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Effects of vitamin A deficiency on thyroid function studied with radioactive iodine

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Effects of vitamin A deficiency on thyroid function studied with radioactive iodine

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Content EFFECTS OF VITAMIN A DEFICIENCY
ON THYROID FUNCTION STUDIED
WITH RADIOACTIVE IODINE
A Thesis
presented to
the Faculty of the School of Medicine
The University of Southern California
In partial Fulfillment
of the Requirements for the Degree
Master of science
by
Mortimer B. Lipsett
August 1947
UMI Number: EP41284
All rights reserved
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This thesis, written by
Mortimer. J3.,„.LL ipsett............. / 7 7* ^
under the guidance of h%f?.... Faculty Committee, t
and app ro ved by a ll its members, has been
presented to and accepted by the Council on
Graduate Study and Research in partial fu lfill
ment of the requirem ents f o r the degree of
M a s . t . e r . . . . . o i ! . . . S . c i e n c . e ............
D e a n
Secretary
D a te.......................
F acu lty Cotnm ittee
{C hairm an ( S
..
..
ACKNOWLEDGEMENT
I wish to express ny gratitude to Dr. Richard j.
Winzler for his interest and suggestions about the work.
I wish to thank coast chemical company for making this
work possible.
TABLE OF CONTENTS
CHAPTER PAGE
I. INTRODUCTION................................ 1
The -thyroid gland........... 1
Vitamin A ............... 4
II. HISTORX AND REVIEW OF THE LITERATURE..... 6
Effects of avitaminosis A and hypervitamin-
osis A on the weight and histology of the
thyroid gland ........ 6
Relation of vitamin A to thyrotropic
hormone 10
Antagonism of thyroxine and vitamin A in
lower forms................. 11
Effect of vitamin A on the basal metabolism
of experimental animals .......... 12
Clinical use of vitamin A ......... • 14
Other effects of vitamin A on reactions in
fluenced by thyroxine . .......... . 15
Summary of results found in the literature 16
III. STATEMENT OF PROBLEM........................ 17
IV. EXPERIMENTAL PROCEDURE AND METHODS.......... 19
Plan of experiment . . • • • ........... * 19
Determination of radioactivity.......... 21
CHAPTER PAGE
IV. ( c ontinued)
Separation and analysis of the various
thyroid fractions ............ ..... 23
Total iodine ............. 23
Fractionation of thyroid iodine . . 24
Thyroxine 25
Inorganic iodine .......... 25
Diiodotyro sine ......... 25
Checks of the method............... 26
V. DISCUSSION OF RESULTS..................... 27
Weights of the thyroid gland . ........ 27
Histology................................ 27
Iodine uptake and distribution ...... 34
Conversion of inorganic iodine to organic
iodine........... 34
Rate of formation of thyroxine......... 36
VI. SUMMARY............................. 37
VII. SUGGESTIONS FOR FURTHER WORK............... 38
BIBLIOGRAPHY.................................. 39
I
LIST OF TABLES AND FIGURES
TABLE PAGE
I. Composition of the diet . ................. 20
II* Thyroid weights of control animals ...... 28
III. Thyroid weights of A-defieient animals .... 29
IV. Thyroid iodine distribution in control animals 30
V. Thyroid iodine distribution in A-deficient
animals .. . . . . . . . . . . . . . . . . 31
VI. Thyroid iodine distribution in high A animals 32
FIGURE
I. Rate of uptake and conversion of inorganic
iodine ............ .......... • 33
II. Rate of formation and removal of thyroxine . . 33
CHAPTER X
INTRODUCTION
The thyroid gland
The thyroid gland is a bi-lobed organ lying in the
neck on either side of the trachea and larynx. This des
cription is applicable to man and to the animals discussed
herein. In these species, the secretion of the thyroid
gland is essential to maintenance of nonnal body metabolism
and, in the young animal, to normal growth.
Histologically, the normal thyroid contains many
epithelium-lined, irregularly spherical follicles. The
lumen of the follicle is filled with colloid, a clear,
viscid, acidophilic material containing large amounts of
iodine. The epithelial cells lining the follicles are
generally cuboidal. The various dysfunctions of the gland
are reflected in changes in the size and type of epithelial
cells, changes in the number of follicles, amount of colloid,
etc. The undefined use of such phrases as "hypertrophy" and
"hyperplasia" in describing the thyroid has led to some con
fusion in the literature. In this discussion, hypertrophy
will mean an increase in the size of the gland and hyperplasia
will be restricted to those cases in which the number of cells
is increased, and exclusive of those cases in which there is
degenerative infiltration of the gland, wherever possible
in the literature survey, an attempt will be made to indicate
the histology of the gland in more specific terms.
Chemically the thyroid is distinguished by its ability
to "trap” iodine. It has been shown that the gland will
selectively © neentrate iodine to a degree five hundred to a
thousand times greater than other tissues. The iodine which
is "trapped" is very quickly incorporated into diiodotyrosine,
The control of some or all of these functions is mediated
by a secretion of the anterior pituitary, the thyrotropic
hormone.
When there is over-secretion of thyrotropic hormone
in the presence of adequate amounts of iodine, then the
gland contains little or no colloid and the epithelial cell
height is greatly increased. Concomitant with these changes
in the thyroid are an increased basal metabolic rate and a
higher blood iodine level. This is the characteristic pic
ture in exophthalmic goiter.
When there is a relative deficiency of iodine in the
diet of an animal, a "simple goiter" may result. This is
which is then used in the synthesis of thyroxine,
X » ^ I
3
usually characterized by development of a large tigroid
gland containing much colloid and lined with flattened epi
thelium. in this condition, the basal metabolic rate may
be normal or lowered.
Myxedema is a clinical state in which insufficient
thyroid secretion may be an etiologic factor. There is
usually a lowered basal metabolic rate and a decreased blood
iodine level. The histology of the gland varies so that
no generalizations may be drawn. There may be atrophy of
the gland, in which case there is little or no follicular
epithelium. There may be a fibrotic invasion of the gland
with only occasional follicles present, often, there are
large sections of the gland which histologically resemble
the gland in simple goiter, in all cases where myxedema
has been diagnosed and the appropriate experiments tried,
it has been found that the rate of iodine uptake is greatly
decreased. However, the gland in simple goiter shows an in
creased uptake of iodine. It can be seen that the histology
of the thyroid can often provide information about its func
tional activity, but that histological examination alone is
sometimes inadequate.
The methods used in this work can differentiate between
the several activities of the thyroid gland. It should be
realized that speaking of an effect on "the activity” of the
thyroid can only be misleading. The gland is active in many
ways: in trapping iodine, in forming diiodotyrosine and
4
thyroxine, in secreting thyroxine into the blood stream
or into the colloid. One or more of these activities may
be hindered by the conditions imposed upon the gland, in
this research, rats have been subjected to severe avitamin
osis A and the effects on thyroid function described, some
general references on thyroid function and physiology are
Means (1937) and Salter (1940).
urated hydrocarbon containing two ^-i on one rings. It could
theoretically yield two molecules of vitamin A.
Vitamin A is essential for the maintenance of life in
man, in the rat, and in the other experimental animals cited
in this work. The mechanism of its action in the physiology
of mammals is, for the most part, unknown. Except for its
participation in the dark adaptation system of the eye, no
specific function can be attributed to it. The following is
a partial list of the main symptoms which appear in vitamin
A deficiency; atrophy of epithelial tissues with keratini-
zation, reduction of growth rate, decrease in resistance to
infection, one of the most characteristic signs of severe
A deficiency is xerophthalmia, a keratinization of the
Vitamin 4
Vitamin A is an unsaturated alcohol containing a
^-ionone ring,
Its most common precursor is/^-carotene which is an unsat-
epithelial mucosa of the eye. in spite of the large amount
of experimental work which has been done on the mechanism
of these changes, only description rather than explanation is
available.
CHAPTER II
HISTORY AND REVIEW OF THE LITERATURE
Effects of avitaminosis A and hypervitaminosis A
on the weight and histology of the thyroid gland
The earliest published observations of the effect of
avitaminosis A on the thyroid gland is that of MCCarrison
- (1914) who noted a hypertrophy of the thyroid in rats fed
*
a diet deficient in the fat soluble (then unidentified)
vitamins. These animals showed occasional ”lymph-adenoidal
degeneration”, in 1930, after the chemistiy and physiology
of vitamin A had been somewhat clarified, Mccarrison re
peated his work using a complete, more purified diet omitting
vitamin A. He found substantially the same picture, hyper
trophy of the gland with cystic degeneration in some cases.
The hypertrophy in this case was due to ' ‘ abnormal distension
of the follicles”. Spence (1930) reported similar results
with rats. His diet, though, contained added potassium
iodide. However, other authors, Drennan, Malcolm and Cox
(1931); and sanpson and Korenchevsky (1932), also using rats,
reported no effect of a vitamin A deficiency on the weight
or histology of the thyroid gland. However, the latter
authors did observe a thyroid hypertrophy when the diet was
deficient in both vitamin A and iodine, what part of this
hypertrophy was due to iodine lack cannot be ascertained
from their data. Remington, Harris and smith (1943) used
the weights of the thyroid glands of rats as an index of
the effect of vitamin A. They concluded that a deficiency
is not an etiologic factor in the development of goiter.
Sure (1938) found no effects of A deficiency on the weight
of the thyroid gland in the rat. unfortunately, in these
last four references, greatest reliance was placed on the
thyroid weights and the histological examination was only
cursory. The weight of the thyroid gland is an inadequate
criterion of the functional state of the thyroid.
Coplan and Sampson (1935) studied this problem very
thoroughly. Their work was designed to show the effects of
avitaminosis A on the thyroid gland with a consideration of
factors of sex, diet, and duration of the vitamin deficiency.
They found that vitamin A deficiency produced a definite
hypertrophy in the female rat but consistent atrophy in the
male, as measured by thyroid weight. However, it is doubt
ful if the difference in weights of the thyroids of the two
sexes is statistically significant. They further found that
a diet deficient in both vitamin A and iodine led to an in
crease in the size of the follicles and the weight of the
glands in both sexes* They attribute their findings to a
specific effect of vitamin A on the thyroid.
In an investigation of the pathology of A avitaminosis,
Hou (1936) noted that of forty-four A deficient rats examined,
thyroid degeneration was second only to xerophthalmia in
frequency of pathological lesions,
Freuderiberger and Clausen (1935) • reported a decrease in
the weights of the thyroid glands of rats after continued
feeding of vitamin A in cod-liver oil. Sadhu and Broda (1947)
noted that vitamin A decreased the thyroid weights of normal
animals.
The next group of references is that in which the in
vestigations were primarily histological. Mitzkewiteh (1934)
used the A-free diet of Osborne and Mendel (1913) which con
tains forth micrograms of iodine per gram of diet, on this
diet he reported, "The follicular epithelium of the A-free
rats is greatly flattened. The follicles are overfilled with
colloid so that the walls are distended. The thyroid was
hypertrophied and showed a clear hypofUnction.1 ’ De Ruyter
(1934) noted atrophy of the thyroid with epithelial degener
ation in severe avitaminosis A.
Sherwood, Toth and Carr (1934) found that the rat thyroid
was depleted of its colloid on a diet supplemented with large
amounts of vitamin A. Sherwood and Luckner (1935) report the
same effects when carotene was used. The follicular epithelium
was increased in height and the colloid depleted. Adminis
tration of excess vitamin A had no appreciable influence on
the histology of the thyroid glands of guinea pigs (Elmer,
Giedosz and Scheps, 1935). However, in other experiments
Giedosz (1935) observed that vitamin a administration led to
numerous follicles with increased amount of colloid present.
Uotila (1938) summarizes his careful histological in
vestigations with the statement that in vitamin a deficiency
there is an inactive colloid gland with histopbysiological
characteristics pointing to hypofUnction. In some of the
glands examined, there were degenerative changes and peculiar
cysts in which the epithelium was metaplastic and keratinized.
In his rats which were made A hypervitaminotic there resulted
a diffuse hyperplasia with active cuboidal epithelium.
Schulze and Hundhausen (1939) after histological exami
nation of the thyroid glands of rats report that avitaainosis
A gives a “tendency to activation". They also found that
excess vitamin A shifted the picture to that of a resting
thyroid gland. This, of course, is opposed to the findings
of Mitzkewiteh, Uotila, and others.
Wegelin (1939) found epithelial lyperplasia when vitamin
A was given in large amounts, in one rat, he observed a
diffuse parenchymatous goiter* Carriere, Moul and Gineste (1939)
reported that giving high daily doses of vitamin A to rabbits
inhibited activity of the thyroid gland, and led to the same
type of gland as found in colloid goiter.
It .can be seen from the foregoing that there is lack of
agreement about the histology of the thyroid in A avitaminosis
or hypervitaminosis. However, the consensus is that with
10
avitaminosis A, an inactive colloid gland is found* in hyper-
vitaminosis a , the colloid seems to be decreased and the epi
thelium hyperplastic.
Relation of vitamin A to thyrotropic hormone
One hypothesis of the action of vitamin A on the thyroid
gland is that there is an antagonism of vitamin A to either the
production or action of thyrotropic hormone. This hypothesis
has been tested by scbneider (1939), Elmer, Giedosz and seheps
(1935) and pellinger and Hochstadt (1936). These authors
found that vitamin A partially prevented the histological
changes in the thyroid gland caused by injections of thyro
tropic hormone. Bearing on this line of investigation is
the work of Schulze and Hundhausen (1939) who found that ad
ministration of vitamin A decreases the content of thyrotropic
hormone in the anterior pituitary, and conversely, that
avitaminosis A led to an increase in the thyrotropic potency
of the hypophysis. Belasco and MUrlin (1940) fed rats two
thousand units of vitamin A with their diet for eight days.
They then measured the oxygen consumption of kidney, liver,
and, thyroid tissue slices by means of the Warburg method.
Vitamin A depressed the Q02 thyroid tissue, but increased
that of kidney and liver. If the animals were also given
thyroxine, and the same experiment tried, vitamin A had no
11
effect. This bears out the stated hypothesis, for thyroid
activity is low when there is a lack of thyrotropic hormone.
However, in a thyroxinized animal, the secretion of thyro
tropic hormone is already reduced to a minimum, so that there
could be little further effect of vitamin A. Sadhu and Broda
(1947) noted that vitamin A decreased the thyroid weights of
thiouracil-fed rats. The usual picture in an animal receiving
thiouraeii is that of a greatly hypertrophied and hyperplastic
gland due to increased secretion of thyrotropic hormone. Thus
the decrease in thyroid weights could indicate a direct anta
gonism between vitamin A and thyrotropic hormone.
The only conflicting evidence is that presented by
Collazo and Rodriguez (1933). Young growing rats which were made
A hypervitaminotic with massive doses of A showed a loss of
weight and exophthalmos. As it has been suggested that ex
ophthalmos is probably due to an increased secretion of thyro
tropic hormone, this experiment would suggest a higher level
of circulating thyrotropic hormone in hypervitaminosis A*
V
Antagonism of thyroxine and vitamin A in lower forms
The effects of vitamin A with respect to its antagonism
to thyroxine has been studied using amphibia as test animals.
Gudematsch (1912) demonstrated that the metamorphosis of
tadpoles was dependent on the presence of the thyroid gland
and that metamorphosis could be hastened by giving thyroxine.
12
This has provided a convenient assay method for thyroactive
compounds. McCarrison (1923) found that cod-liver oil would
slow down the metamorphosis of tadpoles. Eufinger and Gott
lieb (1933, 1935} showed convincingly that vitamin A anta
gonized the growth-accelerating function of thyroxine in tad
poles. Carotene has been shown to retard metamorphosis in
axolotls but to exert no influence on the histology of the
thyroid (RoKhlina, 1939). similar effects have been noted
for the action of vitamin A on salamander larvae (Fleischmann
and Kann, 1936). Thus in amphibia at least, there seems to be
almost unequivocal evidence of a direct antagonism between
vitamin A and thyroxine.
Effect of vitamin A
on the basal metabolism of experimental animals
This effect has been studied extensively but owing
partly to the experimental difficulties of determining
basal metabolic rates of animals, the results are incon
clusive. Abelin (1935) found that the metabolism of rats
receiving thyroxine was decreased by vitamin A. Rappai
and Rosenfeld (1935) found that the metabolism of rats which
were injected with carotene and thyroxine was lower than
that of those injected with the same amount of thyroxine.
However, vitamin A had no influence on the basal metabolic
rate of rats which were already hyperthyroid.
Chevallier and Baert (1934) and chevallier (1936) showed
that vitamin A deficiency increased the basal metabolic rate
of rats and that large amounts of vitamin A decreased the oxy
gen consumption. This latter finding has been denied by Sher
wood, Toth and Carr (1934), Belasco and Murlin (1940) and sheets
and Struck (1942), However the latter authors noted that
after continued feeding of vitamin A to rats, subsequent
treatment with thyroxine resulted in a smaller increase in
oxygen consumption than with control animals that had re
ceived no extra vitamin A.
Other studies by Logaras and Drummond (1938) and Belasco
and Murlin (1940) showed a smaller increase in the oxygen con
sumption of rats injected with thyroxine and vitamin A when
compared with those injected with thyroxine alone, it was also
shown by Logaras and Drummond that vitamin A did not affect
the action of dinitrophenol. Smith and perman (1940), using
cats as their test animals, had similar results, in a recent
paper (Sadhu and Broda, 1947), vitamin A was demonstrated to
decrease the metabolic rate of thyroxinized rats, it is
interesting to note that as early as 1936, Stepp, Kuhnau
and Schneider in "Die vitamine" conclude on the basis of
evidence available at the time that vitamin A is a direct
antagonist to thyroxine. It should also be noted that there
has been much work on the reciprocal effect, the influence
of thyroid activity on carotene metabolism (Drill 1943, 1947).
14
It would seem from the work which has been reported
that vitamin A or carotene may exert its effect directly on
thyroxine without changing the response of the end-organs to
thyroxine. Animals which have been made hyperthyroid do not
show a lowering of the BMR when given high doses of vitamin
A or carotene, yet when the two are given simultaneously there
is a marked effect* This is partly borne out by the obser
vation of Abelin (1933) that a mixture of carotene and thy
roxine shows a gradual decrease in thyroxine activity.
The above results can be esqplained in still another way.
If vitamin A acts on the end-organs antagonistically to thy
roxine, then the effect of simultaneous administration of a
and thyroxine is clear. However, if the enzyme activity
which is reflected in the BMR had already been increased by
thyroxine, then it might be expected that vitamin A would
exert no effect.
• )
Clinical use of vitamin A
Clinically this effect of vitamin A has been utilized
in the treatment of thyrotoxicosis. Mellariby and Mellanby
(1921) reported that patients with exophthalmic goiter
showed a decreased BMR after treatment with cod-liver oil.
Wendt (1935, 1936) observed that patients with Graves*
disease responded well to administration of vitamin A and
manifested a decreased BMR. Fasold (1937) treated seven
15
girls who had adolescent goiter with vitamin a . There was
a regression of the goiter which reappeared when treatment
was stopped. Anderson and Soley (1938) reported that eight
of nine patients with carotenemia showed functional distur
bances of the thyroid gland. There have been other isolated
reports of carotenemia associated with hypothyroidism (Savy,
1939; Escamilla, 1942; Msndelbaum, Candel and Millman, 1942).
In this country, the use of vitamin A for treating hyperthyroid
patients has been rejected and the present trend in Europe,
according to Wegelin (1939), is to use vitamin A only as ad
junct to the classical forms of therapy.
1
Other effects of vitamin A
on reactions influenced by thyroxine
Von Euler and Klussman (1932) found that carotene would
partially prevent the loss of weight caused by daiHy injections
of thyroxine. This was confirmed by Fasold and peters (1933),
Abelin (1935), and sehneider and widmann (1935). However,
from the results of Fasold and peters (1933) and We slaw and
Wroblewski (1939), it seems that the prevention of loss of
weight is at least partly attributable to the solvent used
for vitamin A, since arachis oil and sesame oil alone exert
similar effects. Baumann and Moore (1939) did show a specific
effect of vitamin A. Their animals received thyroxine and
vitamin A, ate less and died earlier than those receiving
16
either alone. The significance of these findings is not
clear.
The effect of vitamin A on the Reid Hunt reaction has
been investigated. Both Fleischmann and Kann (1936) and
Wiesener (1939) observed that vitamin A antagonized the
protective action of thyroxine in the acetonitrile test on
mice.
The increase in the number of mitotic figures in liver
cells which is caused by thyroxine can be partially prevented
by vitamin A (Wegelin, 1939) • The fall in liver glycogen which
occurs as a result of thyroid feeding is prevented by vitamin
A (Abelin, 1935; Wegelin, 1939). Torbk (1938) noted that
vitamin A could temporarily prevent the lowering of serum
lipase caused by thyroxine. There have been various other
reports both affirming and denying the above effects (Drill,
1943).
*
Summary of results found in the literature
Vitamin A is undoubtedly concerned with certain phases
of thyroid metabolism. There is no great area of agreement
among workers in the field on any phase of its action. A
deficiency of vitamin A does seem to produce thyroid hyper
trophy, the gland being similar to that found in colloid
goiter. There are also degenerative changes caused by A
lack. There is possibly an antagonistic effect of vitamin
17
A to thyrotropic hormone. There is agreement as to the
effect of simultaneous administration of vitamin A and
thyroxine in reducing the increased oxygen consumption
caused by thyroxine alone. However, the effects of treating
hyperthyroid animals or humans with vitamin A are still
inconclusive. Specific antagonism of vitamin A and thy
roxine has been demonstrated in amphibia, but with mammals
the work has not been confirmed. The whole field, which
has been subject to only sporadic investigation, awaits a
well-controlled, systematic, long-term study.
CHAPTER III
STATEMENT OF PROBLEM
It has previously been shown that a deficiency of
vitamin A exerts a marked effect on the thyroid gland*
The purpose of this research has been to test the func
tioning of the thyroid gland of the rat in severe avita
minosis A.
CHAPTER IV
EXPERIMENTAL PROCEDURE AND METHODS
Plan of Experiment
The animals used were of mixed sexes from the stock
colony of the university of Southern California strain.
The dietary regime was such as to make the animals suitable
for use in the biological assay for vitamin A* The parents
were maintained for at least two months previous to breeding
and for 14 days after birth of the litter on Sherman diet B
(Sherman, 1924), without the addition of supplementary
lettuce or meat. Litters were reduced to 7 at 3 days of
age and on the fourteenth day, mothers and litters were
placed on a vitamin A low diet. This diet is the same as
the USF XII vitamin A deficient diet except that commercial
casein is used in place of alcohol-extracted casein. The
animals were weaned at 21 days and one group of 30 animals
was placed on the USP XII deficient diet from which the
potassium iodide had been omitted. The composition of this
diet is found in Table I. A second group of animals to be
used as controls was fed the same diet supplemented with 8
units of vitamin A per day given by mouth. A third group
of animals which was available at the time was maintained
on a diet which contained about 20,000 micrograms of caro
tene per kilogram. The iodine content of this diet was
not controlled.
K
TABLE I
20
Composition of the Diet
Casein-------------------------- 18%
Salt Mix ------------ 4
Yeast, dried 8
Starch ------------- 65
Coconut oil - -- -- ------ 5
Viosterol - - 3 gm. per Kgm. of oil
Mixed tocopherol esters - -
3 gm, per Kgm. of oil
Salt Mix
Ca citrate*4 M2O - 308.35 gms.
Ca(H2K>4>2*K20 ~ 112.76
K^P04----- 218.78
KG1 - - - ------- 124.76
H a d ---------------------- 77.08
CaC03 --* ------- 68.60
3 MgC03*Mg(0H)2*3 K20 - - - 35.17
MgS04 ----- 38.34
Trace elements mix ----- 16.16
Trace elements mix
Fe citrate USP XII ---- 95.06
M a F ------------- 3.13
MhS04’2 H20 -------------- I*24
KA1(S04)4*12 H2O --------- - .57
The iodine content of this diet is 16-17 micro
grams per kilogram.
21
After 25 days on the experimental diets the animals
were ready for use. o f the 30 animals on the vitamin A
deficient diet, 4 had died and the others showed xeroph
thalmia of vaiying intensity. The animals were then in-
no 1
jected intraperitoneally with tracer doses of I in
isotonic saline. Groups of 4 to 6 animals were sacrificed
at various intervals after injection and the distribution
of iodine in the gland studied, in a few cases, one lobe
of the thyroid was set aside for histological examination,
and the other lobe used for-analysis.
i
Determination of radioactivity
The experiments described here were carried out using
radioactive iodine, I13i. This isotope of iodine has an
atomic weight of 131; the stable isotope has an atomic weight
of 127. is made by deuteron bombardment of tellurium
as shown by the following reactions
- . H '
The J^l so formed is a and ' f emitter with a half-
life of 8 days. It decays to the stable isotope of xenon;
^ V /3/
T --- ^ -,Ae + e
S T a . sy ~ i
The emitted electrons have a maximum energy of 0.7
million electron volts (Mev). This means that about 60%
of the electrons have energies of emission of 0.35 Mev. or
less. It should be noted then that self-absorption is a
22
factor of importance in the counting of the electrons from
ji31. por this reason, the total solid content in the dried
sample never exceeded 10 mgm. previous testing had shown that
up to 25 mgm. of solid could be deposited without affecting the
number of counts. For this work, the samples to be counted
were deposited on a flat tin ointment dish and dried. The
dish was then placed on a mounted carrier beneath the tube,
so that all samples were counted in the same position.
The counting device used was a Geiger-Muller tube filled
with tetraethyl lead. The counter permitted the choice of
scales ranging from 2 to 64. Most of the work reported here
was done using a scale of 64. The number of counts in the
samples ranged from 1000 to 10,000 per minute. The background
reading was constant at 50 counts per minute. The counting
efficiency was 2.65%. Thus only 2.65% of the number of dis
integrations were measured using this particular system.
The iodine solutions which were used contained no
chemically detectable iodine. When a solution of this type
was injected, the circulating iodine was ' ’labeled'.’ without
any appreciable change in its concentration.
I
23
Separation and Analysis
of the various thyroid fractions
This, procedure follows closely that described by perlman,
Chaikoff and Morton (1941a). The animals were injected intra-
peritoneally with a tracer dose of about 50 microcuries of
jl31 in isotonic saline. After varying periods of time, the
animals were chloroformed and weighed; the thyroids were
carefully excised, trimmed, and weighed to the nearest tenth
of a milligram. The glands were then placed in 2 ml. of 2N-
NaOH and hydrolyzed in a boiling water bath for 15 hours.
After hydrolysis, the contents were made up to 25 ml. and
suitable aliquots taken for determination of each fraction.
Total iodine— Five ml. of the hydrolysate were added
to the digestion mixture consisting of 2 ml. of 50% chromic
acid and 25 ml. of 70% H2SO4 in a 125 ml. Erlenmeyer flask.
About 100 mgm. of casein were added plus a few porcelain
chips to promote smooth boiling. The samples were heated
on a hot plate until fuming occurred. They were then allowed
to cool sufficiently so that 15 ml. of water could be added.
They were then reheated until filming began.
The samples were next transferred quantitatively to a
two-necked distilling flask, using 25 ml. of water. The
distillation procedure is that of Taurog and chaikoff (1946a).
It was found necessary to use a few drops of 30% H2O2 when
adding the phosphorous acid in order to completely release
24
all the iodine. The distillate was made up to 15 ml. and
3 ml. samples taken for determination of radioactivity.
Fractionation of thyroid iodine— The thyroid hydrolysate
was separated into 3 iodine containing fractions using
essentially the same procedure described by perlman, Morton
and Chaikoff (1941b). Butyl alcohol was. used for the
separation of thyroxine and diiodotyrosine, inorganic
iodide remained in the water layer throughout.
Ten ml. of the alkaline thyroid hydrolysate in a
50 ml. centrifuge tube were adjusted to pH 3.5-4 with 4u HCl
using brom-cresol green indicator. This was then vigorously
shaken with butyl alcohol and centrifuged. After centri
fugation the water layer was removed using a syringe and a
15 gauge needle. The syringe was rinsed once, the rinsings
added to the original water layer. This water layer was then
reextracted with 10 ml. of butyl alcohol. After separation,
the two butyl alcohol layers were combined. The butyl alcohol
now contains all of the thyroxine and most of the diiodotyrosine.
To the alcoholic extracts were added 2 ml. of .OlM KI
and 15 ml. of Blau's reagent (4n WaOH + 5% Fa2C03>« They were
then shaken thoroughly, the layers separated by centrifugation,
and the alcohol layer reextracted using 10 ml. of Blau«s
reagent. The 2 aqueous alkaline washings were combined with
the aqueous residue from the first extractions with butyl
alcohol. The water solution now contains the inorganic iodide
25
and diiodo tyro sine. Thyroxine alone is present in the butyl
alcohol.
Thyroxine— The butyl alcohol extracts were transferred
to a two-necked distilling flask and concentrated to dryness
under reduced pressure in a water bath at 70°C. The residue
was digested and distilled as described above and the radio
activity in the thyroxine fraction determined.
inorganic iodine— The combined aqueous extracts were
made acid with K2SO4. One ml. of .0211 KIO3 was added, the
solution shaken, and the resulting iodine extracted 3 times
with 10 ml. portions of 0014* The CCI4 containing all of
the inorganic iodine was then twice extracted with 10 ml. of
•OlF W&gSJBOs* Throughout these extractions, centrifugation
was used to effect complete separation of the layers, ah
aliquot of the thiosulfate solution was made alkaline and
dried for determination of radioactivity.
Diiodotyrosine— The remaining aqueous layer which now -
contains only diiodotyrosine was made up to 100 ml. and 20 ml.
taken for analysis. This was digested with 3 ml. of 50%
chromic acid and 25 ml. of 70% H2S04* The solution was then
distilled and total radioactivity determined.
Checks of the method
To determine the reliability of the methods used, the
following tests were made?
(1) Samples of diiodotyrosine containing i^3! prepared
by the exchange reaction of Miller et al (1944) were digested
and distilled. Recovery was 9214%.
(2) i^-3^ and were added to desiccated thyroid and
carried through the hydrolysis and separation. The j-^-L was
recovered quantitatively as inorganic iodine.
(3) Radioactive diiodotyrosine was added to desiccated
thyroid and carried through the hydrolysis and separation.
Amounts varying from 4 to 7% were found in the inorganic
fraction, but none appeared in the butyl alcohol layer.
(4) Radioactive thyroxine, prepared by Mr. Earl prieden
of this laboratory, was added to desiccated thyroid and
carried through the hydrolysis and separation. A similar
loss of iodine occurred, an average of 5% appearing as in
organic iodine. There was no radioactivity in the diiodo
tyrosine fraction.
It can be seen that the results reported tend to give
a slightly higher inorganic iodine fraction due to the break
down of thyroxine and diiodotyrosine. Because of the correction
value which had to be applied whenever distillation was used,
the values for thyroxine and diiodotyrosine are uncertain to
about i5% of the reported value.
CHAPTER V
DISCUSSION OF .RESULTS
Weights of the thyroid glands
As can'be seen from Tables II and III, the thyroid
weights in the A-deficient animals, when expressed as a
fraction of the body weight, are significantly higher than
the controls. This, of course, only confirms what has pre
viously been reported in the literature. However, the sex
difference which has been reported by Coplan and Sampson
(1936) was not corroborated in this work.
Histology
The thyroid glands of two control and two A-deficient
animals of each sex were examined histologically. The glands
from the control animals were essentially normal; although,
by comparison with other rats in the stock colony, the follicles
seemed slightly enlarged. This was probably due to the re
latively low iodine diet used, in the A-free rats, some areas
of the gland presented the typical picture of colloid goiter,
while other areas showed degenerative changes, in the goitrous
parts of the gland, the follicles were distended and the epi
thelial cells flattened, in the few glands which were studied
there was no noticeable sex difference.
TABLE II 28
Thyroid weights of control animals
i
Body Thyroid Thyroid weight
Rat Weight Weight (ragm./lOO gins, of
Ho. Sex (gms.) (mgm.) Body Weight
61 female 76 7.8 10.3
62 male 84 9.4 11.1
63 female 79 9.5 12.0
64 male 79 10.7 13.5
71 male 101 11.0 10.9
72 male 85 8.1 9.5
73 female 71 9.2 12.9
74 female 80 8.1 10.1
75 female 80 10.1 12.5
81 female 72 9.3 12.9
82 male 83 9.6 11.5
83 male 86 8.5 10.5
84 female 73 9.3 12.7
Group average 11.6*1.1
Average, females 11*9*1.1
Average, males 11.2i0.8
29
TABLE III
Thyroid weights of A-deficient animals
s
Body Thyroid Thyroid weight
Hat Weight Weight (mgm./lOO gms.
No. Sex (gms.) (njgm.) of Body weight)
11
male 65 8.5 13.1
12 male 61
13 female 60 13.0 21.7
14 female 53 7.7 14.5
21 female 73 9.0 12.2
22 male 83 13.7 16.5
23 male 48 11.5 24.0
24 female 85 22.4 26.4
31 female 68 11.5 16.9
32 male 82 16.7 20.4
33 male 62 12.0 19.4
34 female 73 23.5 32.2
35 female 57 9.7 17.0
41 female 82 8.7 10.6
42 female 49 9.0 18.6
43 male 78 12.4 15.9
44 male 57 18.0 31.6
45 female 74 14.5 19.6
46 male 68 19.2 28.7
51 male 90 22.4 24.9
52 female 71 21.1 29.7
53 male 79 18.8 23.8
54 male 67 14.2 21.2
55 male 82 22.5 27.4
56 female 72 19.5 27.1
57 male 74 19.3 26.1
Group average 21.6*5.1
Average, females 20.5±5,7
Average, males 22.514.4
TABLE IV
30
Thyroid iodine distribution in control animals
per cent of administered I3- 31 per cent of total
recovered in thyroid _____ thyroid I3- 31 found
Total as as Total as as
Hours det»d as Diiodo- inor- Reco- as Diiodo-lnor-
after in Thyro- tyro- ganic very Thyro- tyro- ganic
inj ec-Rat gland xine sine iodine 2+3f4 xine sine iodine
tion no. (1) (2) (3) (4) (5) (7) C3) (9)
4 1
2
3
4
AV.
14.9
20.8
15.5
12.2
“IS'.'S
2.26
1.85
1.78
16.2
11.4
8.6
2.31
2.20
1.86
ai*o
i
lsua
10.9
11.9
14.6
“ISIS
78.0
76.8
69.9
11.1
14.2
15.2
13.5
18 11
12
13
14
AV.
16.1
12.0
12.9
15.9
14.2
3.59
2.10
2.49
3.01
22.3
17.5
19.3
18.9
19.5
24 21
22
23
Av.
24.8
23.6
23.0
1 53.8
6.63
5.10
2.35
15.4
13.1
17.1
2.34
2.88
1.73
24.4
21.1
21.2
29.4
21,6
10.4
.20.5
62.2
55.5
74.3
9.4
12.2
7.5
"1577
36 31
32
33
34
35
AV.
16.4
13.2
15.1
17.5
13.4
.'3571
4.30
3.08
3.49
4.83
2.87
26.2
23.3
23,1
27.6
21.4
24.4
48 41
42
43
44
19.5
16.5
14.8
19.4
5.63
4.07
3.74
3.06
9.0
7.9
8.7
13.7
1.68
2.16
1.10
1.54
16.3
14.1
13.5
18.3
28.9
24.7
25.3
15.8
46.2
47.8
58.7
70.7
8.6
13.1
7.4
7.9
Av. 17TB
5375 ' 9.3
72 51
52
53
54
16.3
18.9
11.9
14.7
4.32
3.93
2.55
3.62
26.5
20.8
21.4
24.6
AV. "ir.'B
23.3
TABLE V
31
Thyroid iodine distribution in A-deficient animals
Hours
after
injec-Rat
tion no.
per cent of administered I131
recovered in thyroid______
Total as as Total
det*d as Diiodo- inor- reco
in Thyro- tyro- ganic very
gland xine sine iodine 2+3*4
(1) (2) (3) (4) (5)
per cent o;
thyroid
’ total
1 1 found
as as
as Diiodo-Xhor-
Thyro- tyro- ganic
xine sine iodine
(7) (8) (9)
4 61 18,3 1.51 15.0 1.57 18.1 8.25 82.0 8.6
62 15.4 0.50 12.8 1.00 14.3 3.25 83.3 6.5
63 26.7 0.79 21.1 3.50 25.4 2.96 79.2 13.1
64 10.6 0.71 6.6 2.17 9.5 6.70 62.3 20,5
Av, "17.fi • 5,3 12.2
3 71 24.4 0.64 20.2 3.14 24.0 2.62 82.8 12.9
72 17.5 0.72 14.7 3.04 18.5 4.12 84.1 17.4
73 22.6 1.15 17.9 3.16 22.2 5.08 79,3 14.0
74 19.8 0.90 14.4 4.83 20.1 4.55 78.8 24,4
AV, 21.1
•4.T 1 " 1: 7.2
24 81 20.0 1.97 13.7 3.63 19.3 9,83 68.5 18.2
82 14.3 1.34 9.1 2.74 13* 2 9.30 63.7 19.1
83 20.6 3.23 16.4 5.62 26.3 15.7 79.7 27.2
84 16.5 0.91 6.9 6.65 14.5 5.5 41.8 41.3
85 13.4 1.25 8.5 3.03 12.8 9.3 63.4 22.6
AV. “T77G
9.3 25.7
48 91 17.3 2,66 10.4 4.06 17.1
15.4 60.2 23.5
92 21,7 3.27 12.7 4.82 20.8 15.1 58.6 22.2
93 25.3 • 5.67 15.8 4.58 26.1 22.2 62.4 18.1
94 18.3 3.48 6.3 6.65 16.4 19.0 34.4 39.9
95 31.0 6.26 15,6 7.24 29.1 20.2 50 . 3 23.3
96 18.5 3.28 9.5 4.02 17.8 18.0 51.3 21.7
Av. 22.0
"TS73
"'"SITS
96 101 11.3 2.57 3.8 3.48 9.9 22.7 33.9 30.8
102 7.2 0.94 4.2 1^53 6.7 1.3 58.3 21.3
103 8.6 1.05 5.7 1.65 8.4 12.3 66.3 19.4
104 10.9 1.58 7.3 2.31 11.2 14.5 66.8 21.2
105 26.4 3.08 18.0 3.70
24.8 11.7 68.3 14.0
106 10.3 1.48 7.3 0.96 9.7 14.3 70.9 9.3
107 11.3 1.36 5.4 4.07 10.8 12.0 47,8 36.0
AV. 12.3
12.7 .'5177
I
32
TABLE VI
Thyroid iodine distribution in high a animals
Hours
after
inj ec-Rat
tion no.
per cent of administered
recovered in thyroid______
Total as as Total
det'd as Diiodo- inor- reco
in Thyro- tyro- ganic very
gland xine sine iodine 2+3f4
(2) (3) (4) (5)
per cent of total
thyroid x131 found
as as
as Diiodo-inor-
Thyro- tyro- ganic
xine sine iodine
C7) (8) (9)
4 111 16.0 1.91 1.73 11.9 10.8
112 19.3 2.22 2.45 11.5 12.7
Av. 17'.7 11.7 11.8
24 113 15.0 4,31 2,14 28.7 14.3
114 23.8 5.53 1.32 23.2 11.4
115 21.5 4.38 1.85 20.4 8.6
AV. 20. i
"24.1 .11.4
48 116 18.7 4.53 1.72 24.2 9.2
117 13.6 4.58 1.01 33.7 7.4
118 10.2 3.20 0.78 31.4 7.6
Av. 14.2 '29.8 8.1
P C S C C N T T O T A L THTSOID IO D IN E F O U N O A S T H TR O X IH E I0DISC
33
FIGURE I
2 5 -
a -
M -J
LEGEND1
X -V IT .A OGFIClCKT ANIMALS
0 - CONTROLS* NORMAL ANIMALS
2 0 30 ¥ O SO 40
H O URS AFTER INJECTION OF RADIOIOOINE
TO 80 TO
/
FISURf n
LEGEND1
X -Y IT A M M A DEFICIENT ANIMALS
o~ .... NORMAL ANIM ALS
30 ¥0 50 l
H O URS AFTER INJECTION OF RADIO IODINE
S O t o 70
— 7 .
34
Iodine uptake and distribution
As the injected iodine in these experiments was present
in tracer amounts, it served to label the animals* circu
lating iodine. Thus the distribution of the I131 reflects
the movement of the circulating iodine.
Column (1) in Tables iy, V, and VI shows the uptake of
iodine by the thyroid gland at various intervals after in
jection, expressed as percentage of the injected dose, it
can be seen that these results indicate no difference in the
rate of uptake in the three groups* At twenty-four hours,
there was a maximum of i^-SO- present in the gland.
Thus severe avitaminosis A does not seem to affect the
activity of the gland in "trapping” iodine. It is possible,
though, that the goitrous areas of the glands of the A-free
rats picked up iodine faster than normal and so compensated
for the areas in which there were degenerative changes.
\
Conversion of inorganic iodine to organic iodine
Figure I is the graph of the values tabulated in column
(9) of Tables IV and v . The curve which is obtained for the
inorganic iodine fraction in the thyroid of the control ani
mals is very similar to that obtained by other investigators.
The inorganic iodine in the thyroid reaches a maximum of
about 15% of the total thyroid iodine within four hours after
35
injection and then rapidly drops to an almost constant value
of about 9% of the thyroid iodine. The A-deficient animals,
on the other hand, show a rising inorganic iodine fraction
which reaches its maximum of 25% of the thyroid iodine at
about the same time at which the total iodine in the thyroid
is maximal. There is then a very gradual fall of the in
organic fraction instead of the rapid drop found in the controls.
These differences are very striking when it is realized that
the same percentage of the injected was picked up by
the thyroid gland in each group of animals. These results
can only be interpreted by assuming that the thyroid gland
in severe avitaminosis A is unable to convert inorganic
iodine to organic iodine as rapidly as the normal gland.
The animals which were on a high A diet showed a similar
uptake and subsequent rapid fall of inorganic iodine as was
obtained in the controls. The variations from the values
obtained with the control animals were not significant, but
the values for inorganic iodine tended to be lower than in
the controls. Thus, if a high A diet exerted any effect on
thyroid function in this experiment, it would seem to speed
up the conversion of inorganic iodine to organic iodine.
36
Rate of formation of thyroxine
In the control animals, the I131 of the thyroxine
fraction in the thyroid reached its maximum at about twenty-
four hours after injection. There was subsequently a slow
fall, a value of 23% of the total thyroid iodine being at
tained at 72 hours. This is shown in Figure II which is a
plot of the values in column (7) of Tables IV and V*
With the group of A-deficient animals, the values for
per cent of total thyroid iodine found as thyroxine iodine
were lower at all points than the corresponding values for
the control animals. The difference here is not as striking
as the difference in the per cents of inorganie iodine. How
ever, there is a significantly lower rate of formation of
thyroxine in the A-free rats and a decreased final level at
ninety-six hours, it is impossible to tell whether the lack
of vitamin A hindered the conversion of inorganic iodine to
diiodotyrosine, of diiodotyrosine to thyroxine, or both.
With the group of high-A animals, the values for the
thyroxine fraction were higher than in the control animals.
However, owing to the limited number of animals used, it
cannot be stated that there is a positive effect of vitamin
A on the formation of thyroxine. The values obtained only
tend to suggest this possibility.
CHAPTER VI
SUMMARY
The functioning of the thyroid gland of the rat was
investigated in severe avitaminosis A> using radioactive
iodine as a tracer. The following results were obtained;
1) in vitamin A deficiency, the thyroid glands of
the rat were relatively heavier than in control ani
mals
2) The histological picture of the thyroid glands of
A-deficient animals showed degenerative changes and
distended follicles present within the same gland.
3) vitamin A deficiency did not alter the capacity
of the thyroid gland to concentrate iodine.
4) vitamin A deficiency markedly decreased the rate
of conversion of inorganic iodine to organic iodine.
5) Vitamin A deficiency decreased the rate of
formation of thyroxine.
CHAPTER VII
SUGGESTIONS FOR FURTHER WORK
The effects of single or multiple vitamin deficiencies
on the thyroid gland have been investigated using the weight
and histology of the gland as a criterion of function. With
the methods just outlined, it is possible to determine at
what points in thyroid function a particular vitamin exerts
its effect.
The particular problem which has been studied here
could be continued and expanded, it would be interesting
to test thyroid function in avitaminosis A when thyrotropic
hormone, goitrogens, or both were administered. The maximum
amount of information could be secured by the simultaneous
histological study of the gland and the testing of its
function using radioactive iodine as a tracer. This would
further clarify the role of vitamin A in the physiology of
the thyroid gland.
Acknowledgement - The author wishes to thank Dr.
Barbara Granger for the histological studies of the thyroid
glands and for her assistance in interpreting these findings.
Thanks are also due to Mr. Solly Bemick for the preparation
of the slides.
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Asset Metadata

Creator Lipsett, M. B (author)

Core Title Effects of vitamin A deficiency on thyroid function studied with radioactive iodine

Contributor Digitized by ProQuest (provenance)

Degree Master of Science

Degree Program Nutrition

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag health sciences, nutrition,OAI-PMH Harvest

Language English

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c17-775667

Unique identifier UC11348414

Identifier EP41284.pdf (filename),usctheses-c17-775667 (legacy record id)

Legacy Identifier EP41284.pdf

Dmrecord 775667

Document Type Thesis

Rights Lipsett, M. B.

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA