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On the treatment of congenital goiter
526
Letters to the Editor
The Journal of Pediatrics March 1976
bicarbonate indicating that the drug is initially largely confined to the intravascular compartment. We were surprised with their comment that ventilation was always the obvious treatment for a raised level of P a c o ~. Clearly ventilation is the appropriate treatment if the infant is already being ventilated as we had ourselves suggested. However, there are many practical situations in neonatal intensive care when intubation or face mask ventilation would be less desirable than alkali therapy in rapidly correcting a low pH. It was, o f course, out of the question to have measured pH on the CSF on these infants. The well-known p h e n o m o n e n they quote does not detract from the fact that acidotic infants with 1RDS improve when their intravascular pH is corrected. We are glad that they support our conclusions that sodium bicarbonate should be given slowly so that it does not impose a hypertonic load on the infant and so that CO2 elimination can OCCUr,
J. D. Baum Clinical Reader in Paediatrics University of Oxford John Radcliffe Hospital Headington Oxford OX3 9DU England N.R.C. Roberton Consultant in Paediatrics Addenbrooke's Hospital Cambridge
On the treatment of congenital goiter To the Editor: In their article on thyroid function with congenital goiter, Homoki and associates 1 classify treatment with inorganic iodine as of second choice and hazardous, referring to an article by our group'-' and by Wolff, ~but they do not discuss our recent results in favor of this therapy. ~. " We* would like to make the following comments. 1. The area from which we reported is in immediate western neighborhood to the one from which Homoki and associates reported, i.e., Southern Germany. According to recent studies t Germany has to be regarded as an area of moderately severe iodine deficiency and progressively so from north to south. The populations studied should therefore be comparable. Indeed, both groups found a retarded bone age in 60% of their patients, Homoki and associates reported decreased T~ values and increased TSH in 60% of their newborn infants, whereas we saw decreased T~ values in only 30% o f newborn patients. *Dr. Petrykowski is writing for himself and the authors of references 2 and 5.
2. Different conclusions are drawn, however, by both groups from this comparable basic situation. Homoki and associates suggest thyroid hormone substitution based on the hypothyroid constellation of laboratory tests. Although they mention iodine deficiency first among causative mechanisms and report from an iodine deficient area, they elected not to try whether inorganic iodine supplementation would be as effective in reverting this constellation to normal, but advocate costly hormone therapy. They do not mention whether this is meant for a lifetime. Even for the infants without laboratory evidence o f hypothyroidism, hormone therapy is recommended based on the rapidity of regression of the goiters, but no comparison with the rapidity of iodine effectiveness is offered. While we agree on the hypothyroid constellation in some newborn infants with goiter, we have always been convinced from the rapidity of regression of these goiters upon administration of 5% potassium iodine ointment five to six times every other day, that any hypothyroid constellation would be transient and call for iodine substitution, at least in areas o f iodine deficiency. Permanent hypothyroidism is the rare exception here among newborn infants with goiter. This was confirmed by our studies,2 ~ which excluded hypothyroidism by long-term follow-up of these infants for up to 27 months and by normalization of elevated TSH values within four to 11 days after iodine ointment application. We therefore consider thyroid hormone therapy unnecessary (and expensive) for the vast majority of newborn infants with goiter in iodine-deficient arefis. Of course modern endocrinologic evaluation is recommended for each of these infants, while iodine is administered in the empirical way of ointment. 3. The citation of WoltFs excellent article on "Iodide goiter and the pharmacological effects of excess iodide" by Homoki and associates is unfortunately made in a wrong context since Dr. Wolff states in his introduction, "This review concerns itself with the effects of excess iodide, i.e., amounts greater than those needed for the production of normal amounts of the thyroid hormones." Therefore, the conclusion by Homoki and associates, that iodide treatment is not only of second choice, but dangerous, is not borne out either by their approach nor any of Dr. WolWs statements. Wolfgang v. Petrykowski, M.D. 78 Freiburg i. Br. University Childrens Hospital West Germany REFERENCES
1. Homoki J, Birk J, Loos U, Rothenbuchner (3, Fazekas ATA, and Teller WM: Thyroid function with congenital goiter, J PEDIATR 86:753, 1975. 2. Schuchmann L, Schreiber R, v Petrykowski W, Witt I, and Reinwein H: Struma neonati - Diagnostik, Therapie und Prognose, Monatsschr Kinderheilkd 122:715, 1974. 3. Wolff J: Iodide goiter and the pharmacological effects of excess iodide, Am J Med 47:101, 1969. 4. Scriba PC, Kracht J, and Klein E: Endemic goiter - Iodine prophylaxis, Dtsch Med Wochenschr 100:1350, 1975.
Volume 88 Number 3
Schreiber R, Schuchmann L, and v Petrykowski W: TSHand T4-values in newborns with congenital goiter, Monatsschr. Kinderheilk. 123:451, 1975.
Letters to the Editor
hormones. This mode of therapy most certainly follows the rule: Nil Nocere.
J. Homoki W. M. Teller Department of Pediatrics University of Ulm D-79 Ulm/Donau Federal Republic of Germany
Re#y To the Editor: For the treatment of congenital goiter we advocate the administration of thyroid hormones rather than the application of inorganic iodine ointment. The reasons for this recommendation are manifold: Inorganic iodine has to be incorporated into thyroid h o r m o n e s before it exerts its biologic, hormonal effects. This process takes time. If thyroid hormones in physiologic doses are given, iodine is simultaneously administered in sufficient, well-controlled amounts. This substitution therapy is executed as long as the goiter is palpable, sometimes only for two or three weeks or at other times for two to three months. The application of iodine ointment as r e c o m m e n d e d by S c h u c h m a n and co-workers ' and Schreiber and associates'-' leads to administration of roughly 100 m g of inorganic iodine per treatment course. The adult requires a b o u t 150/zg o f iodine per day orally2 T h e newborn infant certainly requires less. In h u m a n beings very scant data exist on absorption rates o f iodine through skin. Therefore the application of ointment to us seems to be a rather inaccurate and unpredictable mode of therapy. It m a y well be that too m u c h iodine penetrates the skin at a given rubbing procedure. This again m a y lead to the Wolff-Chaikoff effect referred to in our paper? Also, we have been aware of other side effects of iodine treatment, such as iodine goiter, iodine myxedema, and even factitious Graves disease. 4 In this state of uncertainty we prefer to treat newborn infants with an exact, physiologic a m o u n t of hormones of which the absorption is well k n o w n and predictable. In our paper S we deliberately chose not to amplify on our recommendation because this would have been beyond the scope of our topic. It should be mentioned that in a small group of goitrous infants (n = 8) Schreiber and associates? showed the decrease of serum TSH upon application of iodine ointment. However, in their previous report I on the six- to 27-month followup on 24 infants with congenital goiter treated with iodine ointment, 27% still had a retarded bone age of m o r e than two months. T h e a r g u m e n t of costs seems irrelevant to us. The tablet of LTa/LT 4 mixture (5 #g/25/~g) (Novothyrai mite) as we use it once daily for the therapy of congenital goiter costs 5 cents. Even a parent on relief should be in the position to afford this expense for his infant child. Iodine ointment on the other hand is quite unstable. It has to be renewed every two to four weeks, quite to the disadvantage of the parents, their purse, and even to the hospital pharmacy. In s u m m a r y we are of the opinion that like any other therapy the treatment of an infant with congenital goiter should be performed in the most accurate and predictable way possible, that is by short-term substitution o f known a m o u n t s of th~croid
527
REFERENCES 1. Schuchmann L, Schreiber R, v Petrykowski W, Witt I, and Reinwein H: Monatsschr Kinderheilk 122:715, 1974. 2. Schreiber R, S c h u c h m a n n L, and v Petrykowski W: Monatsschr Kinderheilk 123:451, 1975. 3. Welt LG, and Blythe WB: Anions, phosphate, iodide, fluoride, and the ions, in G o o d m a n LS, and Gilman A, editors: The pharmacological basis of therapeutics, London, 1970, The Macmillan Company, p 822. 4, Connolly RJ, Vidor GI, and Stewart JC: Lancet 1:500, 1970. 5. Homoki J, Birk J, Loos U, R o t h e n b u c h n e r (3, Fazekas ATA, and Teller W M : J PEDIATR 86:753, 1975. Dr. Delbert Fisher was asked to c o m m e n t on the tetter from Dr. Petrykowski. Ed.
Comment The letter of Dr. Petrykowski is of considerable interest as are the studies he and his collaborators have published concerning iodine deficiency goiter with and without hypothyroidism in newborn infants in Germany. These investigators have shown that topical application of (potassium) iodide containing Ointment to six goitrous infants with hypothyroid thyroxine (T~) levels measured in the early neonatal period increased the serum T~ from subnormal to normal levels over a period of ten days to four weeks?. ~ Two of three of these infants in w h o m serum thyroid-stimulating h o r m o n e (TSH) m e a s u r e m e n t s were available had modestly elevated values (21 and 27 n g / m l m e a s u r e d at one to three days). In one of these the s e r u m TSH level fell to the normal range within four to 11 days. In the other infant s e r u m TSH remained modestly elevated at one m o n t h of age (10 ng/ml). In this same infant the serum T4 concentration did not increase to the normal range until four weeks of age. Iodide therapy was provided to some two dozen additional newborn infants with goiter, but in these infants the initial serum T~ levels were not abnormal and the m e a n change with iodide therapy in the 11 'infants in whom serum T 4 concentrations were available before and after treatment was modest (12.0 to 16.3 #g/dl). Initial serum TSH values were available in only three of these infants and all were within the normal range. T h e goiters apparently disappeared in all infants treated with iodide but the m e a n duration of goiter is not noted. The results show that topical iodine therapy is effective in treatment of congenital iodine deficiency goiter. However, there
Letters to the Editor
The Journal of Pediatrics March 1976
bicarbonate indicating that the drug is initially largely confined to the intravascular compartment. We were surprised with their comment that ventilation was always the obvious treatment for a raised level of P a c o ~. Clearly ventilation is the appropriate treatment if the infant is already being ventilated as we had ourselves suggested. However, there are many practical situations in neonatal intensive care when intubation or face mask ventilation would be less desirable than alkali therapy in rapidly correcting a low pH. It was, o f course, out of the question to have measured pH on the CSF on these infants. The well-known p h e n o m o n e n they quote does not detract from the fact that acidotic infants with 1RDS improve when their intravascular pH is corrected. We are glad that they support our conclusions that sodium bicarbonate should be given slowly so that it does not impose a hypertonic load on the infant and so that CO2 elimination can OCCUr,
J. D. Baum Clinical Reader in Paediatrics University of Oxford John Radcliffe Hospital Headington Oxford OX3 9DU England N.R.C. Roberton Consultant in Paediatrics Addenbrooke's Hospital Cambridge
On the treatment of congenital goiter To the Editor: In their article on thyroid function with congenital goiter, Homoki and associates 1 classify treatment with inorganic iodine as of second choice and hazardous, referring to an article by our group'-' and by Wolff, ~but they do not discuss our recent results in favor of this therapy. ~. " We* would like to make the following comments. 1. The area from which we reported is in immediate western neighborhood to the one from which Homoki and associates reported, i.e., Southern Germany. According to recent studies t Germany has to be regarded as an area of moderately severe iodine deficiency and progressively so from north to south. The populations studied should therefore be comparable. Indeed, both groups found a retarded bone age in 60% of their patients, Homoki and associates reported decreased T~ values and increased TSH in 60% of their newborn infants, whereas we saw decreased T~ values in only 30% o f newborn patients. *Dr. Petrykowski is writing for himself and the authors of references 2 and 5.
2. Different conclusions are drawn, however, by both groups from this comparable basic situation. Homoki and associates suggest thyroid hormone substitution based on the hypothyroid constellation of laboratory tests. Although they mention iodine deficiency first among causative mechanisms and report from an iodine deficient area, they elected not to try whether inorganic iodine supplementation would be as effective in reverting this constellation to normal, but advocate costly hormone therapy. They do not mention whether this is meant for a lifetime. Even for the infants without laboratory evidence o f hypothyroidism, hormone therapy is recommended based on the rapidity of regression of the goiters, but no comparison with the rapidity of iodine effectiveness is offered. While we agree on the hypothyroid constellation in some newborn infants with goiter, we have always been convinced from the rapidity of regression of these goiters upon administration of 5% potassium iodine ointment five to six times every other day, that any hypothyroid constellation would be transient and call for iodine substitution, at least in areas o f iodine deficiency. Permanent hypothyroidism is the rare exception here among newborn infants with goiter. This was confirmed by our studies,2 ~ which excluded hypothyroidism by long-term follow-up of these infants for up to 27 months and by normalization of elevated TSH values within four to 11 days after iodine ointment application. We therefore consider thyroid hormone therapy unnecessary (and expensive) for the vast majority of newborn infants with goiter in iodine-deficient arefis. Of course modern endocrinologic evaluation is recommended for each of these infants, while iodine is administered in the empirical way of ointment. 3. The citation of WoltFs excellent article on "Iodide goiter and the pharmacological effects of excess iodide" by Homoki and associates is unfortunately made in a wrong context since Dr. Wolff states in his introduction, "This review concerns itself with the effects of excess iodide, i.e., amounts greater than those needed for the production of normal amounts of the thyroid hormones." Therefore, the conclusion by Homoki and associates, that iodide treatment is not only of second choice, but dangerous, is not borne out either by their approach nor any of Dr. WolWs statements. Wolfgang v. Petrykowski, M.D. 78 Freiburg i. Br. University Childrens Hospital West Germany REFERENCES
1. Homoki J, Birk J, Loos U, Rothenbuchner (3, Fazekas ATA, and Teller WM: Thyroid function with congenital goiter, J PEDIATR 86:753, 1975. 2. Schuchmann L, Schreiber R, v Petrykowski W, Witt I, and Reinwein H: Struma neonati - Diagnostik, Therapie und Prognose, Monatsschr Kinderheilkd 122:715, 1974. 3. Wolff J: Iodide goiter and the pharmacological effects of excess iodide, Am J Med 47:101, 1969. 4. Scriba PC, Kracht J, and Klein E: Endemic goiter - Iodine prophylaxis, Dtsch Med Wochenschr 100:1350, 1975.
Volume 88 Number 3
Schreiber R, Schuchmann L, and v Petrykowski W: TSHand T4-values in newborns with congenital goiter, Monatsschr. Kinderheilk. 123:451, 1975.
Letters to the Editor
hormones. This mode of therapy most certainly follows the rule: Nil Nocere.
J. Homoki W. M. Teller Department of Pediatrics University of Ulm D-79 Ulm/Donau Federal Republic of Germany
Re#y To the Editor: For the treatment of congenital goiter we advocate the administration of thyroid hormones rather than the application of inorganic iodine ointment. The reasons for this recommendation are manifold: Inorganic iodine has to be incorporated into thyroid h o r m o n e s before it exerts its biologic, hormonal effects. This process takes time. If thyroid hormones in physiologic doses are given, iodine is simultaneously administered in sufficient, well-controlled amounts. This substitution therapy is executed as long as the goiter is palpable, sometimes only for two or three weeks or at other times for two to three months. The application of iodine ointment as r e c o m m e n d e d by S c h u c h m a n and co-workers ' and Schreiber and associates'-' leads to administration of roughly 100 m g of inorganic iodine per treatment course. The adult requires a b o u t 150/zg o f iodine per day orally2 T h e newborn infant certainly requires less. In h u m a n beings very scant data exist on absorption rates o f iodine through skin. Therefore the application of ointment to us seems to be a rather inaccurate and unpredictable mode of therapy. It m a y well be that too m u c h iodine penetrates the skin at a given rubbing procedure. This again m a y lead to the Wolff-Chaikoff effect referred to in our paper? Also, we have been aware of other side effects of iodine treatment, such as iodine goiter, iodine myxedema, and even factitious Graves disease. 4 In this state of uncertainty we prefer to treat newborn infants with an exact, physiologic a m o u n t of hormones of which the absorption is well k n o w n and predictable. In our paper S we deliberately chose not to amplify on our recommendation because this would have been beyond the scope of our topic. It should be mentioned that in a small group of goitrous infants (n = 8) Schreiber and associates? showed the decrease of serum TSH upon application of iodine ointment. However, in their previous report I on the six- to 27-month followup on 24 infants with congenital goiter treated with iodine ointment, 27% still had a retarded bone age of m o r e than two months. T h e a r g u m e n t of costs seems irrelevant to us. The tablet of LTa/LT 4 mixture (5 #g/25/~g) (Novothyrai mite) as we use it once daily for the therapy of congenital goiter costs 5 cents. Even a parent on relief should be in the position to afford this expense for his infant child. Iodine ointment on the other hand is quite unstable. It has to be renewed every two to four weeks, quite to the disadvantage of the parents, their purse, and even to the hospital pharmacy. In s u m m a r y we are of the opinion that like any other therapy the treatment of an infant with congenital goiter should be performed in the most accurate and predictable way possible, that is by short-term substitution o f known a m o u n t s of th~croid
527
REFERENCES 1. Schuchmann L, Schreiber R, v Petrykowski W, Witt I, and Reinwein H: Monatsschr Kinderheilk 122:715, 1974. 2. Schreiber R, S c h u c h m a n n L, and v Petrykowski W: Monatsschr Kinderheilk 123:451, 1975. 3. Welt LG, and Blythe WB: Anions, phosphate, iodide, fluoride, and the ions, in G o o d m a n LS, and Gilman A, editors: The pharmacological basis of therapeutics, London, 1970, The Macmillan Company, p 822. 4, Connolly RJ, Vidor GI, and Stewart JC: Lancet 1:500, 1970. 5. Homoki J, Birk J, Loos U, R o t h e n b u c h n e r (3, Fazekas ATA, and Teller W M : J PEDIATR 86:753, 1975. Dr. Delbert Fisher was asked to c o m m e n t on the tetter from Dr. Petrykowski. Ed.
Comment The letter of Dr. Petrykowski is of considerable interest as are the studies he and his collaborators have published concerning iodine deficiency goiter with and without hypothyroidism in newborn infants in Germany. These investigators have shown that topical application of (potassium) iodide containing Ointment to six goitrous infants with hypothyroid thyroxine (T~) levels measured in the early neonatal period increased the serum T~ from subnormal to normal levels over a period of ten days to four weeks?. ~ Two of three of these infants in w h o m serum thyroid-stimulating h o r m o n e (TSH) m e a s u r e m e n t s were available had modestly elevated values (21 and 27 n g / m l m e a s u r e d at one to three days). In one of these the s e r u m TSH level fell to the normal range within four to 11 days. In the other infant s e r u m TSH remained modestly elevated at one m o n t h of age (10 ng/ml). In this same infant the serum T4 concentration did not increase to the normal range until four weeks of age. Iodide therapy was provided to some two dozen additional newborn infants with goiter, but in these infants the initial serum T~ levels were not abnormal and the m e a n change with iodide therapy in the 11 'infants in whom serum T 4 concentrations were available before and after treatment was modest (12.0 to 16.3 #g/dl). Initial serum TSH values were available in only three of these infants and all were within the normal range. T h e goiters apparently disappeared in all infants treated with iodide but the m e a n duration of goiter is not noted. The results show that topical iodine therapy is effective in treatment of congenital iodine deficiency goiter. However, there