The treatment of hyperthyroidism in children and younger adolescents

T H E T R E A T M E N T O F . H Y P E R T H Y R O I D I S M IN C H I L D R E N AND YOUNGER. A D O L E S C E N T S ED~,VARD ROSE, M.D., ELIZABETI-IKIRK ROSE, M,D., AND ECGENE P. PENDERGI~ASS, ~ . D . PHILADELPHIA, P A .

P E R T H Y R O I D I S M in children is uncommon, but by no means a H Yrarity. I t h a s been described frequently in the literature, and its treatment has been discussed. Among the more important recent contributions are those by Helmholz,~ Dinsmore, 2 and Abbott. ~ Sas ~ in 1909 reviewed 184 collected eases. Subtotal thyroidectomy or conservat i v e medical treatment with rest and iodization are recommended by most writers. The purpose of this communication is to review briefly the clinical features of ten cases, all in patients under the age of fifteen years, in whom irradiation was employed, and to consider the value of such therapy in juvenile hyperthyroidism. Since the thyroid gland is undoubtedly such an important factor in the changes incident to adolescence, it would app e a r desirable in treating thyrotoxicosis during or before this period to avoid, when possible, actual loss of any of its substance by excision. Furthermore, there is some evidence to suggest that the majority of cases of hyperthyroidism in persons under the age of forty-five years tend toward spontaneous permanent remission without specific therapy ;o this tendency might well be supplemented to a satisfactory degree by a conservative therapeutic procedure such as irradiation. One of the chief objections to radiation in the past has been the lack of standardization of dosage. This objection has been removed by the introduction of the standard r. unit with consequently improved results from treatment. T h e r. unit is defined as " t h e quantity of roentgen radiation which, when the secondary electrons are fully utilized and the wall effect of the chamber is avoided, produce in 1 e.c. of atmosphel~c air at 0 ~ C. and 76 cm. of mercury pressure, such a degree of conductivity that one electrostatic unit of change is measured at saturation current."~ It should' be noted that the mode oi action of roentgen rays upon the toxic thyroid remains unknown. It seems certain that the activity of the normal thyroid, as measured by changes in basal metabolism, is not affected by irradiation. 7 A number of patients without evidence of thyroid disease who have received intensive irradiation over the thyroid in the course of treatment for malignant lesions of the neck, larynx, etc., have shown no significant variation in the basal :metabolic rate. From the Thyroid Section of the l~iedical Clinic, and the :Department of l=toentgenotogy, Hospital of the University o f Pennsylvania. Read before the Pediatric Societ:r of PhiludelDhia, :Feb. 12, 1935. 325

326

THE

JOURNAL

Ol~ P E D I A T R I C S

Three distinct clinical types of hyperthyroidism in children have been observed in the Philadelphia region. There is, first, a frank type which may be called primary in that the appearance of the thyroid enlargement is roughly coincidental with the onset of subjective symptoms. The degree of enlargement is not usually great., but the gland may be quite firm, with occasionally a roughly granular or " p e b b l y " feel to the surface. Frequently, however, the degree of enlargement is very slight, and the gland soft in consistency. The patients in this group present a clinical picture quite comparable to that of the adult form of primary toxic diffuse goiter, except that visceral complications (cardiac, hepatic, etc.) are much Iess frequent. Exophtha]mos is common. The second variety of the disease resembles that just mentioned in all respects except that the symptoms appear as secondary phenomena in patients with previously existing nontoxic goiters, either soft or firm in consistency. The presence of palpable nodules (frequently called "adenomas" without justification), in the toxic goiters of children or ado]escents, is rare in this region. The third type may appear in children with or without preexisting goiter. The thyroid gland is seldom markedly enlarged and is usually soft or elastic in consistency. The clinical picture is that of the forme fruste; most of the characteristic symptoms of the disease are usually present, but often in miniature or with marked variation in intensity from time to time. The basal metabolic rate is usually elevated only moderately or slightly, and these patients pass through prolonged periods of spontaneous remission. Indeed, permanent spontaneous remission is commoner than in the other two groups of patients. ExophthaImos is seldom seen. Thyroid enlargement may persist after the disappearance of all symptoms. Subjective nervousness and tachycardia, the commonest symptoms in this group, may persist for some time after the basal rate has returned to normal levels. In some cases it is impossible, even after prolonged observation, to be certain whether the picture is that of a mild hyperthyroidism or of a nontoxic diffuse goiter with coincidental nervous symptoms and a borderline elevation of the metabolic rate. Mitral stenosis, congenital heart lesions, and paroxysmal tachyeardia a r e occasionally mistaken for hyperthyroidism. The syndrome known as "sympathetic imbalance" or "hyperthyroidism without increased basal metabolism," occasionally offers some diagnostic difficulty in children and adolescents, especially when there coexists a nontoxic goiter. The principal point in differentiation from true hyperthyroidism is that the basal metabolism is never consistently elevated. The histologie picture of the thyroid is not that of toxicity. Specific therapy directed against the thyroid is ineffective, although iodine is said to have caused improvement in a few cases. The immediate precipitating factors are usually the same in juvenile and adult hyperthyroidism--nervous or mental shock, trauma, infec-

ROSE E T A L . :

]~u

327

tions, or infestations. F r e q u e n t l y no such factor can be found to have existed. The p a r t played by iodine in the production of hyperthyroidism remains unsettled. "Iodine-induced h y p e r t h y r o i d i s m " appears as an established entity in the literature, 8 and it is said to be particularly common in goitrous districts, but the factor of coincidence appears to be a difficult one to eliminate. We have seen a few cases in which iodine might well have precipitated toxic change in a previously nontoxic goiter, but in none of them has the relationship been proved. A great many persons, n~wittingly or otherwise, use iodized salt, which contains 0.01 to 0.02 per cent iodine. Ellis 9 found, in a survey made a few years ago, that iodized salt was used in many hotels, clubs, and r e s t a u r a n t s in Philadelphia, and was frequently sold in grocery stores whenever salt was asked for, regardless of whether the iodized variety was requested or not. H e also found that more iodized salt was sold on request in the NAME

AMOUNT OP IHRADIATION

J DURATION OF TR~iT~IENT AND OBSERVATION

radium 8000 mE. hr.

[~//~W///Z~

A~ Q.

F. S. ":'~

1680 R

~f/J//~///~///J//////////~'////~

C. S.

1800 R

LJJ~

L

E. 8.

R 3600R

A. B.

2400 E

L. ~.

120Q R

~i. W. A. G.

21350 000-R

V. S.-~-

2800

E. B.

800

I

I I

I I

R

R

YEARS

!

I

~! ~

I

I

I

I

I

I

0

1

2

3

4

I

'

5

Chart l.--Treatment. -Average dose 1950~---six months. A m o u n t a n d duration (shaded columns) of irradiation, colnpared "with total period of observation (unshaded a n d shaded columns), Patients indicated b y an asterisk are those in " w h o m treatment w a s unsuccessful. Patient V. S. died of cardiac failure while under observation.

better residential districts, where advertising had penetrated more effectively. We do not believe that the indiscriminate sale o r use of iodized salt is advisable in the Philadelphia region, which is not in a goiter belt. We have selected for review only f r a n k cases of hyperthyroidism, in which the diagnosis was beyond question. A number of examples of the forme fruste, in whom p r o m p t and permanent remission followed irradiation, have been excluded. I n 3,090 admissions to our Thyroid Clinic, only thirteen cases of f r a n k hyperthyroidism in children below the age of fifteen have been seen: the ten cases reported here, one boy thirteerL years old who was operated upon, a colored girl aged eight years who did not r e t u r n for treatment, and a white girl fourteen years old who has just come u n d e r observation. The pertinent details of our cases and their treatment are shown in Tables I and I I and Chart 1.

328

JOURNAL OF PEDIATRICS

THE

TABLE I SIGIqIFICANT

Age

8

CLINICAL

FEATURES

IN OUl~ CASES

9 11 12 13 14 Goiter 12 13 14 14

Sex Previous Therapy

All F Operation Iodine Certain Doubtful During tr. Family History 4 Symptoms Nervousness Weight loss Cardiac

1 5 ]Monarcho 2 1 I Onset

Duration

Initial B.lV[.R.*

Exophthahnos

Insomnia ] Dysphagia

8 2 4 6 2

Before onset After onset

2 4

Gradual Sudden Apparent cause

8 2 2

-~onths 1 2 2

Enlarged neck Weakness ] ]3ulimia Tremor Cough I

Moderato Small Soft Firm Present before symptoms

20 20 29 6

32 33 34

3 3 44 45

6?

9 12 9 12 56

60 68

Jomplicationst

Cardiac Infectious (pneum. Pruritus and otit. reed.) Dyspnea Misc. (interos. atEnuresis rophy) *The basal metabolism figures indicate per cent above zero. CThe infectious complications noted included pneumonia and otitis media. Diarrhea

J

}

TABLE II I~ESULT'S 01~ TKF.ATM]~NT :PROMPT

Relief of Symptoms Weight Gain , Decrease in B. M.R. Decrease in Pulse Rate Change in Goiter Recovery Dispersion Phenomena

1 8 1 0 5 disappeared 8 complete 3

GRADUAL 7 1 7 6 3 decreased 2 none

NONE

2 1 2 4 2 no change

T h e f o l l o w i n g p o i n t s i n c o n n e c t i o n with the t r e a t m e n t of these p a t i e n t s m a y be e m p h a s i z e d : (1) The f r e q u e n c y of m a r k e d a n d r a p i d weight g a i n a f t e r the beginn i n g of t r e a t m e n t . (2) R e d u c t i o n of the basal metabolic rate to s u b n o r m a l levels a f t e r t r e a t m e n t - - i n most i n s t a n c e s this was n o t a p e r m a n e n t r e d u c t i o n . Three of t h e f o u r p a t i e n t s i n this g r o u p p r e s e n t e d a n a p p e a r a n c e suggestive of rail d h y p o t h y r o i d i s m d u r i n g this p h a s e b u t d i d n o t e x h i b i t corresponding symptoms. (3) The " d i s p e r s i o n p h e n o m e n o n . " W e have coined this t e r m to i n d i c a t e the d i s c o n t i n u i t y i n the p r o p o r t i o n a t e r e l a t i o n s h i p of the char-

ROSE E T A L . :

329

HYPERTHYROIDIS~I:

acteristic signs and symptoms of hyperthyroidism which frequently occurs during or after specific therapy (iodization, surgery, but particularly radiation). Thus, for example, the basal metabolism may return to 9

!

.

,

,

I

,

,

,

I

9

.

,

I

.

9

9

I

,

,

,

c.s. ,2 4'$ MO. 1800 R

@60"

I--"1"50' Z+40. ~+30' Q'+I O' Z C

~-,o V -ao ~-3o -40

9

'

I'"" I =

"'" ,

I"" ,

I

15o

" .

,

" I

I I

" ~

" " , *

1 I

" t

" .

' 9

I, I

.

=

*

T

.140

130

~ 1~o. Z~I~ / IOO,

90,

70 5C 12

24

36

45

72

MONTHS

C h a r t 2 . - - C o u r s e o f b a s a l m e t a b o l i s m a n d w e i g h t in a t w e l v e - y e a r - o l d c o l o r e d g i r l w h o r e s p o n d e d t o i r r a d i a t i o n b y p r o m p t a n d m a r k e d i m p r o v e m e n t . T h e v e r t i c a l line. p a r a l l e l t o t h e o r d i n a t e in t h i s a n d t h e s u c c e e d i n g f i g u r e s i n d i c a t e s t h e ' p o i n t a t Which t r e a t m e n t w a s s t o p p e d , T, P o i n t a t w h i c h ~%dministration of d e s i c c a t e d t h y r o i d W~s be~,mn ( c o n t i n u e d f o r t w o m o n t h s ) .

A.Q. t h 71 M O ,

F...s Z+so, ~J U+40' n,"4.30 ~'1"

8000

M G.HR,

20,

Z + 10' 0

r -~b. -40,

I....|150. 140'

130. 120"

Z li0, I00. nO 90. 80,

70, 60. 50,

f MONTHS

C h a r t 3.--Course of b a s a l m e t a b o l i s m a n d ~ , e i g h t in a n

eleven-year-old girl who s h o w e d a g r a d u a l p r o g r e s s i v e r e s p o n s e to r a d i u m t r e a t m e n t ,

t h e normal zone while the heart rate remains rapid; or weight gain may be marked despite persistence os an increased metabolic rate aad tachycardia, An analogous, though reversed, dispersion is frequently seen during thyroid opotherapy for hypothyroid states.

330

TtIE JOURI~AL OF PEDI~TI~ICS

(4) The frequency of marked reduction in size or complete disappearance of goiter during treatment. This appears to be relatively more frequent in children than in adults receiving radiation for hyperthyroidism. Our f a t a l case waxrants ~ brief description. The patient, V. S., was a fourteenyear-old white girl who had always lived in or near Philadelphia. Her mother had~ ~n y o u n g adul% life, a goiter which subsequently disappeared. The patient had had the common diseases of childhood without complications, and her tonsils had been rem o v e d at the age of six years. She h a d always been nervous. I a September, 1932, enlargement of her neck was first noticed, and she was given iodine in ascending doses for several weeks. A second period of iodJzation followed in February, 1933, and another in May of the same year. She was first seen by us on J u n e 2, 1933. She ha(t lost ]4 pounds in the preceding year, and she complained of occasional abdominal t

,

,

l

l

,

,

,

I

~

9

9 1 F5 1 55 MO. 1650 R

'

'

I

-I-6 o, }-+so, ~-1-40'

!

U+30, ~+20' ~"t- iO, Z 0 n; --I O, C0-30' -40

9

'

'

I

'

9

,

I

'

I

'

160 150 140,

130,

~

110,

DO0, ~ 90, 80, 70. 60. 5O

MONTHS

Chart 4.~Course of basal metabolism and: weight in a girl. aged fourteen years. with severe hyperthyroidism and exophthalmos, in whom thyroidectomy had been unsuccessful and who failed to improve under irradiation. Her symptoms were much more severe t h a n the degree of elevation of the basal metabolism would indicate. cramps, diarrhea, dyspne% substernal discomfort, a dry cough, and profuse sweating. The onset of symptoms h a d been without apparent cause. E x a m i n a t i o n showed the classical phenomena of hyperthyroidism, with tachyeardia, tremor, sweating, exophthalmos, and a diffuse soft, smooth goiter. The basal metabolism was +45 per cent. It was felt t h a t a trial with x-ray t h e r a p y was justifiable, and she received a total of 2,800 r. in seven t r e a t m e n t s f r o m J u n e 9 to October 14. During this time she showed some early temporary improvement, with a drop in the basal rate to +24 per cent on J u l y 18, but she soon returned to her previous condition. She was not seen by us f r o m A u g u s t 14 to October 17. On the lat%er date she was m u c h worse, being orthopneic and very nervous, with a constant cough and a very rapid but regular heart. She was immediately admitted to the Medical Division to be prepared f o r thyroidectomy. Pm'ipheral edema, slight ascites a n d enlargement of the liver, a n d pulmonary congestio~ appeared, although the basal l~ate on October 20 was only +36 per cent. Marked cardiac enlargement was found by::hrthodiagraphy (86 per cent above predicted normal area), and T~ and T~ were inverted in the electrocardiogram. The shape of the heart ' in the

ROSE ET AL. :

HYPEI~THYROIDISM

331

x-ray film was regarded as suggestive of a double mitral lesion, but neither history nor physical findings confirmed this suggestion. Death occurred suddenly5 presumably from some kind of acute cardiac failure, on October 21. Necropsy was not permi%ted. We must assume the responsibility for this fatality. Our judgment was at fault ia embarking upon a course of roentgen ray therapy, but had we seen her before the circulatory failure was so far advanced she could probably have been operated upon successfully. I n c o n s i d e r i n g a n y disease i n w h i c h t h e t e n d e n c y to s p o n t a n e o u s rem i s s i o n is as m a r k e d as i n j u v e n i l e h y p e r t h y r o i d i s m , conclusions r e g a r d i n g t h e effect of a n y specific t h e r a p y m u s t be e x t r e m e l y g u a r d e d . I t w o u l d a p p e a r , however, f r o m o u r o b s e r v a t i o n os these r e p o r t e d cases a n d others, t h a t a d e q u a t e i r r a d i a t i o n o~ t h e t h y r o i d g l a n d in t h i s disease is f o l l o w e d sufficiently o f t e n b y s a t i s f a c t o r y p e r m a n e n t r e m i s s i o n to j u s t i f y a c a r e f u l l y c o n t r o l l e d t r i a l , p r o v i d e d t h a t efficient a p p a r a t u s is a v a i l a b l e . I f definite i m p r o v e m e n t does n o t a p p e a r w i t h i n t h r e e months, or i f a m a r k e d e x a c e r b a t i o n of t h e disease occurs a t a n y time, r a d i a t i o n s h o u l d be s t o p p e d a n d p r e p a r a t i o n f o r t h y r o i d e c t o m y b e g u n . R:EFERENCES

1. 2. 3. 4. 5. 6.

Helmholz, H . F . : ;L A. )s A. 87: 157, 1926. Dinsmore, R. S.: Surg. G)mec. Obst. 42: 172, 1926. Abbott, A. C.: Internat. Clin. 4: 98, 1932. Quoted by Helmholz.1 Kessel, L , and Hyman, tI. T.: Arch. Surg. 8: 149, 1924. Weatherwax, J . L . : Physics of Radiology, New York, 1931, Paul B. Hoeber, p. 107. 7. Friedmau, IL F., and Blumgart~ It. L.~ J . A . M . A . 102: 17, 1934. 8. Hartsock, C. L . : Ann. Int. Med. 1: 24, ]927. 9. Ellis, MacKinnon: Unpublished observations.