Reaction to iodine of goiters from a goiter area

REACTION

TO IODINE

OF GOITERS FROM A GOITER AREA* FREDERICK A.

COLLER,

ANN

M.D. AND ARBOR,

A

STUDY of the recent Iiterature on the reaction of goiter to iodine shows striking differences of opinion concerning the theory of its action and aIso as to facts of observation. Some of the differences of observation may possibIy be expIained by variations of environment and for purposes of comparison a study of the reaction of iodine and goiter in Michigan has been made. Michigan lies in the Great Lakes goiter beIt and has had carefu1 goiter surveys made by the Michigan State HeaIth Department. It was shown that the iodine content of the water varied from a mere trace in the region adjacent to Lake Superior to 880 parts to IOO biIIion in the southern part of the state. The incidence of goiter was inverseIy proportiona to the amount of iodine in the drinking water. Since 1924 an iodine saIt containing I part of sodium iodide to 5000 parts of tabIe saIt has been soId throughout the state and its use varies in different communities from 50 per cent to 95 per cent of a11 the tabIe salt. It is estimated that each aduIt using this salt gets about 400 mg. of iodine per year. For purposes of study a group of patients with hyperthyroidism treated by operation during a period in 1928 was seIected. These were divided into two groups according to the pathoIogica1 findings in the goiter, exophthaImic goiter and adenomatous goiter. AI1 goiters with mixed findings, that is otherwise typica exophthaImic goiter but with adenomas, were excIuded. AI1 case histories were then gone over and any case not seeming to faI1 cIearIy into our cIinica1 conception of these two types was excIuded. AI1 patients were questioned about the use of iodine and any having had

EUGENE

B. POTTER,

M.D.

MICH.

recent iodine medication were also excIuded from consideration. As a resuIt of this seIection, 128 cases of exophthaImic goiter and 50 cases of adenomatous goiter with hyperthyroidism were chosen, this representing the cIinic ratio of these groups. AI1 patients were given the same amount of iodine daiIy, as I C.C. of compound soIution of iodine (LugoI’s soIution), this dosage being the one used by other cIinics with which we wished to estabIish a comparison. We wished to determine: I. A comparison of the reaction of exophthaImic goiter to that in a non-goiter area. 2. A comparison of the reaction of exophthaImic goiter and of the adenomatous goiter. 3. Facts regarding the reaction of the adenomatous goiters. I. REACTION The

genera1

abIe influence

OF

EXOPHTHALMIC

facts of iodine

regarding

the

GOITER favor-

on the preoperative

postoperative course of this disease are we11 estabIished and our experience is in perfect accord. The effect of the iodine response was measured in terms of basa1 metaboIism, whiIe the cIinica1 improvement and histoIogica1 changes were typica of those described by many observers. An endeavor was made to have at Ieast two or more pre-iodine metaboIic rates but this was impossibIe in certain sick patients in whom the earIy use of iodine was a necessity and in these patients onIy a singIe pre-iodine metaboIic rate was obtained. As a consequence the study is not absoIuteIy accurate but since a11 data were coIIected under about the same conditions, we fee1 that it represents a fair and

* From the Department of Surgery, University Hospital, University of Michigan, Ann Arbor, Mich. Read the AnnuaI Meeting of the American Association for the Study of Goiter, Dayton, March 25-27, 1929. 009

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estimate of the reaction of exopthaImic goiter in the cIinic to iodine. The data are shown in Figure I. For purposes of comI

1

I

I

I

I

I

II

MAY, 1929

decIivity of the curves is in genera1 reIated to the initia1 height; the greater the initia1 basa1 metaboIic rate, the sharper the drop. NO.

IxGoitcr

BMR[

to Iodine

of Cases

32 28'

NO. OF CASES

24' 20, 16' 12' 8

4 2px I

I

2

4

I 6

I 8

I 10

II 12

14

I 16

18

DAYS UFLUGOL~ FIG. I. Responses to iodine in exophthaImic goiter. Average basa1 metabobsm before compared with that after iodine is used. Abscissae represent average time required for response. 128 cases divided into groups according to pre-iodine metabolic rates, each IO point rise defining a group. Solid Iines represent Michigan series. Dotted Iines copied from Means’ study of a simiIar number of cases. Number of cases refers to our group.

parison we chose the report of Means et aI.’ of a study of the iodine reaction in 128 cases of exophthaImic goiter from Massachusetts, a non-goiterous area on the seacoast. A comparison of the drop in the basa1 rate in the two series is shown graphicaIIy in Figure I. In our series as in his the TABLE I TABULAR COMPARISON OF REACTIONSOF TWO SERIES EXOPHTHALMIC GREATER

GOITER RESPONSE

TO

IODINE,

IN MEANS’

SERIES

B.M.R. FOLLOWING IODINE Group by Means Series

B.M.R.

70-80 60-70

34+ 24+ 26+

50-60 40-50 30-40 20-30

24+ 18+ I5f I7+

80-90

%

1?resent Series -_-

Days

1 10 ~ 10

38+ 48+ 4of 39f

IO 10

Days

8

-

I7+

_.*

LJ1tference

14 14

4 24 I4 15

12

I2

I7

~ ~

:

)

OF

SHOWING

1

I2

16 IO

8

1.

0

30%

J

FIG. 2. Comparison of severity of cases in each series showing number of cases in each IO point division of pre-iodine basa1 metabolism. Michigan series black, Means series unshaded.

There are two main differences noted. First, a Ionger period of time is necessary in our series to reach a base Iine and, second, the faI1 in basa1 metaboIic rate is not as great. This is shown in TabIe I, in which one can see that the faI1 of basa1 metaboIic rate in Means’ series is greater in a11except the Iowest group, the others dropping from an average of 4 to 24 points more than corresponding groups in our series. Since the tota number of cases in the two series is the same, a comparison between the severity of the cases can be made and this is shown in Figure 2. There is a sIight preponderance in our series in the groups with a high basa1 metabolic rate. In the tota number of our series 14, or I 1.7 per cent, were refractory and did not react favorabIy to iodine in that there was no change in the basa1 metaboIic rates after the ingestion of the amounts of iodine given to the others. These were not given Iarger amounts of iodine but were treated by operation without the occurrence of thyroid crises which was thought to be due to the iodine aIthough it did not cause any marked preoperative drop in

CoIIer & Potter-Reaction

NEW SERIESVOL.VI, No. 3

basa1 metaboIic rate. The occurrence of these cases in any group causes a ffattening of the decIivity and Iengthening of the BMR

ADENOMATOUS CfOITER I I I I I

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American Journd or surgery 61 I

AI1 of the cases in this group were operated upoti without mortaIity and very few were operated upon by fractiona BMR

I

80

NO. OF CASES

80

to Iodine

70 60 50 40 30 20

lo-

I 2

I

I

I

I

6 6 10 4 DAYS OF IODINE

1

12

I

14

I

16

18

FIG. 3. Response to iodine in adenomatous goiter with hyperthyroidism. Average basa1 metabolism before compared with that after iodine is used. 30 cases divided into groups according to pre-iodine basa1 metabotism rates, each IO point rise defining a group.

curve and may partiaIIy account for these differences in the two series. From these observations we can state that our series of cases of exophthaImic goiter reacts Iess activeIy and arrives at a base Iine more sIowIy than a series of simiIar cases from a non-goitrous area. It may be thought that the use of an iodized tabIe saIt has produced an iodine refractory state in the goiters from this area but it is our impression that this same condition existed in the year prior to the adoption of the genera1 use of the iodized saIt when iodine was used in the preoperative treatment of goiter. UnfortunateIy such a comparison of the iodine reaction before and after the use of iodized saIt cannot be made on any worth whiIe scaIe since frequent basa1 metaboIic determinations were not made in our cIinic during that time. It is not a matter of great practica1 importance to the patient since the use of iodine causes enough improvement to make operation safe and aboIishes postoperative crises.

FIG. 4. Curves of basa1 metabolic rates in cases of adenomatous goiter with hyperthyroidism (1-8 inc1.). Dots show basa1 metabohc determinations. VerticaI Iine marks beginning of iodine.

methods. In none was Iigation done and in IO cases hemithyroidectomies were done at intervaIs. II.

REACTION WITH

OF

ADENOMATOUS

HYPERTHYROIDISM

GOITER

(TOXIC

ADENOMA)

This group of 30 cases entered the hospita1 during the same period of time as did the group of exophthaImic goiters. As stated they incIude onIy cases having a11 the pathoIogica1 and cIinica1 attributes of the typica adenomatous goiter. Many of them had the common cardiac compIications of this disease. AI1 of them were given rest in bed from seven to forty days before iodine was given. In most instances severa basa1 metaboIic rates were taken before and after the administration of iodine. The cases vary greatIy in the duration of their hospita1 stay due to differences in severity of disease, and to socioIogica1 and financia1 considerations. In determining the effect of iodine we have estimated as cIoseIy as possibIe the average basa1 metaboIic rate after bed rest, to compare with the rate after the administration of iodine. The Iength of time of

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iodine administration varied greatIy in that we were obIiged to operate upon those patients earher who were in fit condition BMR

1 1 ’

I

’

I

1 .I

’

I

1 1 ’

I

I

I

’

60

to Iodine

hl.&u. ,920

with Figure I. The decIivity of a11 the curves is Iess than in the exophthalmic goiter group and do not show the uniform BMR‘I

11

’

1 I

I

11

I

I

I

I

1 I

I

I

80I

70 t

't

70

I

00

12108 6+2 Bed

2 4

8 8 10 12 1416 1820 Days IO&ho

FIG. 5. Curves of basal metaboIic rates in cases of adenomatous goiter with hyperthyroidism (g-16 inc1.); g and 13 show very favorabIe response.

for it and keep for longer periods of time those who had cardiac or other complications. WhiIe the study is open to criticism in that perfectIy even IeveIs were not reached either before or after the use of iodine, it offers a fair comparison with the group of exophthaImic goiters which was treated under simiIar conditions. TABLE II COMPARISON IN

128 CASES

OF FALL CASES OF

IN BASAL

OF

METABOLISM

EXOPHTHALMIC

ADENOMATOUS

GREATER FALL IN

ALL

IN

GOITER. ONE

70-80

40-50 30-40 20-30

GOITER

with Iodine

o

’

16

I

~ 20

18

~

I

I4 12

:;

';

I4 10

IO

IO

3

II

1

‘5 14

+z

27 18 ;

/

7

The average reactions of this group to iodine are shown in Figure 3 for comparison

5 10 15 20 25 30 35 4!0 Day&dine

FIG. 6. Curves of basa1 metabolic rates in cases of adenomatous goiter with hyperthyroidism (17-24 inc1.). This group were under observation Ionger periods of time. 17 shows unfavorable response.

downward trend. In one group there is actuaIIy an appreciabIe upward curve. In TabIe II is shown the average figures of these two groups, showing the faI1 in basa1 metaboIic rate with the adenomas is much Iess in a11 except one group. Of a11 adenomas 23, or 46 per cent, were not affected favorabIy by iodine, contrasting with the I 1.7 per cent of the exophthaImic goiters with the same Iack of reaction. This factor was chiefly operative in flattening the decIivity of the curve in the adenoma group. III.

I2

27

117

50

GROUP

1

25 15

IODINE

AND

SHOWlNG

EXOPHTHALMIC

EXCEPT

FaII of B.M.R.

60-70 50-60

WITH

GOITER

3.5 30 7.5 20 15 10 5 Becl

OBSERVATIONS

ON

THE

ADENOMAS

In Figures 4 to 7 are shown the actua1 curves before and after the use of iodine in 32 adenomas chosen as representative members of this group with varying periods of rest in bed and of days of iodine use. The striking fact about these reactions in genera1 is the Iack of uniformity of type. The initiaI metaboIism is usuaIIy much higher than subsequent determinations showing the faIIacy of regarding soIitary observations as of great Importance. A

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remarkabIe improvement is noted with rest aIone in many cases but severa patients had a rise in rate after rest in bed. Sturgis* has pointed out that it takes severa weeks of rest and famiIiarity with the test to arrive at a stabilized basa1 metabolic rate in cases of exophthaImic goiter and there may be Auctuations of metabolism of as much as 23 per cent from day to day. These facts make one doubt the absoIute accuracy of any series of observations made over short periods of time and make their vaIue onIy relative. A number of cases reacted brilIiantIy to iodine and interestingIy enough onIy 4 cases were actuaIIy made worse by iodine. In several cases iodine was given from thirty to forty days without production of any iodine hyperthyroidism either in cases with origina improvement from its use or in those that had remained unimcases remain proved by its use. Other perfectIy unchanged by iodine. One must concIude from these observations that one cannot prophecy what the effect of iodine is going to be in any given case of adenomatous goiter with hyperthyroidism since it may vary from striking improvement, to no action, to marked increase in symptoms. Rest in bed aIone causes a great improvement in many cases but may have no effect on others. COMMENT

There is a difference of opinion as to whether adenomatous goiter with hyperthyroidism and exophthaImic goiter are two separate diseases. It has been commonIy believed that whiIe iodine has a beneficia1 effect on exophthaImic goiter it has a harmful effect on adenomas. Those who believe that fundamentaIIy the diseases are one have attempted to show a simiIarity of response to iodine in the two conditions. Those who beIieve them to be separate entities state that iodine given to adenomas wiI1 cause iodine hyperthyroidism and increase the severity of the disease. There are two commonIy accepted theories as to the mode of action of iodine,

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that of PIummer3 in which exophthaImic goiter is regarded as a dysthyroidism that is converted to a pure hyperthyroidism BMR

11

11

11

1

I I 1 I I I I I I

80-

JO

23

12% 27

2

29

30 20 40

0

32

I I I I I I I

1412108

Bed

7. Curves adenomatous inc1.).

FIG.

7642

I

I I I I I I I I I )

2 4

6 8101214l61620

Days ofkdine of basa1 metabotic rates in cases of goiter with hyperthyroidism (25-32

by the use of iodine, and that of Marine4 who regards the rapid distention of the aIveoIi with coIIoid as causing a pressure retention with temporary bIocking of excretion which is soon compensated for, with a return of symptoms. It has been asserted that differences in reaction of exophthaImic goiter and adenomatous goiter to iodine prove them separate disease entities and it has aIso been asserted that simiIarities of reaction prove them identica1 disease entities. CertainIy the distinction between or simiIar identity of those conditions need not rest on these reactions to iodine. Without entering the controversy, which is of onIy academic interest, if one regards them as the same disease they are markedIy different phases of it, with pathoIogica1 changes in the adenomas that have taken years to form and in the exophthaImic goiter that may occur in a few weeks. On the basis of our findings we are unabIe to agree with those who assert them to be identica1 because of simiIar reactions to iodine. There is a uniformity of reaction in the exophthaImic goiter

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that is Iacking in the adenomas. The adenomas may react as favorabIy as exophthaImic goiter but many react unfavorabIy and others not at aI1, and no one can foreteI1 what the reaction wiI1 be. It is possibIe that Iarger amounts of iodine might have aItered the type of reaction but for this study we feIt it necessary to use a constant amount in a11 cases. They may be reIated cIinica1 entities but their reactions to iodine do not seem paraIIe1 enough to warrant this assumption on this point aIone. Longer and more carefu1 studies of these reactions are necessary before we may be dogmatic. On the other hand we have observed but few cases of adenomas in which it appeared that harm was done by the use of iodine even if taken over periods of thirty to forty days and we fee1 that the dangers of inducing iodine hyperthyroidism or of increasing the severity of the disease are not great with patients -under observation. That iodine hyperthyroidism does occur there can be no doubt since such cases are seen not infrequentIy, usuaIIy due to the unwise use of LugoI’s soIution, and we fee1 that iodine has no part in the non-operative treatment of adenomas but used as a preparation for operation it may be of great benefit and wiI1 not do harm if the patients are cIoseIy watched. Since the introduction of iodized saIt we have watched for evidence of iodine hyperthyroidism that couId be ascribed to a use of the product and whiIe an occasional patient is seen who believes such to be the case we have not been convinced that we have seen a singIe instance of hyperthyroidism due to the use of iodized tabIe saIt. This statement is of interest because of the rather widespread criticism of this method of giving iodine, on theoretica grounds by those not famiIiar with the actua1 resuIts in the state. Another reason for use of iodine in a11 cases of hyperthyroidism is that it is impossibIe at times to differentiate with assurance between the various kinds of

to Iodine

MAY, 1929

goiter and if one withhoIds iodine from exophthaImic goiter or the mixed types in the beIief that it is an adenomatous goiter there may occur distressing postoperative compIications. When one is famiIiar with the wide range of pathoIogica1 pictures that may occur in adenomas varying from acini capabIe of invoIution to histoIogicaIIy formIess masses of caIcification or cysts it is not strange that there occur variations in physioIogica1 response to iodine. Marine5 has shown that certain adenomata wouId invoIute with iodine but that others had Iost this power. It was not possibIe to teI1 from histoIogica1 examination which adenomata wouId and which wouId not react to iodine. It seems IogicaI to account for the difference in reaction of these goiters to iodine by the differences in the pathoIogica1 condition in the gIand, rather than assume that we are deaIing with a variety of diseases. We beIieve that iodine shouId be used as a preoperative measure in a11 cases of adenomatous goiter with hyperthyroidism as we11 as in exophthaImic goiter, if the cases are carefuIIy watched for the occasiona untoward reaction. We do not find enough simiIarity of reaction to iodine between the adenomatous goiter with hyperthyroidism and exophthaImic goiter to warrant the assumption that they are the same disease even though such may be the case. CONCLUSIONS I. A comparison of the reaction to iodine of exophthaImic goiter from a goiter area and a non-goiter area shows that, in generaI, cases from the goiter area do not improve as much and react more sIowIy. 2. In I 1.7 per cent of cases of exophthalmic goiters no drop in basal metaboIic rate occurred with iodine. 3. Adenomatous goiters with hyperthyroidism do not react to simiIar amounts of iodine in a manner enough Iike exophthaImic goiter to warrant the assumption on this ground aIone that they are the .. same drsease.

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4. In 46 per cent of the adenomatous goiters with hyperthyroidism a favorabIe reaction was not obtained. 5. One cannot prophecy what the reaction in adenomatous goiters wiI1 be since it varies between briIIiant improvement, to positive harm. 6. The use of iodine as ? preoperative measure in a11 cases of adenomatous goiter with hyperthyroidism and of exophthaImic goiter is advocated. 7. The danger of inducing iodine hyperthyroidism in adenomatous goiter by preoperative iodine medication is smaI1.

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REFERENCES I. MEANS, J. H., THOMPSON, W. O., THOMPSON, P. K. On the nature of iodine reaction in exophthaImic goiter. Trans. Assoc. Am. Physicians. 43: 146-158, 1928. 2. STURGIS, C. C. Observations on one hundred and ninety-two consecutive days of the basaI metaboIism. food intake. n&e rate. and bodv weieht in a patient with exo’phthalmic goiter. A&b. Internal Med., 32: 50-73, 1923. 3. PLUMMER. H. S. and B~XITHBY,W. M. The vaIue of iodine in exophthaImic goiter. Jour. Iowa State Med. Sot., 14: 66, 1924. 4. MARINE, D. Iodin in diseases of thyroid gIand. Medicine, 6: 127-141, 1927. 5. MARINE, D. Benign epitheIia1 tumors of the thyroid gIand. J. Med. Research, 27: 229, 1913.