman RT, Castor WO, and Wiese HF: The essential fatty
Editorial correspondence
Volume 93
1069
Number 6
acid requirement of infants and the assessment of their dietary intake of linoleate by serum fatty acid analysis, Am 1 Clin Nutr 14:70, 1964. 7. Wene 10, Connor WE, and DenBesten L: The development of essential fatty acid deficiency in healthy man fed fat-free diets intravenously and orally, 1 Clin Invest 56: 127, 1975. 8. Friedman Z, Lamberth El., Stahlman MT, and Oates 1A: Platelet dysfunction in the neonate with essential fatty acid deficiency, 1 PEDIATR 90:439, 1977. 9. Friedman Z, Seyberth H, Lamberth EL, et al: Decreased prostaglandin E turnover in infants with essential fatty acid deficiency, Pediatr Res 12:711, 1978. 10. Friedman Z, Danon A, Lamberth El., and Mann W1: Cord blood fatty acid composition in infants and in their mothers during the third trimester, J PEDIATR 92:461, 1978.
Reply To the Editor: We are pleased to have the opportunity to respond to the thoughtful comments contained in the above letter. We also are aware of the previous data indicating the beneficial effects of inunction and originally initiated our control study to better document these benefits. One of the potential explanations suggested in the letter for our inability to demonstrate biochemical improvement in plasma phospholipids was that our duration of inunction was too brief and, therefore, that a more prolonged interval of inunction would be required to demonstrate replenishment of depleted tissue stores. However, falling far short of replenishment, we were not even able to prevent significant progression of essential fatty acid (EFA) deficiency with our low-dose inunction. Further, if a larger topical dose applied for a prolonged period of time were all that is required to replenish depleted tissue EFA stores, then we should have been able to prevent the severe deficiency state which developed in the four infants receiving high-dose inunction for several weeks. The second potential explanation suggested for our inability to document biochemical improvement in Our EFA-deficient patients is that, in simple terms, we' did not look in the right place. That is, they suggest that incorporation of topically applied linoleic acid into tissues did occur and would have been documented had we obtained any tissue measurements. Although the availability of animal or human data which includes simultaneous tissue and serum levels is quite limited, we have yet to observe an instance in which tissue EFA levels were normal or improving despite persistently abnormal or worsening serum levels. We should thus expect that the lipid in transit to its site of use should be detectable and, in other investigations, it has in fact been measurable. We also are aware of insulin-related suppression of linoleic acid au tflow from adipose tissue. This effect of insulin most likely explains the temporary EFA deficiency that can occur with high-glucose infusions. Nevertheless, the question as to whether or not we have been curing tissue deficiency while not changing serum lipids is irrelevant in that skin signs of EFA deficiency, when present, did not improve, indicating inadequacy of linoleic acid at the site of synthesis of skin lipids,
The final point to be discussed pertains to the validity of our normal values, which were obtained from cord blood samples in ten healthy term infants. Our normal data for early infancy indicate that linoleic acid content of serum phospholipid fatty acids increases to approximately 30%, arachidonic acid falls to about 10%,20:3119 decreases over the first year, total 116 acids increase slightly during infancy, and the triene:tetraene ratio tends to decrease during infancy. Our negative values for the calculated value 18:2S'l6 - 20:3n9 + 20:4116 in our study patients are dramatically different from control values, whether the controls be neonates or young infants. All of the measurements that we have used to evaluate EFA deficiency were thus not restored by inunction, irrespective of whether the control values were derived from cord blood or from young infants. Finally, as discussed in the above letter, when infants are fed diets containing EFA, blood values rapidly change, with increasing serum linoleic acid levels and decreasing arachidonic and 5,8,11eicosatrienoic acids. Since our patients followed an opposite trend in their serum levels, we still have to conclude that linoleic acid was not absorbed in sufficient quantity to affect serum (or tissue) EFA levels, even at the larger topical dose. We believe that the major significance of our data is an awareness that inunction ofEFA-rich oil may not be successful in all patients. To better clarify the reason for our poor results with inunction, additional studies are required in which tissue and serum levels of the major indices of EFA deficiency are measured. Pending such additional studies, however, we do not believe that inunction, whatever the dose of linoleic acid applied, can be assumed to be preventing or reversing deficient tissue stores. In this regard it is of interest that in a recent personal communication Mead and Robinson' have reported their inability to relieve biochemical EFA deficiency in three infants by safflower-seed oil inunction.
Carl E. Hunt, M.D. Rolf R. Engel, M.D. Ralph T. Holman, Ph.D Northwestern University Children's Memorial Hospital 2300 Children's Plaza Chicago, IL 60614 and University of Minnesota, Minneapolis and A listin. MN
REFERENCE I.
Mead 1F and Robinson S: Departments of Biochemistry and Pediatrics, UCLA, Los Angeles, Calif.
Upper airway conductance re neonatal mortality To the Editor: It was with considerable interest that we read the article by North and MacDonald' in which they reported the lower neonatal mortality rates in .small black infants when compared
