ESSENTIAL FATTY ACIDS AND INFANT NUTRITION · ESSENTIAL FATTY ACIDS AND INFANT NUTRITION Borden...

ESSENTIAL FATTY ACIDS AND INFANT NUTRITION

Borden Award Address

By Arild E. Hansen, M.D., Ph.D.Department of Pediatrics, University of Texas School of Medicine

494

PEDIAmIcs, March 1958

ARILD EDSTEN HANSEN was born in Minne-

apolis during the last year of the last centuryand grew up in that city. He was educated inthe schools of Minneapolis and at the Univer-sity of Minnesota where he received his de-grees: B.S. in 1923, M.B. in 1924, M.D. in

1925 and Ph.D. in 1934. Arild Hansen alsospent the years 1929 and 1930 in post-gradu-

ate studies at Heidelberg and Vienna. He

served the University of Minnesota as an As-

sistant and an Instructor of Pediatrics until

1934. The year 1934-35 was spent as anAlexander Brown Coxe Fellow at Yale Uni-versity. Upon returning to Minnesota, Dr.

Hansen became Assistant Professor of Pedi-atrics, in 1937 Associate Professor and in 1942

Professor. In 1944 Dr. Hansen traveled fromthe extreme north to the extreme south of the

United States to become Professor of Pediatricsand Head of the Department at the Universityof Texas Medical Branch in Galveston. Dr.

Hansen is a member of numerous scientificsocieties. He has a long career in investigation

and published many articles on a variety of

topics but especially on lipid metabolism.

T N A PRESENTATION such as this, no doubt,I one is allowed the equivalent of a cer-

tam degree of “poetic license” in reviewing

the work which has led to commendation

by the Committee on Awards of the Amen-

can Academy of Pediatrics. Collaboration

is not only an essential feature of present-

day investigative endeavors, but also a so-

cial reward. As with everyone else, per-

haps, who has attempted to pursue “ideas,”

the writer has found persons who stand out

as vital and indispensable in seeking to

establish fantasy or fact in relation to con-

cepts conceived. In regard to the subject

of the essential fatty ‘acids, it has been my

Presented at the Annual Meeting, October 8, 1957.ADDRESS: Galveston, Texas.

pleasure and privilege to work in the most

stimulating manner with the late William

R. Brown, Mildred R. Ziegler, George 0.

Burr, Irvine McQuarrie, William R. Wilson

and in recent studies for which this award

is being given with Doris J. D. Adam, and

especially with Hilda F. Wiese of the Uni-

versity of Texas School of Medicine.

Each of us can recall events from our

school years which have harried us long

after their direct relationship to the subject

has been forgotten. A statement during my

premedical days, which for some reason or

other stuck as “gum to a shoe,” was made

by Professor Lee I. Smith of the Depart-

ment of Organic Chemistry while dis-

cussing the subject of fat. After mentioning

that the fatty acids found in nature have

an even number of carbon atoms, he added,

“there are some which have unsaturated

linkages, but no one knows the reason for

this.” I still recall placing a question mark

in my notebook to indicate “I wonder why.”

EARLY CLINICAL AND CHEMICALOBSERVATIONS

It was purely a clinical impression some

years later,� which stimulated my interest

in the significance of dietary fat, particu-

lan!>’ in regard to the essential nature of cer-

tam unsaturated fatty acids in human nu-

tnition. In caring for the infant with eczema,

it was the general therapeutic practice to

remove fat from the diet. During my hos-

pital-training years, as well as in private

practice, I followed this procedure; how-

ever, the results were unimpressive. Still,

the problem of eczema seemed to offer a

challenge, especially after I had visited a

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TABLE II

LIPID IN SERUM IN RATS AND Doos

AMERICAN ACADEMY OF PEDIATRICS-PROCEEDINGS 495

number of the Children’s Hospitals of

Europe and noted the uniformity of the

problem, i.e., similarity of manifestations

and difficulty in management.

It was about this time that Burr and

Burr2 had published their astute observa-

tions on the effects of fat-free diets on rats.

The idea that lack of dietary fat could pro-

duce profound changes in the appearance

of the skin, which were cured by the addi-

tion of special fats to the diet, was an allur-

ing idea. After some deliberation, this new

approach to the problem of eczema was

tried. A number of infants suffering with

eczematous eruptions were given supple-

ments of fats, such as fresh lard, corn oil

or raw linseed oil, which contain unsatu-

rated fatty acids. In none did the eruption

become worse; whereas, after several weeks

some infants appeared to be definitely im-

proved.

It was these clinical observations which

led me to the laboratory to learn something

about lipid analysis in order to study blood

fats. It was found that the iodine numbers

of the fatty acids of the serum of infants

with eczema were lower than those of in-

fants free from such skin 3 In our

initial studies it was found that with no

essential difference in the concentration of

the total fatty acids of the serum, the iodine

number of the fatty acids was 84 on the

average in the infants with eczema com-

pared with 111 in control infants (Table I).

Following the administration of dietary fats

which contained unsaturated fatty acids,

TABLE I

LIPID IN SERUM IN INFANTS WITH

ECZEMA AND IN CONTROLS

Total Fatty Acid.�

(mg/100 ml) (mean iodine no.)

Control’ 361 111

Eczema’ 34� 84

Control’ 339.4± 6.� 11�.O±3.7

Eczema3 387.3± 1�L5 87.O±�.�

Total F aLly Acid.�

(mg/100 ml) (mean iodine no.)

Rats5

Control diet �8S 136

Low-fat diet �58 107

Dogs7

Control diet 53� 117

Low-fat diet 455 9�

the iodine values of the serum fatty acids

were found to be in the same range as for

the control subjects.4 The changes in iodine

number of the fatty acids frequently coin-

cided with clinical improvement. After dis-

cussing these observations with Dr. Mc-

Q uarnie he suggested that I see Dr. Burr

who was a member of the Department of

Botany in the same institution. From him

it was learned that no studies of the serum

fatty acids in rats had been made, but he

agreed that such a project was worthy of

pursuit.

Arrangements were made to analyze the

serum lipids of fat-deficient and control

6 The results showed that the differ-

ence in iodine numbers of the serum fatty

acids between animals suffering from fat

deficiency and healthy control animals was

of the same order of magnitude as was ob-

served between eczematous and control in-

fants. As indicated in Table II, subse-

quently this also was found to hold for

dogs.7 These preliminary observations mdi-

cated that a thorough study of blood lipids

in relation to dietary fat might be helpful

in evaluating the role of fat in the mainte-

nance of healthy skin. However, to conduct

such a study two features were apparent:

Firstly, a method for the determination of

specific fatty acids in blood serum would

assist materially in carrying out such a

project; secondly, actual experience with

low-fat diets would be necessary to estab-

lish an essential role of fatty acids in hu-

man nutrition.


FIG. 1. Young dogs of same age since weaning (a, left) fed on diet in which fat (fresh lard) comprised

29% of the calories and (b, right) same diet except sucrose substituted for fat (total tat 1% of total

caloric intake).

496 ESSENTIAL FATTY ACIDS

DEVELOPMENT OF METHODS FORLIPID ANALYSIS AND THEIR

APPLICATION

The first step in the development of

methods was a semimicrogravimetric pro-

cedure for the direct determination of fat

by Wilson and Hansen,8 wherein it was

possible to separate the fatty acids from

the unsaponifiable fraction. Further frac-

tionation allowed one to determine the

amount and average degree of unsaturation

of the fatty acids present as phospholipids.�

Subsequently, by means of alkaline conju-

gation of unsaturated fatty acids and spec-

trographic analysis by the method of Wiese

and Hansen,1#{176} it was possible to measure

the amount of the 2-, 3- and 4-double-bond

fatty acids in blood serum and body tissues.

Next, in order to establish correlations

between dietary fat and clinical appearance

of the skin, as well as between dietary fat

and concentration of specffic fatty acids in

the serum, an extensive series of expeni-

ments were carried out with young pup-

pies.1114 Incidentally, our first efforts at

feeding a diet extremely low in fat to dogs

resulted in vitamin E deficiency, which

was evidenced by the development of

paralysis of the hind extremities. Recovery

occurred with the addition of alpha-

tocopherol to the diet, but not by the addi-

tion of fat.

To date, well over 100 dogs have been

studied, some of which have been under

observation for as long as 6 years. These

studies established the following facts:

1. Signs of fat deficiency readily develop

in young puppies. These are characterized

by dryness of the skin and loss of hair, des-

quamation, erythema and pigmentation of

the skin, running of the ears, oozing of the

paws and a tremulous, nervous behavior.

Some of these signs are not unlike those

observed in some infants who have been on

diets very low in fat. The rate at which the

symptoms of deficiency in dogs disappear

is directly related to the quantity of linoleic

acid in the diet. Examples of control and

fat-deficient dogs are shown in Figure 1.

Adult dogs did not show the severe signs

of deficiency which were observed in young

animals. In spite of a caloric intake per

unit body weight equal to that of control

animals, marked emaciation ultimately de-

velops in young animals which do not re-

ceive fat in the diet.

2. Histologic examination reveals marked

alterations in the structure of the skin of

fat-deficient animals. There is parakeratosis

with peeling of the outer layers and pres-


1,-� -

-. ‘.‘ �__..�,‘l�’z

� :-�

�

.w’� �,

- I’ �

,5_��% � w

lI�i�i-i f,�

AMERICAN ACADE�lY OF PEDIATRICS-PROCEEDINGS 497

FIG. 2. Histologic appearance of skin from (a, left) healthy control dog receiving fat in the diet and

(h, right) animal on diet low in fat.

ence of nucleated cells in the stratum cor-

neum, an increase in the cell layers of the

epidermis and hair follicles, plugging of the

hair follicles, increased activity in the Se-

baceous glands and later signs of atrophy,

evidence of activity of sudoriparous glands,

infiltration of the dermis and uneven col-

lagen fibers. Examples of the skin changes

in control and fat-deficient animals are

shown in Figure 2. The rate at which the

abnormal histologic structures disappear is

related to the linoleic acid content of the

dietary fat.

3. Although the iodine number of the

serum fatty acids of dogs decreases with

a low-fat diet as indicated in Table II,

greater significance is assigned to the direct

correlation between dienoic (linoleic) acid

content of the serum and the linoleic acid

content of the diet. The concentration of

tetraenoic (arachidonic) acid in the serum

changes in the same direction as that of

dienoic acid, whereas the change for tn-

enoic acid is in the opposite direction (Table

III). The increase in trienoic acid in fat-

deficient animals is a subject of considera-

ble interest to a number of workers in this

field.

It was concluded from the studies with

dogs that: Young subjects appear to be

much more sensitive to a lack of fat in the

diet than adults; dermal structures are af-

fected particularly; metabolic processes

concerned with utilization of calories are

altered; and measurement of the di-, tn-

and tetraenoic acids of the blood serum

(2-, 3- and 4-double-bond fatty acids) might

well give one an index for determining the

requirement for unsaturated fatty acids in

the diet of infants.

ATTEMPT TO ESTABLISH THE INFANT’SREQUIREMENT FOR UNSATURATED

FATtY ACIDS

Clinical Observations on Human Subjects

Maintained on Diets Low in Fat

During the first short-term studies of in-

fants given diets low in fat, it was observed

that impetiginous skin eruptions were diffi-

cult to heal. One infant with chylous

TABLE Ill

UNSATURATED FATTY ACIDS IN SERUM OF D0GS’#{176}

‘ Total � Dienoic Trienoic Tetra-

. P.4. � enouI)�et

(mgi

� 1(X) ml) � (per cent of TFA)

Low-fat � 367 5.’2 15.9 3.5

Fat (lard) 30%

of calories 479 �2�t .7 1 . ‘2 ‘21 .1



ascites,15 who for almost 2 years was given

a diet very low in fat, showed: (1) Normal

increase in height (not possible to evaluate

weight curve); (2) food consumption greater

than expected; (3) evidences of disturbed

skin function as indicated from develop-

ment of a chronic dermatitis following

prickly heat, periodic eczematous lesions

and resistance to treatment of impetigo.

An adult subject’6 for a 6-month period

was maintained on a diet low in fat (com-

posed of skimmed milk, cane sugar, potato

starch, baking powder, sodium chloride,

orange juice, ferric chloride, Viosterol#{174}, and

carotene, with liquid petrolatum incorpo-

rated as a shortening in the attempt to make

something equivalent to biscuits); the total

fat intake was not more than 2 gm per day.

Rats maintained on the same diet devel-

oped typical signs of fat deficiency. The

adult subject maintained a state of well

being during the 6-month period. At the

beginning of the study the blood pressure

bordered on the hypertensive level, but

while on the low-fat diet was within the

normal range. During this time he did not

suffer headaches to which he had been sub-

ject periodically. He lost 14 pounds in weight

in spite of a caloric intake and degree of

physical activity similar to that to which he

was accustomed both before and after the

special-diet period. Determinations of the

respiratory quotient indicated that the hu-

man subject reacted metabolically similar

to the rat.

These observations of an infant with

chylous ascites and of an adult subject are

presented in some detail because of subse-

quent findings in two large groups of in-

fants. In a study of 20 infants under 1 year

of age, fed diets containing variable

amounts of fat and linoleic acid, it was ob-

served on several occasions that use of a

low-fat diet was associated with changes in

the skin. In another more extensive study

which is now underway, it has been demon-

strated that linoleic acid plays a definite

role in the maintenance of healthy skin in

young babies.

Chemical Observations on Serum Lipids

With a diet low in fat, in human subjects,

the iodine number of the serum fatty acids

decreases. More significant, however, seems

to be the observationl7 that the 2- and 4-

double-bond fatty acids decrease while the

3-double-bond fatty acids increase. Al-

though the values for the unsaturated fatty

acids in human subjects and dogs are dif-

ferent, the change is in the same direction

as has been noted for dogs.18 This phase

of our studies will be discussed in greater

detail in subsequent reports.

Caloric Consumption in Relation to

Linoleic Acid Intake

Although studies relating the caloric in-

take to linoleic acid in the diet have been

completed, only preliminary reports19 have

been presented. We are desirous of ac-

knowledging the valuable assistance in

these studies provided by a contract from

the United States Department of Agnicul-

ture, Human Nutrition Research Division.

The study was undertaken primarily to as-

certain whether or not one could determine

the infant’s requirement for linoleic acid

by using the concentrations of di-, tn- and

tetraenoic acids in the serum as an index

of adequacy of intake. Milk mixtures were

fed which varied in contents of fat as well

as linoleic acid. Close relationships were

found between the concentration of the

unsaturated fatty acids in the serum and the

linoleic acid intake (Table IV).

In addition, careful clinical observations

and ordinary laboratory studies were made

and accurate records of the food intake

were kept. When the caloric intakes and

the body weights were fitted to straight

lines, it was found that the caloric intake

varied with the linoleic acid content of the

milk mixture. The data from a male infant

who was 2 weeks of age at the beginning of

the study are presented graphically in Fig-

ure 3. One may note no essential change in

the slope of the weight curve whether the

infant received the skimmed-milk prepara-

tion (contained 1% of the calories as fat,


4.1

3.8

(-DIET A (SKIM MILK)-)�----- -DIET B (EVAP. M1LK)-�

WEIGHT GAIN 25 am P11 DAY WEIGHT GMN 27 am P11 DAY

3.5

3.2

2.9

2.3

02 8 14 20 26 32 38 44 50 56


TABLE IV

LIPID IN SERUM PROM INFANTS CONSUMING Mn.xs on VARIABLE CONTENT OF

FAT AND LIN0riac AciD

Diet No. of InfantsTotal F.A.

(mg/100 ml)

Dienoic Trienoic Tel raenoic

(per cent of TFA)

Low-fat 3 .5.� 4.8

Evaporatedmilk 4 10.4 3.4 5.�Breastmilk 4 �67 �13.1 0.4 10.6

0.04% of the calories as linoleic acid) or the

evaporated-milk mixture (contained 40% of

the calories as fat, 1% of the calories as

linoleic acid). Both preparations contained

20 calories per ounce.

At the beginning of the study this infant

was consuming food at the rate of about

110 cal/kg/day. After 4 weeks this had

increased to about 160 cal/kg/day. As soon

as fat was added to the diet, in an evapo-

rated-milk formula, a definite decrease in

2.6

the calories consumed per unit body weight

occurred, so that after 4 weeks he was con-

suming food at the rate of about 100 cal/

kg/day. The average gains in weight were

25 and 27 gm/day on the skimmed-milk

and evaporated-milk mixtures, respectively.

In the final report of the study, data will

be presented which indicate that a similar

decrease in calories consumed per kilogram

per day occurred when the skimmed-milk

mixture was supplemented with small

�Ys

C)

P1

Cl)

I

Fic. 3. Data from an infant who was fed a skimmed-milk mixture from 2 to 6 weeks of age and an

evaporated-milk mixture from 6 to 10 weeks of age.



amounts of linoleic acid. It appears that

linoleic acid plays a signfficant metabolic

role in infant nutrition. This tentative con-

clusion is based on incomplete evaluation

of data obtained from study of 20 different

infants.20

Finally, it may be of interest to note that

the presentation of the Borden Award on

behalf of the American Academy of Pe-

diatrics for 1957 is being made to one who

comes from the same town (Galveston)

where Gail Borden carried on his work

which led to his epoch-making discovery.

The one hundredth anniversary of his com-

pany is now being celebrated. Just last

week I visited his homesite, read some of

his original communications in our city

(Rosenberg) library, and was again im-

pressed with the extraordinary versatility

and accomplishments of this unusual man.

He lived in Galveston from 1837-1851 and

returned there just a century ago to join

his family before going on to seek further

financial assistance to put his discovery of

a process for evaporating milk to use. It

was in Galveston in 1840 that Gail Borden,

J r. made his basic observations regarding

the evaporation of milk under vacuum to

produce a product which would stay clean

for long periods. It is noteworthy that he

did not undertake his investigative efforts

strenuously until he was approaching 50

years of age. Among his accomplishments

we find that as a surveyor he compiled the

first topographical map of Texas and laid

out the City of Galveston. He published the

first newspaper in Texas (Telegraph and

Texas Register) in which was first printed

the Declaration of Independence of Texas

(1835) as well as its Constitution which

he helped to write. He was the first collec-

ton of customs and helped to organize the

First Baptist Church in Galveston (his

mother was a great, great granddaughter

of Roger Williams). He was a close friend,

counsellor and collaborator of the great

leaders and patriots of Texas, Stephen F.

Austin and Sam Houston. After diligent

endeavors he invented a meat biscuit which

received acclaim, but failed to impress the

food buyers for the army, yet orders from

England indicated that his product was

sent to Florence Nightingale to help her

in her plight during the Crimean War. Mr.

Borden went to England where he received

The Great Counsel Medal at the London

International Exposition. Upon returning to

Galveston in 1851 the cows on board ship

became ill, and he observed that the infants

on ship also became ill and some died.

Apparently, it was this experience which

spurred him on to work upon his idea of

milk processing to produce a clean milk.

He believed in cleanness of milk long before

the concept of microbes had been intro-

duced. What he learned in pursuing the

idea of making a desiccated meatball or

meat biscuit and the accidental discovery

of a method for keeping milk clean and

safe has been the turning point in the lives

of many men.

Let this be an inspiration to us all, old

and young, in medicine and science: Casual

observations, if carefully made, often prove

to be more than incidental in importance!

REFERENCES

1. Hansen, A. E. : Study of iodine number ofserum fatty acids in infantile eczema.Proc. Soc. Exper. Biol. & Med., 30:1198,1933.

2. Burr, G. 0., and Burr, M. M. : A new de-ficiency disease produced by the rigidexclusion of fat from the diet. J. Biol.

Chem., 82:345, 1929.3. Hansen, A. E. : Serum lipids in eczema

and in other pathologic conditions. Am.J. Dis. Child., 53:933, 1937.

4. Hansen, A. E. : Serum lipid changes andtherapeutic effects of various oils in in-fantile eczema. Proc. Soc. Exper. Biol.

& Med., 31:160, 1933.5. Hansen, A. E., and Burr, G. 0. : Iodine

numbers of serum lipids in rats fed onfat-free diets. Proc. Soc. Exper. Biol. &Med., 30:1201, 1933.

6. Hansen, A. E., and Brown, W. R. : Theeffect of low fat diets on serum lipidsof rats. J. Nutrition, 13:351, 1937.

7. Hansen, A. E., and Wiese, H. F. : Studieswith dogs maintained on diets low infat. Proc. Soc. Exper. Biol. & Med., 52:205, 1943.

8. Wilson, W. R., and Hansen, A. E. : Study

of the serum lipids by a microgravimet-



nc technique. J. Biol. Chem. 112:457,1936.

9. Hansen, A. E. : Nature of fatty acids of

acetone insoluble (phospholipid) fractionof serum. Proc. Soc. Exper. Biol. & Med.,40:376, 1939.

10. Wiese, H. F., and Hansen, A. E. : Semi-micromethod for unsaturated fatty acids

of blood serum. J. Biol. Chem., 202:417,1953.

11. Hansen, A. E., and Wiese, H. F. : Fat inthe diet in relation to nutrition of thedog. I. Characteristic appearance andgross changes of animals fed diets withand without fat. Texas Rep. Biol. &Med., 9:491, 1951.

12. Wiese, H. F., and Hansen, A. E. : Fat inthe diet in relation to nutrition of thedog. II. Lipid composition of tissuesfrom animals fed diets with and withoutfat. Texas Rep. Biol. & Med., 9:516,1951.

13. Wiese, H. F., and Hansen, A. E. : Fat inthe diet in relation to nutrition of thedog. III. Spectral analysis for unsatu-rated fatty acid content of tissues fromanimals fed diets with and without fat.Texas Rep. Biol. & Med., 9:545, 1951.

14. Hansen, A. E., Holmes, S. G., and Wiese,H. F. : Fat in the diet in relation to nu-trition of the dog. N. Histologic fea-

tures of skin from animals fed dietswith and without fat. Texas Rep. Biol.& Med., 9:555, 1951.

15. Hansen, A. E., and Wiese, H. F. : Tissuelipids in child with chylous ascites main-tamed on low fat diet. Fed. Proc., 5:233,1946.

16. Brown, W. R., Hansen, A. E., Burr, C. 0.,and McQuarnie, I. : Effects of prolongeduse of extremely low-fat diet on an adulthuman subject. J. Nutrition, 16:511,1938.

17. Wiese, H. F., Hansen, A. E., Adam, D.

J. D., and Baughan, M. A. : Effect ofintake of linoleic acid on unsaturatedfatty acids of serum of infants. Fed.Proc., 15:577, 1956.

18. Wiese, H. F., Baughan, M. A., and Han-sen, A. E. : Influence of fat in diet ondistribution of unsaturated fatty acids inserum of dogs. Fed. Proc., 14:453, 1955.

19. Hansen, A. E., Wiese, H. F., Lawlis, M.,Adam, D. J. D., and Baughan, M. A.:Effect of dietary fat on unsaturated fattyacids of serum of infants. Fed. Proc.,14:436, 1955.

20. Hansen, A. E., et al.: Intake of linoleicacid in relation to serum unsaturatedfatty acids and fat deficiency symptomsin infants (abstract). A.M.A. J. Dis.Child., 94:398, 1957.


1958;21;494Pediatrics Arild E. Hansen

ESSENTIAL FATTY ACIDS AND INFANT NUTRITION: Borden Award Address

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