Western Reserve University BULLETIN NO. 7 • OL. /XVI JULY. 1923 THE PREVENTION OF SIMPLE GOITRE STUDIES b1_ C. H. LENHART, O. and J. M. ROGOFF COMPILED AND EDITED BY G. N. STEWArJ Director of the H. K. Cushing Laboratory of Experimental Medicine Western Reserve University Issued Monthly by WESTERN RESERVE UNIVERSITY 10940 Euclid Avenue, Cleveland [Entered at the Post-Office at Cleveland, Ohio, as second-class matter Acceptance for mailing at special rate of postage provided for in Section 1103, Act of October 3, 1917, authorized February 6, 1919.] THE PREVENTION OF SIMPLE GOITRE STUDIES BY DAVID MARINE, C. H. LENHART, O. P. KIMBALL, AND J. M. ROGOFF COMPILED AND EDITED BY G. N. STEWART Director of the H. K. Cushing Laboratory of Experimental Medicine Western Reserve University WESTERN RESERVE UNIVERSITY 3 TABLE OF CONTENTS The Prevention of Goitre David Marine 7 Further Observations on the Relation of lodin to the Structure of the Thyroid Gland in the Sheep, Dog, Hog and Ox. David Marine and C. H. Lenhart 9 Further Observations and Experiments on the so-called Thyroid Carcinoma of the Brook Trout (Salvelinus Fontinalis) and its Relation to Endemic Goitre David Marine and C. H. Lenhart 21 Further Observations and Experiments on Goitre (so-called Thyroid Carcinoma) in Brook Trout (Salvelinus Fontinalis) .. .David Marine 39 The Rapidity of the Involution of Active Thyroid Hyperplasias of Brook Trout Following the Use of Fresh Sea Fish as a Food. David Marine 55 The Prevention of Simple Goitre in Man. David Marine and O. P. Kimball 61 The Prevention of Simple Goitre in Man-Second Paper. O. P. Kimball and David Marine 73 The Prevention of Simple Goitre in Man-Third Paper. O. P. Kimball, J. M. Rogoff, and David Marine 79 The Prevention of Simple Goitre in Man-Fourth Paper. David Marine and O. P. Kimball 83 The Prevention of Simple Goitre in Man. David Marine and O. P. Kimball 95 The Prevention of Simple Goitre in Man O. P. Kimball 103 Progress of the Work to Date on the Prevention of Simple Goitre. O. P. Kimball 121 INTRODUCTORY NOTE This reprint is issued in response to many requests from Public Health Authorities and individual members of the medical profession, especially in the goitre regions of the United States and Canada, for information on the prevention of simple goitre. The practical measures devised and carried out with brilliant success by Dr. David Marine and his collaborators, and since adopted in es- sentials in other parts of the world, were based upon a many- sided study of the physiology and pathology of the thyroid gland extending over more than 10 years, and grew as naturally, and indeed inevitably, out of this study as the branch grows out of the stem. The papers reprinted have been selected so as to illustrate the fundamental unity and sequence of the work. We are indebted to the American Medical Association, the Jorirnal of Experimental Medicine, the Journal of Laboratory and Clinical Medicine, the American Jottrnal of the Medical Sciences, and Public Health, Michigan, for permission to reprint articles, and to the Jottrnal of Experimental Medicine for the cut on page 40. G. N. Stewart, M. D. Director of the H. K. Cushing Laboratory of Experimental Medicine, May 7, 1923. Western Reserve University, Cleveland, Ohio. FIGURE 1. FIGURE 2. FIGURE 3. EXPLANATION OF PLATE Figure I. Section of thyroid removed November 25, 1908, show- ing high grade myxedematous atrophy. Some alveoli well preserved, others very atrophic. All alveoli wide- ly separated by soft, vascular, markedly hypertrophied stroma. Figure 2. Same thyroid. Section removed December 17, 1908, showing marked decrease in stroma and a correspond- ing relative increase in the more differentiated alveoli. Figure 3. Section of same thyroid removed January 18, 1909, showing further absorption of the stroma and nearly complete differentiation of the thyroid alveoli. Note: This puppy was one of a litter of four typical congenital cretins brought to the Laboratory at the age of six weeks on November 16, 1908. All had marked thyroid enlargement. The illustrations show the typical appear- ance of the thyroid qf a goitrous cretin in the late stages of exhaustion, atrophy and the remarkable recovery, as regards the anatomical and chemical condition of the thyroid, following the administration of a few milli- grams of iodin daily over a period of two months. Clini- cally the animal developed into a normal dog. WESTERN RESERVE UNIVERSITY 7 [Reprinted from Public Health, Mich. 1923, xi, 23-24.] THE PREVENTION OF GOITRE By DAVID MARINE, M. D., Montefiore Hospital, New York City. The old adage that an ounce of prevention is worth a pound of cure is outdone in the case of goitre, where one milligram of preven- tion is worth more than a thousand milligrams of cure. The admin- istration of 100 to 200 mgms. of iodin in any form twice a year is sufficient to prevent simple goitre in man. lodin has been know- ingly used in the treatment of human goitre since 1820 and in its prevention since 1917. In young individuals with thyroid enlarge- ments of recent development the curative effects of iodin are very striking, and amount to complete relief. In long standing goitre, neither iodin nor desiccated thyroid are of much value in relieving the deformity. The dangers and untoward effects of iodin when used in proper amounts are negligible. lodin, like all other foods, has been greatly abused, and its abuse in the treatment of goitre will continue until the profession as a whole realizes that the maxi- mum storage capacity of the normal thyroid for iodin is not over 30 milligrams, and that such a store is sufficient to meet the ordinary physiological needs of the organism for months. Desiccated thy- roid is theoretically better than iodin in the treatment and prevention of goitre, but practically it is too dangerous a drug to be recom- mended at present. Simple or endemic goitre most commonly develops (1) during fetal life, (2) during adolescence, and (3) during pregnancy and lactation. Any plan of prevention that controls thyroid growth during these three periods would practically eliminate goitre. Goitre in the mother and fetus can be prevented as easily and as simply as that of adolescents and by the same means. The greatest number of goitres develop around the age of puberty, and in the endemic districts of the United States the administration of iodin between the ages of eleven and seventeen would almost completely prevent these enlargements. As to the best method of applying prophy- laxis, I believe that at present in endemic goitre districts it should be a public health measure administered through the public school systems under medical supervision. The prevention of fetal, mater- 8 THE PREVENTION OF SIMPLE GOITRE nal and sporadic goitre would probably be the responsibility of the private physician. (Perhaps ultimately the household use of iodized or sea salt will become the preferred plan). But before we can intelligently introduce preventive measures, it will be necessary to ascertain the incidence of goitre in representative units of popula- tion in various parts of the State. There is a deplorable lack of such information. Such a survey could be conducted in the public schools with practically no additional expense or personnel. The incidence of goitre among children of school age, I believe, would be a fair index of the frequency of goitre. With such data one could then determine whether to recommend preventive treatment as a public health measure or whether it could be carried out by the individual physician. The prevention of simple goitre means vastly more than pre- serving the normal outlines of the neck. It means in addition the control of those forms of physical an'd mental degeneration, such as cretinism, mutism and idiocy, which are dependent upon thyroid insufficiency. Further, it would prevent the development of thy- roid adenomas. The terminal metamorphoses of adenomas are far more serious than those of simple hyperplasia since, in addition to hemorrhages and cyst formation, probably 90 per cent of the malig- nant tumors of the thyroid arise from these growths. Further, cases with long standing goitre are apparently more susceptible to the development of exophthalmic goitre, especially around the meno- pause. These forms of exophthalmic goitre are often designated as secondary exophthalmic goitre or so-called toxic adenoma. The prevention of simple goitre would probably materially reduce these forms of exophthalmic goitre. In conclusion, I would like to emphasize that simple goitre is the easiest of all known disease to prevent, and that it may be ex- cluded for all practical purposes from the list of human diseases as soon as society determines to make the effort, and it will require but a feeble effort. WESTERN RESERVE UNIVERSITY 9 FURTHER OBSERVATIONS ON THE RELATION OF IODIN-TO THE STRUCTURE OF THE THYROID GLAND IN THE SHEEP, DOG, HOG AND OX* DAVID MARINE, M. D.. and C. H. LENHART, M. D. CLEVELAND, OHIO INTRODUCTION In this report we have collected our observations on the relation of the iodin content to the structure of the thyroid to include sheep, ox and hog thyroids. It is thus only a continuation of the work pre- viously reported1 concerning dogs' thyroids. The methods used and the anatomic classifications adopted are the same as those fully des- cribed in the above-mentioned article and elsewhere.2 COMPARISON OF THE 10DIN CONTENTS OF SHEEP, DOG, HOG AND OX THYROIDS WITH THEIR RESPECTIVE ANATOMIC STRUCTURES The following tables are compiled from iodin determinations made on the thyroids of 40 sheep, 67 dogs, 26 hogs, and 37 oxen. As the basis of these tables we have used nine anatomic groups, viz.: 1. Normal glands. 2. Colloid glands (goiters). 3. Colloid-early glandular hyperplasia. 4. Normal-early glandular hyperplasia. 5. Early-glandular hyperplasia. 6. Early-moderate glandular hyperplasia. 7. Moderate glandular hyperplasia. 8. Moderate-marked glandular hyperplasia. 9. Marked glandular hyperplasia. The normal and colloid groups are well defined, while the re- maining seven groups are purely arbitrary divisions of the hyper- plasias made for the purpose of facilitating analysis, since in reality one has to deal with continuous gradation of hyperplastic changes occurring in either normal or colloid glands. In order to express this gradation, we have used the following terms: normal-early glandular hyperplasia to include those glands showing the very earliest hyperplastic changes occurring in normal glands; colloid- early glandular hyperplasia to include glands showing the earliest hyperplastic changes occurring in colloid glands, and the terms early, * From the Laboratories of Experimental Medicine and Pharmacology, Western Reserve University. Reprinted from The Archives of Internal Medicine, 1909, iii, 66-77. 1 Marine (David) and Williams (W. W.): The Archives of Internal Medicine, 1908, i, 349. 2 Marine (David): The occurrence and physiological nature of glandular hyperplasia, etc. Johns Hopkins Hosp. Bull., 1907, xviii, 359. 10 THE PREVENTION OF SIMPLE GOITRE moderate, marked, etc., to include the other gradations up to and including the most extensive glandular hyperplasias met with. In placing these glands in these several anatomic groups, we have compared all the glands of the four animals, the one with the other, in order that the same standard of classification might obtain in all. In each of the following tables we have listed for comparison the iodin contents of sheep, dog, hog, and ox thyroids having the same anatomic structure. Animal No. Cases. lodin E. per^gm. dried. A. lodin E. per gm. M. fresh. A. Sheep 19 4.614 1.247 2.288 2.467 1.318 0.318 0.694 0.686 Dog 3 4.722 1.990 3.205 3.322 1.064 0.512 0.757 0.777 Hog 18 4.153 1.538 2.412 2.515 1.456 0.425 0.778 0.884 Ox 17 4.768 2.730 3.254 3.461 1.592 0.892 1.069 1.117 Table 1.-Normal Glands* It will be seen that the upper extremes of iodin contents are fairly constant for all four animals, while' the lower extremes show moderately wide variations, although the lowest of these lower ex- tremes is always far in excess of the highest extremes of the suc- ceeding group-normal-early glandular hyperplasias. This would indicate that there are considerable variations in the iodin contents within the group, even when no noteworthy anatomic changes are observed, although if individual comparisons of the iodin contents with the corresponding histologic preparations be made one can dis- tinguish changes in the structure (too slight to warrant the intro- duction of a new group) corresponding to the variations in the iodin content; that is, glands with the highest iodin contents have a more flattened alveolar epithelium and vice versa, although all these glands appear in the table as normal. The average iodin contents for the four animals show a sur- prising constancy and parallelism, viz.: 2.467 mg. for the sheep, 2.515 for the hog, 3.322 for the dog and 3.461 for the ox per gm. of dried thyroid. The ox thyroids in our series have distinctly higher iodin contents than either the dog, sheep or hog. To * In each table E., M., A. are abbreviations for extreme, mean and average, respectively. WESTERN RESERVE UNIVERSITY 11 know whether this is normally true would be of value in determ- ining what relation exists between the normal iodin content and the normal weight of the thyroid, since oxen appear to have less thyroid per kilogram of body weight than do the other animals mentioned. From the experimental side it has been definitely shown that the amount of iodin in the thyroid does to a great extent control the size of the gland. No. lodin per gm. dried. lodin per gm. fresh. Animal Cases. E. M. A. E. M. A. 3.691 1.027 Sheep 3 3.529 2.996 0.974 0.818 1.769 0.455 3.608 1.039 Dog 8 1.816 1.985 0.406 0.459 0.846 0.132 2.768 0.805 Hog 2 2.353 0.681 1.938 0.557 Ox 0 Table 2.-Colloid Glands Owing to the small number of cases included, it is not possible to speak very specifically. However, in all three animals in which colloids were observed the upper extremes of iodin content are fairly constant, while the lower extremes show moderate variations. This agrees with what was observed in the normal glands, and our expla- nation is the same. Another point worthy of note is that, while the iodin per gram of colloid gland is in general lower than that of normal glands, yet, as will be seen, they approach nearest to the normal iodin content so far as we have found and may be raised to an equal content with the normal glands. Table 3.-Colloid-Early Glandular Hyperplasia Animal No. Cases. lodin per gm. dried. lodin E. 0.282 per gm. M. fresh. A. E. 1.000 M. A. Sheep 4 0.853 0.792 0.201 0.206 0.461 0.138 1.443 0.302 Dog 4 0.953 0.945 0.221 0.217 0.431 0.125 Hog 0 Ox 0 Table 3 and Table 4 deal with the most important anatomic and chemical changes concerned with the production of goitre, in that they represent the first deviation or change from the normal-colloid or quiescent glands. Colloid-early glandular hyperplasias differ from normal-early glandular hyperplasias in that the former are 12 THE PREVENTION OF SIMPLE GOITRE secondary3 hyperplasias, while the latter are primary. It is to be regretted that more colloid-early glands were not obtainable (the probable reason for this will be pointed out later). The extremes show a fair constancy. In the sheep the highest extreme iodin con- tent is below the lowest pure colloid extreme. In the case of the dog this is in general true, though there are exceptions which we are not able to explain. The existence of these exceptions suggests, however, that from the histology alone one is unable to say whether a given gland is undergoing further hyperplasia from a less marked hyperplasia or vice versa. The averages also are constant and in every instance show the great drop in the percentage of iodin from that of pure colloid glands. This drop is, as will be seen in Table 4, identical with that occurring between the normal and normal-early glandular hyperplasia. Between no other groups are there compar- able drops. This means that in both colloid and normal glands there are wide variations in the amount of iodin present, but that there is a quite constant lower limit of the iodin content necessary to main- tain normal gland or pure colloid gland structure, and that this lower limit for colloids is slightly in excess of 0.217 mg. per gram of fresh thyroid for dogs and 0.206 mg. per gram of fresh gland for sheep, corresponding to 0.792 mg. and 0.945 mg. per gram of dried gland, respectively. Table 4.-Normal-Early Glandular Hyperplasia Animal No. Cases. lodin per gm. dried. lodin per gm. fresh. A. E. M. A. E. M. Sheep 1 1296 0.677 0.318 0.176 Dog 7 0.483 0.815 0.879 0.018 0.153 0.174 Hog 1 2.676 1230 0.726 0.337 Ox 7 2.000 2.307 2.317 0.482 0.653 0.628 Table 4, together with Table 3, deals with the most important thyroid changes concerned in the production of goitre. It is seen that the highest extremes of iodin content are invariably below the lowest extreme iodin contents of normal glands. This is even more evident with the means and averages. The table also shows that there is considerable difference between the average iodin content of sheeps' thyroids and that of oxen thyroids, just as was seen to be true of the normal glands of these animals. It suggests, as was 3 Secondary in the sense that this is the second time these glands have undergone active hyperplasia. WESTERN RESERVE UNIVERSITY 13 stated under Table 1, that oxen normally have more iodin and less thyroid per kilogram of body weight. In accordance with this, hyperplastic changes are manifest with an iodin content nearly four times that of the sheeps' thyroids. But the most striking thing, just as in the colloid-early glands, is the great drop in iodin content from the normal, which must occur before hyperplastic changes are observed. The table shows that the lower limit of iodin necessary for the maintenance of normal structure is somewhat in excess of 0.176 mg. per gram of fresh gland for sheep, 0.174 for dogs, 0.337 for hogs and 0.628 for cattle, or 0.677, 0.879, 1.230, 2.317 mg. per gram of dried gland, respectively. Table 5.-Early Glandular Hyperplasia Animal No. Cases. lodin E. per gm. dried. lodin per gm. fresh. A. M. A. E. M. Sheep 0 1.028 0.235 Dog 9 0.654 0.625 0.113 0.139 0.243 0.063 1.158 0.291 Hog 2 1.102 0.285 1.046 0.279 2.186 0.615 Ox 3 1.630 1.646 0.456 0.462 1.123 0.314 In the group of early glandular hyperplasia the iodin contents are still further lowered and the drop is practically the same in all four animals. The ox thyroids still show higher iodin contents than the other animals' glands for the same degree of thyroid hyperplasia as was also noted in the normal and normal-early glands. Table 6.-Early-Moderate Glandular Hyperplasia Animal No. Cases. lodin per gm. dried. A. lodin per gm. fresh. E. M. E. M. A. Sheep 1 0.548 0.131 Dog 1 0.262 0.082 0.846 0.241 Hog 3 0.769 0.769 0.795 0.198 0.233 0.224 1.030 0.252 Ox 5 1.000 1.000 0.222 0.226 0.969 0.205 In the table of early-moderate glandular hyperplasia are col- lected those glands which histologically show a degree of epithelial proliferation (hyperplasia) too pronounced to be considered as early glandular hyperplasia and not sufficient to be classed as moderate glandular hyperplasia. As regards their iodin contents, the upper 14 THE PREVENTION OF SIMPLE GOITRE extremes are in every instance lower than the lower extremes of the preceding group (early glandular hyperplasia). So also the average iodin contents are about as much below those of the group of early glandular hyperplasias as the early glandular hyperplasias are below the group of normal-early glandular hyperplasias. Table 7.-Moderate Glandular Hyperplasia Animal No. Cases. lodin E. per gm. M. dried. A. lodin E. per ^gm. fresh. A. Sheep 1 0.854 0.400 0.136 0.091 Dog 9 0.101 0.345 0.368 0.026 0.076 0.078 Hog 0 Ox 0 There being no glands from hogs or oxen and but one from the sheep series that histologically belonged to the group of moderate glandular hyperplasia, comparisons are impossible. The average iodin contents of the cases recorded are as usual below those of the preceding group. Table 8.-Moderate-Marked Glandular Hyperplasia No. lodin per gm. dried. lodin per gm. fresh. Animal Cases. E. M. A. E. M. A. 0.092 0.014 Sheep 5 0.024 0.031 0.003 0.004 0.000 0.000 0.660 0.109 Dog 9 0.231 0.283 0.042 0.055 0.058 0.011 Hog 0 Ox 0 In the group of moderate-marked hyperplasia also there are but two animals represented. The extremes of iodin content in the dog thyroids are widely separated. As has already been pointed out, it is impossible to tell from the histology alone whether a given gland is undergoing further hyperplasia or is reverting to a lesser degree, in which latter event the iodin would be higher. Another factor must also be considered, that is, that dogs live under far less con- stant conditions than sheep and oxen. It will be shown later that the more constant the conditions of life the more constant are the iodin contents. The averages show the same drop in the iodin con- tents proportional to the degree of increase of the hyperplasia. WESTERN RESERVE UNIVERSITY 15 No. lodin per gm. dried. lodin per gm. fresh. Animal Cases. E. M. A. E. M. A. 0.036 0.006 Sheep 6 0.000 0.006 0.000 0.001 0.000 0.000 0.640 0.123 Dog 18 0.073 0.114 0.014 0.023 0.008 0.002 Hog 0 0.270 0.062 Ox 5 0.215 0.189 0.042 0.041 0.077 0.016 Table 9.-Marked Glandular Hyperplasia Table 9 includes those glands having the most marked degree of thyroid hyperplasia and in consequence the lowest iodin contents. The only glands in which no estimable amount of iodin was found were in sheep, although, histologically, the degree of hyperplasia was no greater than in other glands which showed traces of iodin. The average iodin contents are all lower than the averages of the pre- ceding group. So also the extremes are lower except in dogs' thy- roids, in which the same wide variations are noted as in Table 8. Our explanation is the same. SUMMARY AND DISCUSSION Table 10, showing average iodin contents, has been introduced both as a summary and to emphasize the relation which exists be- tween the iodin contents and the corresponding histologic structure. Tarle 10.-Averages. Anatomic Groups Sheep. Dog. lodin per gm. Hog. lodin per gm. Ox. lodin per gm. lodin Dried per gm. Fresh Dried Fnesh Dried Fresh Dried Fresh Normal . 2.467 0.686 3.322 0.777 2.515 0.884 3.461 1.117 Normal-early .. 0.677 0.176 0.879 0.174 1.230 0.337 2.317 0.628 Early 0.625 0.139 1.102 0.285 1.646 0.462 Early-moderate ... .. 0.548 0.131 0.262 0.082 0.795 0.224 1.000 0.226 Moderate .. 0.400 0.091 0.368 0.078 Moderate-marked .. 0.031 0.004 0.283 0.055 Marked .. 0.006 0.001 0.114 0.023 6.189 6.04 i Colloid .. 2.996 0.818 1.985 0.459 2.353 0.681 Colloid-early .. 0.792 0.206 0.945 0.217 Since colloid glands differ from normal glands essentially in that they have undergone active hyperplasia, two series (1), normal, and (2), colloid, must be recognized. Taking up the normal series, which is practically complete in that it contains all the gradations of hyperplasia, it is seen that in all four species of animals the strictly normal glands have the highest iodin contents and those with mark- ed glandular hyperplasia the lowest. The intervening groups show 16 THE PREVENTION OF SIMPLE GOITRE progressive decline, depending on the extent of the hyperplasia. The greatest drop in iodin content between any two successive groups occurs between the normal and the normal-early glandular hyper- plasias, that is, those glands showing the earliest histologic deviation from normal. This great drop occurs with all four species and is similar in nature to the drop which occurs between the pure colloid glands and the colloid-early glandular hyper- plasias. As has been said, this drop suggests that there is a minimum iodin content necessary for the maintenance of the normal or colloid state of the gland, and, since the amount of iodin present in normal or colloid glands is, as a rule, far in excess of this minimum, it is possible, that this difference repre- sents the reserve or factor of safety. Certain details of this relation of iodin to the structure of the glands are more clearly shown in the full Tables 11, 12 and 13. Here it will be seen that by arranging the iodin contents in series from minimum to maximum, the glands are also arranged in series accord- ing to their histology, their colloid contents and their weights. In other words, the weights of the glands vary directly with the degree of hyperplasia and inversely with the percentage iodin content; the stainable colloid varies inversely with the degree of hyperplasia and directly with the iodin content, and the degree of hyperplasia varies inversely with the iodin contents (the normal and colloid series being, of course, considered separately). It is also noticed that within any anatomic group there is con- siderable variation in the iodin contents. This is for the greater part due to the arbitrary anatomic groups, since the glands show histologic variations corresponding to the iodin variations, but not sufficient to warrant separate grouping. In other words, the arbi- trary groups but imperfectly represent the gradations which the complete tables fully picture. It may also be added that no special stress is laid on the actual figures of the iodin determinations, but only their relative importance as a series has been considered. Other observers with other methods may obtain different figures, but the relation between the iodin con tent and the gland structures, we believe, will always be found con- stant. Passing now to the colloid series, it will be seen that only two groups of colloid glands have been observed: (1) pure colloids, (2) colloid-early glandular hyperplasia. This is noteworthy because in WESTERN RESERVE UNIVERSITY 17 TABLE 11.-PIGS' THYROIDS P. 2. P. M. P. 21. P. 17. P. 7. P. 16. P. 6. P. 18. P. 5. P. 19. P. 25. P. 12 P. 20. P. 4. P. 26. P. 10. P. 23. P. 14. P. 11. P. 9. P. 8. P. 1. P. 15. P. 3. P. 22 P. 13. - ° 2 o» ? 8 10 mos. F. 8 mos. F. 8 mos. F. 8 mos. M. 2 yrs. F.. 10 mos. M 8 mos M. 10 mos. M 9 mos. F. 10 mos. F. 10 mos. M. 10 mos. F. 10 mos. F. 10 mos. M. 8 mos. M 8 mos. M 1 10 mos. M .♦ 10 mos. M. 10 mos. F. 10 mos. M. 10 mos. F, 9 mos. F. 10 mos. M. 10 mos M 10 mos. F. Age. Sex. Good .. Condition. Iowa ? Iowa Locality. Weight of Gland. * Pale yellow, transluc. Clear vellow-red - - - " Yellow-red, transluc.. 1 Color. Moderately soft. Moderately soft. Moderately soft. Moderate.... Firm Consistency. 1 Reduced. Visible.. XT ' 1 Normal.. Colloid. + + + + +: + + + + + + + + + + : + + +: : .: : : : I Normal. I Colloid. Normal-Early. Colloid-Early. 1 Early. 1 Early-Moderate. I Moderate. Moderate-Marked. I Marked. 0.769 0.769 0.846 1.046 1.158 1.230 1.538 1.538 1.938 1.938 1.938 1.938 1.938 1.984 1.997 2.307 2.517 2.615 2.768 2.768 2.768 3 230 3.691 3.691 3.728 4.154 lodin per gm. Dried. 0.198 0.233 0.241 0.279 0.291 0.337 0.425 0.553 0.523 0.557 0.596 0.599 0.603 0.774 0.601 0.783 0.587 1.071 0.905 0.910 0 805 1.121 1.220 1.456 1 140 1.298 lodin per gm. Fresh. ' *Age estimated by butchers. TABLE 12.-CATTLE THYROIDS General. Gross. Microscopical. Chemical. Case. No. Age.' Sex. Condition. Locality. Weight of Glands in gms. Color. Consistency. Colloid. I Normal. | Colloid. I Normal-Early. I Colloid-Early. 1 Early. 1 Early-Moderate. I Moderate. 1 Moderate-Marked. I Marked. i h-2 lodin. per gm., Fresh. C. 34. C. 36. C. 29. Young steer.* Calf, female. Good .. Poor... Northern Ohio. Northern Ohio. Michigan.. 41 53 370 Opaque, pale brown. Very pale brown.... Soft Absent .. + + + 0,077 0.154 0.215 0.016 0 031 0.042 C. 30. Young steer. Good .. Northern Ohio. Northern Ohio. Northern Ohio. Northern Ohio. Northern Ohio. Northern Ohio. Northern Ohio. Northern Ohio. Northern Ohio. Northern Ohio. Texas 39 44 44 44 + 0.231 0.052 C. 35. C. 40. C. 33. C. 31. C. 37. C. 38. C. 39. C. 32. C. 65. C. 46. C. 51. C 45 13 27 17 17 16 19 16 13 12 12 13 Dark brown-red.... Brown red. Dark brown-red.... Translucent, brown- red. Pale brown, trans- lucent. Pale brown, trans- lucent. Brown red, translu- cent. Brown red, translu- cent. Dark brown-red, translucent. Pale brown-red, Moderate. .. Firm Visible .. Normal.. - + + + + + + + + + •• •• t 0.270 0.969 0.969 1.030 1.000 1.030 1.123 1.630 2.153 2.000 2.186 0.062 0.205 0.205 0.222 0.248 0.252 0.314 0.456 0.482 0.585 0.615 aa 44 44 13 translucent. Very pale yellow + 2.076 0.617 C. 48. C. 64. C. 41. C. 42. C. 47. C. 44 C. 43. C. 49. C. 52. C. 57. C. 56. C. 63. C. 55. C. 50. C. 62. C. 61. C. 60 Young bull.. Young steer. U 4* 44 44 •• Northern Ohio. Texasf..... 12 13 11 5 12 11 15 11 11 12 12 11 11 12 11 12 12 11 brown, transluc. Pale yellow brown, translucent. Pale yellow brown, translucent. Pale yellow brown, translucent Pale yellow brown, translucent. Yellow-brown, translucent. Pale brown, trans- lucent. Pale brown, trans- lucent. > Pale brown, trans- lucent. Brown red, translu- cent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. Pale yellow, trans- 44 44 44 + + + + + + + + + + + + + - ■+ + •• 2.307 2.615 2.676 2,384 2.730 2.922 2.037 3.107 3.091 3.254 3.537 3.230 3.230 3.381 3.630 3.630 3 230 0.653 0.664 0.666 0.726 0.892 0.901 0.952 0.988 0.992 1.020 1.039 1.040 1.069 1.133 1.152 1.161 1.208 C. 58. C. 53 C.54. C. 59. 12 13 11 11 lucent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. Pale yellow, trans- lucent. + + + + •• 3.999 3.999 4 153 4.768 1.215 1.292 1 347 1 592 •i.e. 3 to 5 yrs. as estimated by cattlemen. tGeneral term among cattlemen, meaning any part of Great Plaias. table 13.-sheep thyroids General. Gross. Microscopical. Chemical. Case No. Age. Sex. । Condition. | Locality. Weight in gms. Color. Consistency. Colloid. 1 4- + : : -|r + 4~~l~4~4~ + + 4~4~ + +. 4- + 4~ + + . . | Normal. 1 . : : 4- -K : , I ,5 = : 5 : : : : : : + • : : : : : : : : : : : : : : : : : : : : : r | Colloid. ce W E 0 25 + © 3 + lodin, per gm., Dried. lodin, per gm , Fresh. S. 33. S. 37. S. 39. S. 45. 8. 20. S. 36. S. 38. S. 34. S 35. S. 59. S. 21. S. 49. S. 47. 8. 32. S. 43 S. 51. S. 50. S. 46. S. 52. S. 53. S. 55 S. 48. S. 63 S.60a S. 58. S. 60. S. 61. S. 62. 8. 65. S. 44. S. 67. S. 57. S. 70. S. 69. S. 66. S. 54. 8. 64 8. 19 S. 56 S. 68. F 8 mos... M. 10 mos . M. 9inos... M.8 mos... 7 8 mos... M. 9 mos... M. 10 mos.. F. 9 mos... F. 9 mos... 7 lyr M. 1 yr F. 8 mos... M. 9 mos... F. 4 yrs.... F. 5 yrs.... M.9 mos... M. 9 mos... riyn... 1 lyr 1 1 yr 7 1 yr F. 9 mos... F. 3 yrs.... M.2yrs.... 7 1 yr F.3 yrs.... F.3 yrs.... F. 4 yrs.... F. 4yrs.... F. 4 yrs.... 7 lyr 7 1 yr F. 4 yrs.... F. 3yrs.... F. 3 yrs.... 7 lyr..... 7 I yr M. 2yrs.... M.1 yr M. 10 mos.. Good... Fair. .. Good... Fair, .. Good... Fair. .. Good... Fair. .. Good... Excel- lent. Good... Seville, Ohio. Seville, Ohio. Seville, Ohio. Seville, Ohio. 7 Seville, Ohio. Seville, Ohio. Seville, Ohio. Seville, Ohio. 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 N orthern Ohio. Nor them Ohio. N^o r t hern Ohio. N o r t hern Ohio. 7 7 7 N o rthern Ohio. Nor them Ohio. N o r them Ohio. 7 N o r t hern Ohio. 7 7 Nor them Ohio. 95.0 115.0 85.0 55.0 110.0 120.0 130.0 98.0 110.0 6.0 61 0 48 0 6.0 370.0 15.0 18.0 16.0 25.0 ?.9 6.7 6.5 5.9 8.0 58 0 4.5 8.0 8.5 8.0 8.5 6.0 7.5 5.4 7.0 8.0 7.5 6.55 8.0 52.0 6.4 7.5 Gray red, translu- cent. Gray red, opaque... Gray, translucent... Opaque, red, granu- lar. Opaque, red, granu- lar. Opaque, red, granu- lar, R^d-gray, translu- cent. Red-yellow, trans- lucent. Red-yellow, trans- lucent. Red-yellow, trans- lucent. Red-yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans lucent. Clear yellow, trans- lucent, Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. ■ Clear, yellow, trans- lucent. • Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Clear yellow, trans- lucent. Soft Moderate.... Firm v • • ? • • • ' • . 44 Visible... None .... Visible... None Visible... Normal.. Visible... Normal, 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.024 0.040 0 036 0.092 0 400 0.548 0.461 0.677 0.923 0.784 1 000 1.260 1.247 1 425 1 602 1.615 1.769 1.812 2.153 2.288 2.153 2.392 2.250 2.644 3 292 3.054 3.058 3.150 2.500 3.691 3.529 4.368 4.614 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.003 0.005 0.006 0.014 0.091 0.131 0.138 0.176 0.201 0.202 0.282 0.308 0 313 0 365 0.405 0.430 0.455 0.468 0.564 0.582 0.608 0.694 0.727 0.735 0.823 0.861 0.872 0.873 0.890 0.974 1.087 1.200 1.318 -4. 20 THE PREVENTION OF SIMPLE GOITRE our human collection (to be reported), using the same anatomic classification and methods, the colloid series will contain sufficient gradations of the hyperplasias to parallel the normal series through- out and will be discussed with equal emphasis. These two groups of colloid glands suffice, however, to illustrate first, the fact that pure colloid glands of the different animals have iodin contents very closely approaching those of normal glands, and, second, that colloid-early glandular hyperplasias have iodin contents similarly close to those with normal-early glandular hyperplasias. We believe that if all the conditions (diet, etc.) could be strictly controlled the iodin content of colloid glands would absolutely paral- lel those of normal glands and that a like parallelism would be seen throughout the gradations of hyperplasia of both the normal and colloid series. The probable reasons why we rarely obtain colloid glands in sheep, cattle and hogs are (1) that they are killed at an age when the natural occurrence of colloid glands is rare, and (2) that the conditions of life (as regards habits, food and locality) are more constant than obtain for man or dogs. So striking a uniformity in the anatomic changes for widely different animals can not be without significance. It suggests that the etiologic factor or factors in the production of thyroid hyperplasia (goitre) are probably the same in all these animals. The constant relation between structure and iodin content suggests that iodin is a common factor in all these animals. It seems fair to infer from this comparative study of anatomic structure and iodin content that iodin is a very important factor, act- ing in the same direction and manner in all classes of animals in which hyperplasias (goitrous changes) are observed, and that, therefore, for a general study of goitre, any of the animals men- tioned may be used as a basis, and the results be applicable to man. Note.-In conclusion we wish to thank Professors Torald Sollmann and G. N. Stewart for their careful criticisms and suggestions. WESTERN RESERVE UNIVERSITY 21 | Reprinted from Journal of Experimental Medicine, Vol. xiii, No. 4, 1911.] FURTHER OBSERVATIONS AND EXPERIMENTS ON THE SO-CALLED THYROID CARCINOMA OF THE BROOK TROUT (SALVELINUS FONTINALIS) AND ITS RELATION TO ENDEMIC GOITRE* By David Marine, M. D., and C. H. Lenhart, M. D. {From the H. K. Cushing Laboratory of Experimental Medicine, Western Reserve University. Cleveland, in conjunction with the Pennsylvania State Fish Commission.') Plates LX and LXI.t PART I. INTRODUCTION In our first report1 on this subject the following observations were emphasized: (1) That all the trout, irrespective of age or location, in the ponds of the hatchery were affected with thyroid hyperplasia. (2) That it was most marked in the younger fish. (3) That a definite relation existed between the amount of water, the concen- tration of fish, and the quantity of food, and the severity of the disease. (4) That older trout are less susceptible to the disease, as shown by a tendency towards spontaneous recovery under con- stant conditions as regards the concentration of fish, the water supply, and the food. (5) That recovery from the less marked degrees of thyroid hyperplasia constantly occurred either on tak- ing them from the ponds and putting them in their native environ- ment (the brook) or on leaving them in the theoretically polluted pond water, but reducing the food and the concentration of fish, or on the addition of small amounts of iodin. (6) That our at- tempts to transplant the hyperplastic thyroid tissue from one fish to another of the same age and stock were negative. (7) That anatomical studies alone were insufficient criteria upon which to make a diagnosis of cancer, because the thyroid of the bony fish is normally a widely and loosely distributed non-encapsulated gland, any growth of which would give the appearance of invasion of the surounding tissues. (8) That there was no experimental basis for considering the disease, in its early stages at least, other than severe endemic goitre. * Received for publication, February 6, 1911. t The plates have been omitted in this reprint. ijour. Exper. Med.., 1910, xii, 311. 22 THE PREVENTION OF SIMPLE GOITRE In the following report we shall present our observations on the earliest manifestations of thyroid hyperplasia in the very young fish; our observations on the spontaneous recovery of the affected fish when transferred to a natural environment; and our experi- ments with the late stages of the disease, or those stages associated with large, visible and ulcerated goitres. These observations and experiments were made during the sum- mer of 1910 at the same hatchery at which the earlier work was done. OBSERVATIONS ON THE HISTOLOGICAL CONDITION OF THE THYROIDS OF TROUT FRY. In order to determine how early in the life of hatchery trout thyroid hyperplasia (goitre) begins, we collected weekly specimens of the fry, beginning as soon as the egg membranes were shed (January 15, 1910) and continuing until October 8, 1910.2 Sections have been prepared from the thyroid areas of the entire series. It is difficult to distinguish the thyroid tissue in these fry up to the end of the second month, and we should hesitate to state that the thyroids at this age were hyperplastic, although there is no colloid present and the epithelium lining the follicles is high cubical. In fortunate sections it is possible to distinguish an alveolar lumen. Beginning with sections taken on March 16, one can state positively that hyperplasia has begun. The thyroid tissue in most cases fills the areolar space about the ventral aorta. The epithelium lining the follicles is high cubical, regular in type, with bluish tinted cytoplasm. There is no stainable colloid. The first evidence of infiltration or invasion of the surrounding structures is seen in the specimens taken on April 30. The thyroid follicles have filled the aortic space and have extended around the bundles of lateral muscles and dorsally toward the floor of the pharynx. From this age (three and one-half months) the growth is pro- gressive, extending into the more resistant structures, as striped muscle and bone. As the gland follicles grow into the pharyn- 2 The entire series was collected from a single cypress hatch trough. This was one of a series of eight-all of the same size (13 feet long, by 20 inches wide, by 6 inches deep). Water was supplied directly from the spring in sufficient quantity to replace the contents of the trough every twenty minutes. These troughs were cleaned every day. The fry were fed four times daily for the first month with an aqueous suspension of hog's liver strained through muslin. During the second and third months, a similar suspension strained through coarser muslin was fed. Beginning with the fourth month, they were fed finely ground hog's heart muscle freed from adventitious tissues. As the fish grew, the heart muscle was ground coarser. No estimation was made of the number of fry in the trough at a given time. They were thinned from time to time and though always crowded had free swimming space. For the plan of the hatchery see page 40. WESTERN RESERVE UNIVERSITY 23 geal submucosa, the vascularity of the newly formed thyroid tis- sue is transmitted through the translucent mucosa of the pharynx as a pale red discoloration of the floor of the pharynx between the first and third gill arches. This pharyngeal discoloration was detectable in these particular fry about the middle of July (six months old). It may occur earlier in fish kept under less favor- able conditions. The appearance of visible goitres is always a late manifestation, and we have never observed it until the sub- pharyngeal tissues were filled with thyroid tissue. Gaylord3 has observed visible goitres in brook trout fry of about six months old. We have seen goitres in brook trout fry of about seven months old. This is not common, however, and indicates unusually favorable conditions for thyroid growth and hence unfavorable conditions of food and environment. The results of this study show that thyroid hyperplasia begins at a very early age and is detectable at the end of the second month of extra-oval life. These fry developed thyroid hyperplasia while living in unused water direct from the spring and under unusually clean surroundings as regards any gross appearance of filth. The crowding and the food, therefore, seem to be the most im- portant factors, and the food would appear to be more important than the crowding. The influence that crowding may have on the nutrition of the fish is at this time purely speculative. It would seem that its determination may lie in the field of biochemistry, either by the detection of some substance developed under the con- ditions of food, environment, and overcrowding, which the thyroid growth attempts to counteract, or by showing that the water con- tains salts necessary for the normal nutrition of the fish in suffi- cient amounts under natural conditions, but insufficient under these highly artificial conditions. The influence which food may have is also at this time specula- tive, as little is known of the food requirements of these fish. Liver or heart muscle is a highly abnormal diet and is probably deficient in many of the elements necessary for normal nutrition. When fed in excessive amounts, it is conceivable that it may be in- jurious from the excess of certain, as well as from the deficiency of other elements. lodin has a preventative and curative effect on these early hyperplasias. The explanation of the action of iodin would probably explain the cause of thyroid hyperplasia. It may 3 Jour. Am. Med. Assn., 1910, liv, 227. 24 THE PREVENTION OF SIMPLE GOITRE be stated that there is a deficiency of iodin in all actively hyper- plastic thyroids, but it is not known where the iodin originates or what are the underlying factors which bring about this condition. OBSERVATIONS ON THE HISTOLOGICAL STATE OF THE THYROID GLANDS IN A SERIES OF FISH REPRESENTING SPECIMENS FROM ALL TANKS (PONDS). Similar observations were made in October, 1909, when the ages of the fish were thirty-two, twenty, and eight months respec- tively. In June, 1910, the ages were twenty-nine, seventeen, and five months, the three year old fish having been transferred to the trout stream in April, 1910, and the two and the one year old fish moved down to take their places and to make room for the 1910 fry. Apart from the different ages of the fish and their changed loca- tion, there were but two general conditions markedly different from those obtaining in 1909: (1) season (summer vs. autumn) and (2) a decreased water supply owing to the pipe line not being in operation for the past six months. It was thought that this second examination might offer additional data concerning any seasonal influence or the effect of a lessened water supply, and also serve as a control for the observations made in October. The histological examination of the thyroids of one hundred and five trout showed that they all had well marked hyperplasia. The thyroids of the upper division (houses I to VI, see text-figure 1) were less hyperplastic than at the first examination in October, while the thyroids of the lower division (houses VII to XI) were more markedly hyperplastic than in October.4 The food both as to quantity and quality was. the same as last year. The crowding of the fish was probably not so great. The water supply to the first six houses of the series was increased probably to a third more that that available in October. This was due to a decreased flow from the spring during the months of July, August, September, and October. We believe that the increased water supply during the winter and spring months largely explains the better condition of the fish thyroids in houses I to VI in June than that which existed in October, 1909. In the lower division (houses VII to XI), it will be recalled that in October, with the pipe line in operation, the thyroids were under- 4 The degree of hyperplasia is judged by the amount of stainable colloid and the size of the epithelial cells, and not by the total amount of thyroid tissue or its extension into the surrounding structures, which is present in all of these hatchery fish. WESTERN RESERVE UNIVERSITY 25 going spontaneous involution, while in June, with the pipe line out of operation for the past six months the thyroids in general were more hyperplastic than those of the upper division, with the ex- ception of house VII, which is the first house the water enters after its passage along the original brook bed from the upper division, and to which a small spring is added. In this house (VII) the thyroids are noticeably less active as judged by the standards above mentioned, and it is our opinion that the pas- sage of the water along the brook and its slight increase in volume favorably alter in some unknown manner the effect on the fish. We also look upon the absence of additional water supply from the pipe line for the past six months as an import- ant factor in bringing about the much more active thyroid hyperplasia present throughout the lower division than existed at the examination in October. There was no evidence of any noteworthy seasonal effect. It is generally stated that in mam- mals the thyroid tends to be less active (hyperplastic) during the winter months. Summing up these observations, one may say that they offer further evidence that increasing or decreasing the water supply modifies the condition of the thyroid. We are still ignorant of how an increased water supply lessens the thyroid hyperplasia. It may be that the salts in solution are necessary for normal nutrition and that their reduction disturbs the physiological balance, or that the susceptibility to some infectious agent is decreased by dilution, or by improving the fish's general nutrition. OBSERVATIONS ON THE HISTOLOGICAL CONDITION OF THE THYROIDS OF THE TROUT OBTAINED FROM THE RUNWAYS ABOVE, BETWEEN, AND BELOW THE SEVERAL TANKS (PONDS). Of this series of twenty-five trout, varying in age from seven- teen months to four years, five were taken from the brook above all houses, sixteen from the runways within and between the eleven houses, and four from the tailrace below all houses. Of the five taken from the brook above all houses, one was twenty-nine months old and four were seventeen months old. They were normally colored, strong, vigorous fish and had spent their entire lives in this space of about fifty yards. All had normal thyroids both as regards the individual units, the follicles, and the total amount of thyroid tissue. They had not been fed or cared for in any way. 26 THE PREVENTION OF SIMPLE GOITRE Of the sixteen fish taken from the wooden runways within and between the several houses, seven were considered as being seven- teen months old, three as twenty-nine months old, and six as being over three years old. None of these fish had normal thyroids. In all there was more or less extensive spreading of the thyroid tissue beyond the normal area. In eleven of the fish the thyroids were in the colloid or resting stage, i. e., the individual follicles con- tained normally staining colloid and the epithelium was normal in type, although the total number of follicles was greatly increased above the normal. The remaining five fish had mild degrees of active hyperplasia. These sixteen fish had escaped from the ponds, but there was no way of ascertaining how long they had lived in the runways except by their size and the development of the color pigment in the skin, which indicated a stay of many months, and, in some instances, of years. The four trout taken from the tailrace below the last house were fish that had been transferred to the trout stream not later than April 15, 1910, and had, therefore, spent at least two months, and perhaps longer, outside the ponds. All were large three year old fish with darkly pigmented bodies. Two of these had pure colloid goitres, and in the remaining two involution was not complete. Summing up the observations in this series, it is seen that the trout which lived in the raceway above all houses and which had never been confined in the ponds or fed or cared for in any way, developed normally and maintained normal thyroids throughout their lives, while fish not a yard away, but confined in the ponds, artificially fed, and overcrowded, quickly developed marked thy- roid hyperplasia. Next, it is seen that fish taken from the small plank troughs which conduct the water from one pond to another may have colloid or quiescent thyroids, that is they may recover from the hyperplasia present at the time of their escape from the ponds, even though fish in ponds above and below them are at the same time developing thyroid hyperplasia. Such observations do not accord with our present conceptions of a water-borne infectious agent as the etiological factor. On the other hand, certain of these fish had active hyperplasia, showing that the same factors which operate within the ponds are also operative in the raceways, but to a lesser degree. Lastly, fish taken from the tailrace show the same tendency WESTERN RESERVE UNIVERSITY 27 toward recovery, although living in the theoretically most polluted water. No general conclusion can be drawn from these observa- tions beyond the negative evidence against a water-borne infection as the cause of goitre, and in favor of the interaction of several factors of a chemical nature influencing the nutrition of the fish. OBSERVATIONS ON THE HISTOLOGICAL CONDITION OF THE THYROIDS OF THE TROUT TAKEN FROM THE TROUT STREAM. There were eighteen trout in this series. All of these fish had spent at least two months in the stream. Two of them had the gross appearance of native trout, and as their thyroids were histologically normal, it may be concluded that they had never been confined in the ponds. The remaining sixteen fish had enlarged thyroids. Three had small external goitres. In most of the cases the thyroid had returned to the pure colloid state, but in certain specimens the involution was not complete. To sum up this series, it appears that fish hatched and reared in the stream do not develop thyroid hyperplasia, and also that fish whose thyroids undergo marked hyperplasia during their stay in the ponds (without exception, so far as our observations on fifty- two cases are concerned) proceed to spontaneous recovery when transferred to the trout stream. We have also examined pickerel, suckers, and cat fish from this stream and have never observed ab- normal thyroids in them. PART II. EXPERIMENTAL OBSERVATIONS These experiments were undertaken to supplement the experi- ments made in October, 1909, when the effects of iodin on mild degrees of hyperplasia5 were studied, and to extend these observa- tions to include the severest grades; namely, fish with large, ulcer- ated, ventral goitres. The experiments can be divided into three series. In the first, was studied the effect of iodin on forty-one months old fish, with large, ulcerated, ventral goitres and with gen- 5 The first constant and readily detectable clinical sign of thyroid hyperplasia is the reddish discoloration of the floor of the pharynx. This reddening depends on the extension of the highly vascular thyroid tissue up to the mucosa of the pharnyx and the transmission of the color of this tissue through the translucent mucosa. The extent of the area of reddish discoloration is a good clinical index of the extent of the thyroid overgrowth, the color of the normal pharyngeal floor being white or grayish white. As the hyperplasia changes to the colloid or quiescent state during recovery, the vascularity decreases, and with it the reddish color fades to a yellow or yellowish brown which persists throughout the life of the fish. The coloration depends upon the thyroid follicles with their colloid contents. 28 THE PREVENTION OF SIMPLE GOITRE eral emaciation; in the second, the effect of iodin on twenty-nine months old fish with small, visible goitres, but otherwise of a clean, healthy appearance; and in the third, the effect of the non-adminis- tration of iodin on twenty-nine months old trout with small ventral goitres. Experiment I. Effect of lodin on Large Ulcerated Goitres.6-Twelve forty-one months old, emaciated brook trout, instead of being destroyed, as is usually done, were saved for this purpose when the three year old fish were transferred to the trout stream in April. On June 20th they were placed in a cypress trough 13 feet long, 20 inches wide, and 8 inches deep. The water used was taken directly from a spring at the small brook at the right of figure 1. Its temperature was 48-50 degrees F. The flow through the trough was adjusted so that it was sufficient to fill the trough in one hour. All the fish had large ventral ulcerated and bleeding goitres. Three had gill fungus and died during the experiment. Of the remaining nine, five were sacrificed on the fortieth day, and four on the sixty-second day. The food consisted of about three ounces of finely chopped hog's heart or liver given each morning, and on three occasions during the first forty days live minnows were given. One cubic centimeter of the U. 'S. Pharmacopeia tincture of iodin (potassium iodid 5 grams, iodin 7 grams, alcohol (95 per cent.) to 100 c.c.) was added to the trough contents each morning before feeding. The trough was located in a well shaded gully and wire cloth was fastened about it to prevent the fish from jumping out. Once each week the debris (leaves, uneaten food, and feces) was removed from the trough by flushing. The examination of the nine fish at the time of removal revealed remarkable changes in their appear- ance. They had all gained greatly in weight. They had lost much of their dark pigment, and the color pigment had developed in the fins and along the sides of the fish. They were lighter in color than the native trout, having the silvery sheen approaching that of the true salmon. They were all robust clean fish. Of the five removed on the fortieth day, three still had visibly flattened and ulcerated goitres. Of the four removed on the sixty-second day, only one had distinct ulceration, the ulceration on the others having practically healed. The histological condition of the thyroids of these nine trout is given in table I. Of the five removed on the fortieth day, all showed evidence of infection. In two, the infection had nearly resolved. The stroma was increased in all, probably abnormally so on account of the infection. In the more protected follicles to which the infection had not extended, or in which it had cleared up, there was the normal accumulation of colloid with the return of the follicular epithelium to the flat cubical type. Throughout the infected areas the follicles contained large numbers of leucocytes and shed epithelial cells, and the stroma was cellula'r, giving the appearance of much new connective tissue formation (granuloma) together with an infiltration of leucocytes. This appearance at first gives one the impression of a connective tissue tumor rather than of thyroid granulation tissue. In two there were 6 Ulceration and infection are very common complications of the large goitres. The most important causes predisposing to them are: (1) Injury. The goitre being the most prominent point on the ventral surface of the fish is exposed to frequent trauma, especially in the confined quarters of the ponds. (2) As the goitre enlarges, the skin over it is thinned by pressure atrophy, and perhaps a break in continuity may occur from this cause alone. When once the skin is broken, infection is practically unavoidable on account of the rich bacterial flora of the ponds and because of the increased susceptibility of these fish which the growing goitre implies. After infection occurs, the necrotic tissue is worn away by friction, so that as we see these goitres they often have flat ventral surfaces practically in a plane with the ventral surfaces of the bodies of the fish. Therefore it follows that by placing such fish in shallow troughs for experimental purposes the chances of healing are reduced, because the exposed surface of the goitre is frequently rubbed against the bottom. The occurrence of infection in fish goitre is perhaps the most important and most frequent complication, and should be considered in any interpretation of histological data. WESTERN RESERVE UNIVERSITY 29 No. of fish. Duration of iodin treatment Histological condition of thyroid gland. Diagnosis and general remarks. Distribution, infiltration. Stroma. Stainable colloid. Epithelium. 1 40 days Large ulcerated goitre; all tissues beneath pharyngeal mucosa in- filtrated ; disappear- ance of bone and mus- cle. Markedly thick- ened through- out ; densely in- filtrated with leucocytes; ar- eas of abscess formation. In the more pro- tected areas just beneath pharyngeal mucosa and along gill arch arteries are areas with well stained colloid and but few leucocytes. Flat cubical in the involuted areas ; little distinguish- able thyroid epithel- ium in the infected area; one papillo- adenoma unaffected by iodin. This is an example of a severely ulcerated goitre with marked general inflammatory reaction giving the appearance in places of sarcoma. Most of the thyroid follicles are filled with leuco- c y t e s - involution, general infection, and papillo-adenoma. 2 40 days Large ulcerated goitre; much thyroid tissue throughout, which has extended into all sub- pharyngeal tissues; absorption of bone and cartilage; compression of aorta. Everywhere thickened and densely infiltrat- ed with leuco- cytes throughout most of goitre. Well preserved fol- licles contain col- loid. Entire lower portion is an infil- trated mass of leu- cocytes and granu- lation tissue. Cubical in the pre- served portions, while in the infected area the epithelium is not clearly dis- tinguishable. Old infected goitre with destruction of most of the true thy- roid tissue by the in- flammatory process. 3 40 days Large, flattened, nearly healed goitre; all sub- pharyngeal tissues in- filtrated ; absorption of bone, muscle, and cartilage; compression of aorta; thyroid growth at tip of lower jaw. Increased throughout, es- pecially in the exposed parts. Colloid normal throughout goitre; leucocytes in the colloid of the ex- posed and inflam- matory area. Cuboidal in general but columnar on the crests of many of the infoldings and particularly in the p a p i 11 o - adenom- atous area. Rapid involution of goitre with healing of the infection; here is an adenoma- tous area that is be- ginning to change; the submaxillary thy- roid tissue has changed to the pure colloid state. 4 40 days Large ulcerated goitre; all subpharyngeal tis- sues infiltrated. Everywhere i n- creased; much cellular exudate throughout ven- tral portion of goitre. All follicles of pro- tected areas contain colloid. Those in the infected area are ill-defined and filled with leuco- cytes. In general cuboidal in the uncompli- cated areas but col- umnar in the ' in- fected area. Example of involution to the colloid state occurring in a mildly infected goitre; in- fection resolving. TABLE I. 30 THE PREVENTION OF SIMPLE GOITRE No. of fish. Duration of iodin treatment. Histological condition of thyroid gland Diagnosis and general remarks. Distribution, infiltration. Stroma. Stainable colloid. Epithelium. 5 40 days Small non-ulcerated or healed goitre; all tis- sues beneath pharyn- geal mucosa invaded; absorption of bone. Markedly i n- creased through- out- probably largely scar tissue. Follicles small, col- 1 o i d - containing; few leucocytes still still present in cer- tain follicles. Cuboidal throughout. Example of nearly complete involution with healing of the ulcerated and infect- ed goitre. 6 62 days All subpharyngeal tis- sues involved; little normal thyroid pres ent; absorption o f bone and compression of aorta. Granulation t i s- sue overgrowth; inflammatory ex- udate through- out stroma. Colloid follicles scat- tered through dor- sal part of goitre. Cuboidal in the col- loid-containing fol- licles. Much of the thyroid tissue re- placed by cellular exudate and granu- lation tissue. Example of slight in- volution in 62 days. This is probably due to the marked infec- tion and illustrates the disturbing influ- ence of infection on involution. 7 62 days Small healed goitre; all subpharyngeal tissues invaded; absorption of muscle and bone. Everywhere i n- creased, espec- ially in ventral portion. Follicles small; col- loid-c ontaiming throughout. Cuboidal regular, and uniform. Example of complete healing of infected area and of complete involution to the col- loid state. 8 62 days Healed goitre; all sub- pharyngeal tissues in- vaded including bone and cartilage. Very dense - probably result of old infection. Follicles very small; contain normal col- loid ; one area with marked infoldings of lining epithelium and containing very little colloid-like material. Cuboidal throughout the colloid-contain- ing portion; the adenomatous area still has high col- umnar epithelium. Example of involution and healing of an in- fected goitre. The goitre also contains an adenoma with papillomatous i n - growths which has been slightly modi- fied by the iodin in the 62 days. 9 62 days Healed goitre; all tis- sues beneath pharyn- geal mucosa invaded and also small nodules projecting into phar- ynx ; absorption o f bone and muscle. Slightly increas- ed. Follicles everywhere contain colloid ; some exudate i n places in stroma. Cuboidal, regular, uniform. Example of healing and involution o f pure type of hyper- plasia, where the only complication was infection. TABLE I. (Continued.) WESTERN RESERVE UNIVERSITY 31 somewhat circumscribed areas with very striking papillomatous outgrowths and infoldings of the lining epithelium. In one of these tumor nodules, iodin had had no detectable effect toward involution, while in the second and less extensive papillomatous growth, iodin had stopped its growth and brought about the early changes of involution, i. e., beginning colloid formation and shrinkage in the size of the epithelial cells. These more or less circumscribed areas of rapidly growing thyroid tissue, with a tendency toward arborescence, are frequently seen in fish goitres, and, as they have many of the attributes of true thyroid tumors (localized, rapid growth, a typical follicle development, and slight or no reaction with iodin), we look upon them as true tumors; and, until something suggestive of malignancy can be recognized, as benign tumors comparable to the ordinary tumors in human goitres. Of the four trout removed on the sixty-second day, one had a papillomatous tumor with complete involution of the surrounding original hyperplasia while the tumor was only slightly modified, again suggesting that in such cases the thyroid cells have lost certain of the attributes of ordinary hyperplastic thyroid cells. All of these sixty-two day fish thyroids showed practically complete involu- tion, with nearly complete healing of the infections. Summing up this experiment, the more striking features are: (1) the remarkable improvement that may take place in these fish in a short time; (2) the extent and frequency of infectious processes in fish goitres, and the influence which they exert in retarding in- volution from iodin; (3) the presence of adeno-papillomatous areas, in three of the nine cases, that resemble in many respects true thy- roid tumors. These nine cases represent the very advanced stage of fish goitre. Such fish are always destroyed by the caretaker when the transfers are made, because it is popularly believed that they can not recover. This is erroneous. They can and do recover in most instances when sufficiently favorable hygienic con- ditions are instituted. The goitre does not ordinarily disappear as the fish recovers, for the same reason that it does not disappear with recovery in mammals. It does, however, change to the col- loid or quiescent stage, just as in mammals, and this is the nearest approach to the normal state possible for them. There is, there- fore. no biological evidence that these severe grades of goitre are cancerous. Experiment II.7 Effect of lodin on Thyroid Hyperplasia of Twenty-Nine Months Old Fish with Small Ventral Goitres but Otherwise of Healthy Appearance.--This experiment was carried out in exactly the same way as experiment I. The trough was of the same size and situated alongside of that used in experiment I. The water supply, both as regards quality and quantity, the food, the amount of iodin, and the general care were similar. Seven trout were placed in the trough on June 20, 1910. Four were removed on July 30, and three on September 1, 1910. They had all gained greatly in weight. Much of the dark skin pigment had disappeared. The orange colored pigment in the fins and the yellow-red spots along the sides of the body had 7 Control experiments with trout can not be carried out as with mammals for the reason that the hemorrhage and infection consequent upon removing portions of the goitre can not be controlled. We therefore took as controls five fish of the same age and from the same pond, showing small ventral goitres. The histological examination showed well marked active hyperplasia in all these specimens. 32 THE PREVENTION OF SIMPLE GOITRE No. of fish. Duration of iodin treatment. Histological condition of thyroid gland. Diagnosis and general remarks. Distribution, infiltration. Stroma. Stainable colloid Epithelium. 1 40 days Entire space beneath pharyngeal mucosa in- filtrated with thyroid tissue; absorption of bone, cartilage, and muscle; ventral sur- face of goitre worn away by friction and ulceration. Generalized i n - crease; also ex- tensive cellular exudate and granulation tis- sue formation. • Many follicles with normal colloid throughout goitre; extensive areas where follicles con- tain shed epithel- ium and leucocytes with little true col- loid. Flat cubical in all follicles with norm- al co/lloid; columnar in the inflammatory areas; one area has arborescent o u t - growths of lining epithelium (tumor). Involution to colloid state well advanced. The ulceration and inflammatory reac- tion are complicating and retarding fac- tors. One large cir- cumscribed papillo- matous area (adeno- ma). 2 40 days Entire space beneath pharyngeal mucosa in- filtrated with thyroid tissue including bone and cartilage. Slightly increased especially about bone and skin. Follicles generally enlarged and filled with normally staining colloid. Uniform, flat, cu- boidal. Complete involution to colloid state. No complicating factor. 3 40 days Entire space beneath pharyngeal mucosa in- filtrated with ulcerated thyroid tissue. Marked increase in stroma and extension of in- flammatory re- action through- out goitre. Follicles in less in- flamed portion are filled with colloid; in the main mass of the goitre the fol- licles contain leuco- cytes and granular albuminous debris. Throughout the more infected areas the follicles have col- umnar epithelium while the remaining follicles have cu- boidal epithelium. Involution well ad- vanced in the areas free from inflamma- tory reaction. 4 40 days Entire space beneath pharyngeal mucosa in- vaded with thyroid tis- sue, including bone and muscle. Slight general increase. Follicles enlarged and show infold- ings of the lining epithelium; colloid normal. Cuboidal throughout. Complete involution of a small uncompli- cated goitre. 5 62 days Entire space beneath Well marked in- pharyngeal mucosa in- crease. vaded and infiltrated with thyroid. Follicles small rounded and filled with colloid. Cuboidal. Complete involution. No complication. TABLE II. WESTERN RESERVE UNIVERSITY 33 No. of fish. Duration of iodin treatment. Histological condition of thyroid gland. Diagnosis and general remarks. Distribution, infiltration. Stroma. Stainable colloid Epithelium. 6 62 days Small nodular growths of thyroid tissue ele- vating the pharyngeal mucosa. All tissues beneath mucosa i n - vaded, extensions along gill arch arteries. Slight increase. Follicles enlarged and filled with col- loid. Cuboidal. Complete involution to colloid state. No complication. Acces- sory thyroid growth at tip of lower lip showing complete in- volution. 7 62 days Entire subpharyngeal space filled with thy- roid tissue; erosion of bone and cartilage. Stroma increased about more re- sistant s t r u c - tures. Follicles large in the body of the goitre but small and sep- arated by stroma bands at periphery; colloid normal. Cuboidal. Complete involution. N o complication. Some evidence of a previous mild infec- tion. Table II. (Continued.) 34 THE PREVENTION OF SIMPLE GOITRE developed. The pharyngeal mucosa had lost much of the original reddish discoloration, and the ventral goitres, which at the beginning of the experiment varied in size from 3 to 6 mm. in diameter, became much smaller and of a yellowish translucent appearance, showing that the fish goitre in common with the mammalian goitre usually becomes smaller as the involution to the! colloid state takes place. Two trout had ulcerated and infected goitres, probably the result of rubbing against the trough walls. The histological condition is tabulated in table II, and may be summarized as follows: In all specimens, the thyroid-tissue had infiltrated all the structures beneath the pharyngeal mucosa. There were extensions into the gill arches along the arteries. The adjacent muscle in some cases was totally replaced by thyroid tissue. There was much absorption of the adjacent bony and cartilaginous parts. While the thyroid tissue completely surrounded the aorta, there was no case where it had extended beyond the adventitial coat. There was often compression of the aorta and its branches by the adjacent thyroid tissue. In the two infected specimens there was a very marked increase in the stroma, which was probably largely of inflammatory origin. The stroma is normally increased in active hyperplasia, being more pronounced about the more resistant structures, such as the bone, skin, and arteries. With the exception of the ulcerated goitres, the follicles all contained normally staining colloid. The epithelium had returned to the normal cubical form, and the blood supply was reduced. In one case there was a small accessory goitre at the tip of the lower lip, which upon histological examination showed complete involution to the colloid state, as was tne case of the thyroid proper. This is the best or biological evidence that these submaxillary growths are not metastases, but embryologically misplaced thyroid anlagen.8 Taking the experiment as a whole, we find that these mild de- grees of visible goitres are affected by iodin in the same way as the still earlier stages, before visible goitres appear, and hence are not true tumors, but merely the more advanced stage of the common goitrous process. Experiment 111. Effect on the Thyroid Glands of Tzventy-Nine Months Old Tish (Trout) of a Residence of Thirty-Eight Days in the Trout Stream. -A pond was made in the trout stream (at extreme right of text-figure 1, p. 40) by fencing off with wire cloth a portion of a pool forty feet long where an overhanging bank afforded cover and shade for the fish. This also allowed free entrance and exit for the passing water, and closely approximated the natural environment of the native trout. Fifteen twenty-nine months old fish with very small ventral goitres, but otherwise of healthful appearance, were transferred on June 22 from the ponds to the enclosure above described. No iodin was used and the only food given directly was some live minnows on three occasions. On July 30 we were able to recover eight of these trout. Their general color was perhaps somewhat brighter than at the beginning of the experiment, and there had occurred a slight development of the orange and yellow skin spots. All were active, clean, vigorous, well nourished fish. The pharyngeal mucosa was still somewhat reddish in color and the ventral tumors were still visible. 8 We have never observed true thyroid metastases. By some observers the submaxillary growths have been looked upon as metastases. They were present in 2 to 3 per cent, of all fish with visible ventral goitres examined by us. We have observed one instance of an abdominal goitre in a twenty-nine months old fish. The thyroid mass was round and encapsulated and measured 1 by 1.2 cm. It was attached to the cardiac end of the stomach by a connective tissue pedicle. This fish also had a large ventral goitre histologically identical with the abdominal growth. Careful examination of the visceral organs did net show any thyroid tissue. We therefore look upon this specimen as an enlarged aberrant thyroid like the submaxillary growths. WESTERN RESERVE UNIVERSITY 35 Histological examination of these eight fish showed the usual generalized invasion of all the subpharyngeal tissues, with extensions to the gill arches. In general the follicles were large, but about the more resistant structures where the stroma is normally dense, they were small. All the follicles con- tained stainable colloid, but in none had it returned to its normal staining. The epithelium lining the follicles was still columnar or high cubical. When these fish were compared with the controls, however, it was found that a great change had taken place in the thirty-eight days. That is, the thyroids were changing to the colloid stage, but the process was still far from complete. This slow change was to be expected since we had uniformly found the same changes occurring in the thyroids of the trout taken at random from the trout stream after their residence in the stream for varying lengths of time. When this experiment is considered in connection with experi- ments I and II, it is seen that spontaneous involution (recovery) of the thyroid is much slower than the induced involution from iodin. It will be recalled in this connection that similar differences between the spontaneous involution and the induced involution from iodin occur in mammals. However, the end stage of both processes, namely, the colloid gland, agrees anatomically and physio- logically in both groups. In a series of observations upon the thyroids of brook trout, extending from the time of hatching to fish of four or more years old, we have been able to follow step by step the development of thyroid hyperplasia. In these hatchery trout, thyroid overgrowth may be recognized anatomically at the end of the second month of extra-oval life. Under the conditions in which these fish live, the thyroid overgrowth progressively increases, at first filling the aortic space and then invading the surrounding bone and muscle. In our series, this extension into the adjacent tissues was not recognizable until the fourth month of extra-oval life. The time when invasion of the surrounding tissues is first noticed is, of course, subject to great variation in different years and different hatcheries, depend- ing on the general hygienic conditions, food, water supply, etc. If the growth continues, as it usually does, throughout the rapid growing period of the fish, it may first be detected clinically by a reddening of the pharyngeal floor as the thyroid tissue spreads to the submucosa. Later, definite external goitres appear ventrally. These may be present as early as the sixth month of life. The thyroid being, as in mammals, most active during the growing period, the greatest number of visible goitres appear during the second and third years of life. In older fish the thyroid again becomes less active and there is a tendency toward spontaneous SUMMARY 36 THE PREVENTION OF SIMPLE GOITRE recovery. There is no noteworthy change in the anatomical ap- pearance of the thyroid growth, whether seen in very young or in older fish, other than that clearly dependent on the age of the fish, mechanical factors, as size of the goitre, and complicating factors, as infection, hemorrhage, degeneration, etc. There exists, there- fore, no anatomical basis for the diagnosis of cancer in the older fish that is not also present in the youngest fish with thyroid hyper- plasia. All the appearances of invasion, atypical cell growth, etc., are the results of the progressive growth and consequent extension of a non-encapsulated epithelial tissue along the paths of least resistance. In many of the larger goitres there are more or less distinct areas of thyroid hyperplasia, histologically different from the surround- ing thyroid tissue, which we look upon as benign tumors comparable to the benign tumors seen in human goitres. We class them as tumors because they do not react with iodin as does the ordinary hyperplasia. To call these tumors cancer is going beyond our present knowledge and is unjustified, even though analogy with mammalian tumors suggests that certain ones might proceed to true carcinomata. The most common type of the benign tumors is the arborescent-papillomatous form and its many modifications. Infection is a frequent complication in the larger goitres, for the reasons given. It is necessary to recognize this factor in in- terpreting the histological conditions met with, as otherwise, using mammalian standards, some of the appearances observed could easily be mistaken for sarcoma. The effect of iodin on the thyroid hyperplasia has been studied in the early, middle, and late stages. All stages react with iodin, the mild degrees seemingly more rapidly then the severer degrees. Thus the early stages undergo involution in from two to three weeks, while the late stages may require one to two months. The process, therefore, is slower than the iodin reaction time in mam- malian hyperplasia. True tumors do not react with iodin as does ordinary hyperplasia. Infection or other complication modifies the reaction. The reaction with iodin is a specific test for functional hyperplasia of the thyroid. As we have not been able to find any stage in the process that does not react with iodin, we must con- clude that there is none that may be looked upon biologically as cancer. Just as iodin invariably stops the hyperplasia and causes the thyroid to return to the colloid or resting state (from which it WESTERN RESERVE UNIVERSITY 37 may undergo hyperplasia a second, third, or more times, exactly as in mammals), so also spontaneous involution occurs when the fish are transferred to a natural environment. This spontaneous invo- lution has been followed in experiments and has been seen in ex- amples taken at random from the streams. We have never seen an exception to this rule, save in the case of true tumors. As pointed out above, recovery does not imply a disappearance of the goitre; it implies a cessation of growth and return of the active hyper- plasia to the colloid or resting stage. Thyroid hyperplasia is a compensatory reaction, the exact cause of which is still to be sought. There is no evidence that in fish or in man it is either infectious or contagious. All the biological data at present available favor the view that fish goitre in common with mammalian goitre is the symptomatic manifestation of a metabolic and nutritional disturbance. There are three major con- ditions which, in some way still obscure, 'influence the thyroid growth; namely, a limited water supply, overcrozvding, and over- feeding with a highly artificial and incomplete food. The water of the hatchery observed is not intrinsically goitre-producing, as the fish will not develop goitre unless at least the factor of overfeeding with an incomplete food operates at the same time. On the other hand, they recover if the overfeeding and overcrowding are cor- rected, although they remain in the same water. Therefore it seems probable that the food is the major factor acting to bring about a fault of nutrition favorable for goitre development. It is impos- sible at this time to suggest what elements in the food may be at fault, whether, for example, it is deficiency or excess or dis- proportion in the relative food values. CONCLUSIONS. 1. There is no stage of thyroid hyperplasia in brook trout that may be classified biologically as carcinoma. 2. The incidence of true carcinoma in fish goitre is not greater than in mammalian goitre. 3. There is no evidence that goitre is either infectious or con- tagious. 4. Goitre is endemic in all hatcheries where the salmonidae are artificially reared. Its severity is quantitatively related to the general hygienic conditions prevailing, and to the food, water supply, and degree of crowding. THE PREVENTION OF SIMPLE GOITRE 38 5. The immediate cause of goitre is unknown, but it depends in all probability on a disproportion in, or a lack of, certain of the elements necessary for proper nutrition. This study was made possible through facilities granted by and through the cooperation of the Honorable W. E. Meehan, Com- missioner of Fisheries for the State of Pennsylvania. We wish to express our obligations and thanks to Mr. Meehan, to the officers of the Blooming Grove Hunting and Fishing Club, and to Mr. Florence Rolonson, Superintendent at the hatchery, for their aid and interest. WESTERN RESERVE UNIVERSITY 39 [Reprinted from the Journal of Experimental Medicine, Vol. XIX, No. 1, 1914.] FURTHER OBSERVATIONS AND EXPERIMENTS ON GOITRE (SO CALLED THYROID CARCINOMA) IN BROOK TROUT (SALVELINUS FONTINALIS). III. Its Prevention and Cure.* David Marine, M. D. (From the FI. K. Cushing Laboratory of Experimental Medicine of Western Reserve University, Cleveland.) Plates 13 to 17.t Investigations (1) made at the trout hatchery of the Blooming Grove Hunting and Fishing Club during 1909 and 1910 showed that all the fish were then goitrous. It was found that the thyroid hyperplasia began in the fry as soon as feeding was instituted, and advanced overgrowth was present at the fourth month of extraoval life; that the overgrowth progressively increased to the stage of clinical detectability, as ascertained by the reddening of the pharyngeal floor over the thyroid area, about the tenth month in this hatchery; that visible goitres usually manifested themselves about the beginning of the second year, though they may be present as early as the sixth month, depending on the favorableness of conditions for overgrowth, and progressively increased during the second and third years; that older fish were more resistant and tended toward spontaneous recovery; that the water in which these fish lived was not naturally goitre-producing, since fish living wild in the stream and raceways did not develop thyroid overgrowth. It was further shown that overcrowding and overfeeding with the highly abnormal and incomplete diet of hog's liver and heart were the major gross etiological factors, and of these the food was the more important factor in bringing about a fault of nutrition which stimulated the thyroid to compensa- tory overgrowth. No evidence was obtained that the disease was either infectious or contagious, or that a direct contagium vivum could account for the phenomenon. The above summary of the work of 1909 and 1910 will serve as an introduction to the observations included in this report, which were made during August. 1913, and deal with the effect of chang- ing the food from liver to fresh sea fish. Comparison of the General Conditions Prevailing in 1909, 1910, and 1913.-The water supply has remained unchanged as regards source and volume (text-figure 1). The Club is holding more trout in each pond than in 1909 and 1910, hence the untoward factor of overcrowding is increased. The distribution of the fish is in gen- eral the same (text-figure 1),-the fry (hatch of 1913) in the upper, the nineteen months old trout in the middle, and the thirty- one months old trout in the lower ponds. The fry have always * Received for publication, October 9, 1913. t The plates have been omitted in this reprint. Fig. 1 Text-Fig. i. Semidiagrammatic drawing of the plan, arrangements, and location of the hatchery, water supplies, houses, and retaining tanks. WESTERN RESERVE UNIVERSITY 41 been scrupulously cared for by daily cleaning and sweeping the troughs and ponds. With the older fish (nineteen and thirty-one months) there is clearly less detritus in the ponds than in 1909 and 1910, although little additional attention has been paid to these ponds, the difference being due mainly to the change of food. Therefore, apart from the increased number of fish being held in the same pond space and the water supply, the only important change has been in the food. The Food.-Beginning with October, 1911, fresh sea fish (but- ter fish (Stromateus triacanthtis) and occasionally weak fish (Cyno- scion regalis) have been fed six times weekly to the older fish to the exclusion of all other foods. The fry are fed two to three times daily as in previous years, with finely divided hog's liver for the first four to five months of life, then heart muscle (hog) is added to this diet. This is continued until October (i. e., nine months), when all the fry are removed to the ponds. At this time the change to fish diet is also made and maintained during the remainder of their stay in captivity.1 Comparison of the Gross Appearance of the Fish of 1913 with Those of 1909 and 1910.-Very striking differences are apparent. The nineteen months and the thirty-one months old fish are active and alert, while those of corresponding ages in 1909 and 1910 were sluggish and lumbersome. In handling large numbers of them in each of these three years, the 1913 fish are clearly stronger, show more fight, fatigue less easily, and do not die so quickly when re- moved from the water. The fish are now more trout-shaped, that is, they have lost the pot-bellied appearance of 1909-1910. The skin pigments are 1 It is as yet impossible to change, to the fish diet earlier than the ninth month on account of the inability to hash the fish finely enough with the present machinery. This will soon be remedied, however, and then much of the thyroid overgrowth that now occurs during the period of liver feeding will be prevented. Several kinds of fish have been tried as food, among which are sea bass (Centropristes striatus), herring (Clupea harcngus), weak fish (Cynoscion regalis), and whiting (Merlangus americanus). All have been found unsuitable either on account of bones or scales and have been abandoned. The fish scales being unaffected by digestion form rouleaux in the gut and produce intestinal obstruction followed by the usual sequelae cf enteritis, distention peritonitis, and death. I had the opportunity of examining two mild cases of partial intestinal obstruction, although for the past year only an occasional large scaled fish has been included in the food. In the two fish examined the obstruction was intermittent, as the scales were small (from weak fish) and could only obstruct when arranged transversely in the gut. There was well developed enteritis of the straight gut with extension through to the mesentery. Bones, if fine and rigid as in herring, are not broken up by the hasher and often perforate thq stomach wall before the gastric acid can decalcify them. Fish with cartilagenous endoskeletons, such as skates, rays, sharks, etc., have not been tried owing to the difficulty as yet in obtaining them in the markets. There seems no objection to their use since they would obviate the two great objections, scales and sharp perforating bones, and in addition might be less expensive than the usual market fish. Butter fish (Stromateus triacanthus) have been found least objectionable of the obtainable fish and are now used almost exclusively. They are! received frozen and therefore in better' condition than usually obtains with liver. 42 THE PREVENTION OF SIMPLE GOITRE brighter and better differentiated. It will be recalled from the de- scriptions of 1909-1910 that in all the fish the black pigment was excessively developed. The greenish grey marbling of the back was absent and the orange and pink color spots of the sides were wholly invisible. So also the orange and yellow colors of the fins and ventral surface were nearly absent. The silvery sheen of the sides was masked by the black pigment. In the fish of 1913 the colors approached closely those of the normal trout. The greenish marbling of the dorsum is detectable. The lateral color spots are well differ- entiated and the yellow and orange pigments of the ventral surface and fins are developed. The silvery sheen of the sides is perhaps better developed than in the average wild trout.2 As regards weight I have no exact data, although the impres- sion is distinct that they are a trifle smaller on the average than in 1909 and 1910. The fry of 1913 are to all appearances the same as on previous examinations. Of other diseases independent of goitre, as the myxosporidian infection (Taumelkrankheit, cramps), fungus, and enlarged gills (so called sore gills), there is a definite decrease. Comparison of the Gross Thyroid Condition of 1909 and 1910 with that Obtaining in 1913.-These data are obtained from the clinical examination of the thyroid areas of a series of fish from the ponds for the presence of (a) reddening of the pharyngeal mucosa between the first and third gill segments as the first clinical evidence of thyroid overgrowth, and for (b) visible goitres projecting either dorsally in the floor of the mouth or in the gills, or ventrally in the angle of the attachment of the operculum as a late sign. The fry were not thus examined. From the above tabulation it is seen that in 1909 89 per cent, of the fish had distinct reddening of the pharyngeal floor, and 0.23 per cent, had visible goitres. In 1910 a similar examination of fish from the same ponds and of nearly the same ages showed distinct reddening of the pharyngeal floor in 74 per cent, and visible goitres in 0.17 per cent. In 1913 a third examination of the fish from the same ponds and of approximately the same ages as those of 1909 2 These colors being readily adaptable to environment are modified by the color of the water, hence native trout from the brook are slightly darker than trout living in the spring water of the hatchery. It may also be recalled that in the experiments of 1910 the excessive black pigment diminished rapidly upon changing the food and removal of the fish from the ponds to troughs or to the trout stream. It would therefore appear that the food was a factor in the excess of the black pigment developed. WESTERN RESERVE UNIVERSITY 43 TABLE f. October 12, 1909. June 27, 1910. August 10, 1913. Pond No. Age in yrs. No. of fish ex- amined. Red- dening of pha- ryngeal mucosa. No. with goitre. | Age in yrs. No. of fish ex- amined. Red- dening of pha- ryngeal mucosa. No. rwith goitre. | Age in yrs. No. of fish ex- amined. Yellowish discolora- tion of pharynx. No. with goitre. 6 1.5 41 10 0 1-7 25 1? trace 0 14 1-5 51 45 I i-7 32 2? trace 0 19 1.8 210 197 7 r-5 60 5i 2 i-7 22 2 trace 0 20 1.8 210 175 3 1-5 54 . 40 0 i-7 30 0 0 21 i-7 25 0 0 25 1.8 67 6l 2 1-5 48 4i I i-7 24 1 trace 0 26 2.7 22 3 trace 0 32 2.8 60 58 2 2-5 50 38 I 2-7 29 3 trace 0 35 2.5 40 28 2 2.7 32 4 trace 0 36 1.8 210 183 4 3-7 16 3 0 Totals 757 89% 0.23% 344 74% 0.17% 257 0.07% 0.0% and 1910 showed only a slight yellowish discoloration of the pharyn- geal floor3 in 0.07 per cent., and visible goitres in none. These percentages illustrate the average condition of all the fish at the time of the examinations and are controlled by the histological examination of specimens removed at the same time from all the ponds during each of these years. The differences in the gross con- dition of the thyroids for the years 1909 and 1910 are unimportant but illustrate the severity and extent of the disease. The differences in the thyroid conditions of 1909-1910 and of 1913 were beyond what I had expected and demonstrate clearly that the disease in the 1913 fish had been completely arrested. There were none with reddening of the floor of the pharynx nor with goitre, hence none with any active overgrowth of the thyroid. The few instances where slight yellowish discoloration was present is indicative of colloid- filled follicles beneath the mucosa. How can this most striking difference in the thyroid condition be accounted for? The only noteworthy determinable factor of difference between the conditions prevailing in 1909 and 1910 and those of 1913 is the food,--sea fish in 1913 and liver in 1909 and 1910. That the change of food accounts for the differences in the thyroid condition will become more apparent from the following observations and comparisons of the histological conditions of the thyroids of the entire pond series for the three years. 3 The reddening of the pharyngeal floor is due to the vascular thyroid tissue growing up to the pharyngeal mucosa. The yellow discoloration of the same region is due to the thyroid follicles rich in colloid and decreased vascularity, i. e., recovery or colloid stage of a preceding hyperplasia. 44 THE PREVENTION OF SIMPLE GOITRE Observations on the Histological Condition of the Thyroids from Speci- mens from All Ponds.-For comparison I have tabulated the anatomical state of the thyroids in 1909 and 1910 with that of 1913. In this table all the fish are included: (1) the fry, (2) the one to two years old, and (3) the two to three years old fish. In the case of the fry for 1909-1913, all conditions, including food, water, crowding, cleaning, and general hygienic conditions are as nearly identical as it is possible to keep them. This is most fortunate in that it makes com- parisons of the thyroid conditions for each year possible under constant con- ditions. It also gives a broad foundation for estimating the average thyroid hyperplasia present in the fry and is therefore valuable for checking any changes found in the older fish. With the one to two years old trout and the two to three years old trout of 1913 all conditions except the food are similar to those of 1909 and 1910. The one to two years old trout of 1913 have been fed sea fish for the past ten months. The two to three years old trout have been fed sea fish for twenty-two months, while the one to two years and two to three years old trout of 1909 and 1910 had been fed with liver only. All the fry of 1909, 1910, and 1913 exhibited the same general thyroid condition of active hyperplasia. The thyroid area is completely filled with thyroid tissue and extension to the adjacent bone and muscle is present in all. The differences in the different years are only of slight degree and are probably dependent on the slight age differences at the time of examination: 1909, 8 to 9 months old; 1910, 6 months old; 1913, 7 months old. The indi- vidual variations within a given year are also slight and in general the same for all years. The examinations in each year comprised two specimens taken without choice from the twenty-one troughs in the hatch house and thirteen pairs of ponds of the pond series for the fry and also two specimens for each pond of the remaining twenty-three pairs for the older fish. From the examination of the fry in 1910, which, in addition to the above, included a series taken at weekly intervals from the time of hatching (January 15) to October, it was shown that the thyroid overgrowth began as soon as the fish began feeding and was easily detectable at the fourth month of extra-oval life, whence it progressively increased through the following months of the first and second years, rarely becoming clinically detectable before the tenth month at this hatchery. In some hatcheries the overgrowth has been clinically detectable at the sixth to the seventh month, depending on more favorable conditions for thyroid overgrowth. The fry of 1911 and 1912 were not examined, but these same fish were included in the 1913 examination as thirty- one months and nineteen months old fish, respectively, and from this examina- tion there is complete evidence that their thyroids had undergone changes identical with those in the years 1909, 1910, and 1913. Passing now to the nineteen months old fish, one finds a most striking change also noted in the gross examination of the thyroid area. All the follicles are in the colloid state, although their distribution extends into the bone and muscle and often up to the pharyngeal mucosa. The fish from the same ponds and of approxi- mately the same age in 1909 and 1910 all had well marked active hyperplasia greater in amount and more widely distributed in muscle, bone, gills, and pharyngeal mucosa than those of 1913. The growth in nineteen months old fish of 1913 was found to be completely arrested, and the hyperplasia had completely involuted, while in the fish of 1909 and 1910 of the same age the growth was extending rapidly. As the arrest of the growth corresponds in time with the change in food, and as no other factor of difference is present, one is forced to the conclusion that the food is the major cause of the change. While the fish have grown rapidly during the ten months since the feeding of fish began, their thyroid tissue is no greater in amount nor more extensive in distribution than that reached during the first ten months of life. So also with the thirty-one months old fish which have been fed fish for twenty-two months the thyroids are completely involuted to the colloid state and the amount and distribution of the follicles are the same as those of the nineteen months old fish, and hence no greater than that attained during the first ten WESTERN RESERVE UNIVERSITY 45 Pond or trough No. Age of fish in months. 1909. Ccndltion of thyroid. _ _ _ _ _ Jr* _ _ _ Age of fish o> as as as as oo osas as as as • in months. 1910. Condition of thyroid. ^5 -4 -j -i Age of fish in months. 1913. Condition of thyroid. Extent of overgrowth. Classification. Extent of overgrowth. Classification. Extent of overgrowth. Classification. Trough 1 Trough 5 Trough 10 Trough 15 Trough 20 Nor mal above all ponds Pond 1 Pond 2 Pond 3 Pond 4 Pond 5a 8 8 8 8 8 20 8 8 8 8 8 All subpharyngeal structures, - bone and muscle All subpharyngeal structures, - bone and muscle Entire aortic area including bone and muscle Entire aortic area including bone and muscle Entire aortic area including bone and muscle Scattered follicles about aorta, filled with colloid Entire thyroid area packed with fol- licles. in bone and muscle Entire thyroid area packed with fol- licles, in bone and muscle Entire thyroid area filled Entire thyroid area filled Entire thyroid area filled Marked hyper- plasia Marked hyper- plasia Marked hyper- plasia Marked hyper- plasia Marked hyper- plasia Normal Marked hyper- plasia Marked hyper- plasia Moderate hyp- erplasia Moderate hyp- erplasia Moderate hyp- erplasia Entire aortic area; no invasion of bone or muscle Entire aortic area; no invasion of bone or muscle Entire aortic area; invasion of bone and muscle Entire aortic area; invasion of bone and muscle Entire aortic area; invasion of bone and muscle Scattered large fol- licles in aortic area filled with colloid Entire aortic area filled; invasion of bone and muscle Thyroid area filled Thyroid area filled; invasion of bone Thyroid area filled; invasion of bone Thyroid area filled; invasion of bone Moderate hyp erplasia Moderate hyp- erplasia Marked hyper- plasia Marked hyper- plasia Marked hyper- plasia Normal Marked hyper- plasia Moderate hyp- erplasia Moderate hyp- erplasia Moderate hyp- erplasia Moderate hyp- erplasia Entire aortic area; invasion of bone and muscle All subpharyngeal structures in bone and muscle All subpharyngeal structures in bone and muscle Entire aortic area Entire aortic area Scattered large fol- licles in aortic area filled with colloid Entire aortic area filled; invasion of bone Entire aortic area filled; invasion of bone Entire aortic area filled; invasion of bone Entire aortic area filled; invasion of bone Entire aortic area filled; invasion of bone Marked hyper- plasia Marked hyper- plasia Marked hyper- plasia Moderate hyp- plasia Marked hyper- erplasia Normal Moderate hyp- erplasia Moderate hyp- erplasia Marked hyper- plasia Moderate hyp- erplasia Moderate hyp- erplasia TABLE II. 46 THE PREVENTION OF SIMPLE GOITRE Pond or trough No. Age of fish in months. 1909. Condition of thyroid. Age of fish in months. | 1910. Condition of thyroid. Age of fish in months. 1913. Condition of thyroid. Extent of overgrowth. Classification. Extent of overgrowth. Classification. Extent of overgrowth. Classification. Pond 5b 8 Entire thyroid area filled Moderate erplasia hyp- 6 Thyroid area filled; invasion of bone Moderate erplasia hyp- 7 Entire aortic area filled; invasion of bone Moderate hyp- erplasia Pond 6 8 Entire thyroid area filled Moderate erplasia hyp- 18 Entire thyroid area filled, in bone and muscle; infold- ings; no colloid Marked plasia hyper- 19 Numerous small and large colloid- filled follicles in entire thyroid area Colloid goitre Pond 7 8 Entire thyroid area filled, in bone and muscle Marked plasia hyper- 6 Entire thyroid area filled, in bone Moderate erplasia hyp- 7 Aortic area filled, extension to bone Moderate hyp- erplasia Pond 8 8 Entire thyroid area filled, in bone and muscle Marked plasia hyper- 6 Entire aortic area filled, in bone and muscle Marked plasia hyper- 7 Aortic area filled; extension to sub- mucosa Marked plasia hyper- Pond 9 8 Entire thyroid area filled, in bone and muscle Marked plasia hyper- 6 Entire aortic area filled, in bone and muscle Marked plasia hyper- 7 Aortic area filled; extension to sub- mucosa Marked plasia hyper- Pond 10 8 Entire thyroid area filled, in bone and muscle Marked plasia hyper- 6 Entire aortic area filled, in bone and muscle Marked plasia hyper- 7 Aortic area filled; extension to sub- mucosa Marked plasia hyper- Pond 11 8 Entire thyroid area filled, in bone and muscle Marked plasia hyper- 6 Entire aortic area filled, in bone and muscle Marked plasia hyper- 7 Aortic area filled; extension to sub- mucosa Marked plasia hyper- Pond 12 8 Entire thyroid area filled, in bone and muscle Marked plasia hyper- 6 Entire aortic area filled, in bone and muscle Marked plasia hyper- 7 Aortic area filled; extension to sub- mucosa Marked plasia hyper- Pond 13 8 Entire thyroid area filled, in bone and muscle Marked plasia hyper- 6 Entire aortic area filled, in bone and muscle Marked plasia hyper- 7 Aortic area filled; extension to sub- mucosa Marked plasia hyper- Pond 14 20 Entire subpharyn- geal space filled, in bone and mus- cle Marked plasia hyper- 18 Entire subpharyn- geal space filled, in bone and mus- cle Marked plasia hyper- 19 Numerous colloid- filled follicles in entire aortic area Colloid goitre Pond 19 20 Entire subpharyn- geal space filled, in bone and mus- cle Marked plasia hvper- 18 Entire subpharyn- geal space filled, in bone and mus- Marked plasia hyper- 19 Numerous colloid- filled follicles in entire aortic area Colloid goitre TABLE II.- (Continued.) WESTERN RESERVE UNIVERSITY 47 Pond or trough No. of fish onths. 1909. Condition of thyroid. of fish onths. 1910. C( ndition of thyroid. of fish onths. 1913. Condition of thyroid. Extent of overgrowth. Classification. hC c <5 Extent of overgrowth. Classification. o c - <H Extent of overgrowth Classification. Pond 20 20 Entire subpharyn- Colloid, moder- geal space filled, ate hyperplasia in bone and mus- (hyperplasia cle involuting) 18 Entire subpharyn- geal space filled, in bone and mus- cle Marked hyper- plasia 19 Numerous colloid- filled follicles in entire aortic area Colloid goitre Pond 21 20 Entire subpharyn- Colloid, moder- geal space filled, ate hyperplasia in bone and mus- (hyperplasia cle involuting) 18 Entire subpharyn- geal space filled, in bone and mus- cle Marked hyper- plasia 19 Numerous colloid- filled follicles in entire aortic area Colloid goitre Pond 25 20 Entire subpharyn- Colloid, moder- geal space filled, ate hyperplasia in bone and mus- (hyperplasia cle involuting) 18 Entire subpharyn- geal space filled, in bone and mus- cle ; visible goitre Marked hyper- plasia 19 Numerous colloid- filled follicles in entire aortic area Colloid goitre Pond 26 32 Entire subpharyn- Marked hyper- geal space filled, plasia, small in bone and mus- visible goitre cle 30 Entire subpharyn- geal space filled, in bone and mus- cle Marked hyper- plasia 31 Numerous colloid- filled follicles in entire aortic area; number of fol- licles same as in 19 mos. old fish Colloid goitre Pond 32 32 Entire subpharyn- Marked hyper- geal space filled, plasia in bone and mus- cle 30 Entire subpharyn- geal space filled, in bone and mus- cle Marked hyper- plasia 31 Numerous colloid- filled follicles in entire aortic area; number of fol- licles same as in 19 mos. old fish Colloid goitre Pond 35 32 Entire subpharyn- Marked hyper- geal space filled, plasia, slight in bone and mus- general fibrosis cle 30 Entire subpharyn- geal space filled, in bone and mus- cle ; visible goitre Marked hyper- plasia 31 Numerous colloid- filled follicles in entire aortic area; number of fol- licles same as in 19 mos. old fish Colloid goitre Pond 36 20 Entire subpharyn- Marked hyper- geal space filled, plasia in bone and mus- cle 30 Entire thyroid area filled, extension to skin, bone and muscle Marked hyper- plasia 43 Entire subpharyn- geal area filled with colloid fol- licles. in bone and muscle; number of follicles much greater than in the 19 or 31 mos. old fish Colloid goitre TABLE II.- (Continued.) 48 THE PREVENTION OF SIMPLE GOITRE months of life, although the fish have made their normal annual growth. One sees, therefore, fish nineteen months and thirty-one months old with thyroids identical in all particulars and no greater in amount nor more extensive in distribution than those of liver-fed fry of ten months in this hatchery. That the growth was arrested and involution started at the time of the change from liver to sea fish cannot be doubted, although for the sake of completeness it will be necessary to make a series of weekly examinations beginning before and continuing for some months after the change of food to fresh sea fish. This is now being done. Additional proof that change of food is the cause of the arrest of thyroid growth is the preservation of 250 forty-three months old fish which had been fed liver for the first twenty-one months of life and sea fish for the last twenty-two months. In these I found three out of the sixteen examined having distinct yellowish discoloration of the pharyngeal floor, and in the two specimens examined histologically the thyroid was com- nletely involuted to the colloid state; but the amount and distribution were far more extensive than in the thirty-one and nineteen months old fish, show- ing that the thyroid overgrowth had progressed much farther before the involution began, and corresponds to the extra year of liver as food. It is well known that foods influence the mammalian thyroid to a marked degree. Baumann (2) noticed that flesh diets stimulate the thyroid in dogs to active hyperplasia. I have repeatedly made such observations, liver being the most important food in, this regard. Reid Hunt (3) in his acetonitrile experiments noted that liver stimulates the thyroid of white mice. Watson (4) has described the effect of different diets on rat thyroids and also noted that meats produce hyperplasia, while mixed diets do not. I have made similar observations. Dogs spontaneously recover from goitre on a mixed diet, while meats, especially liver, maintain hyperplasia. In zoological gardens where carnivores are held and bred in captivity and the diet is for the most part beef, goitre, rickets, and osteomalacic states are quite common. Foods modify the thyroid slowly, involution extending over months, while iodin involutes hyperplasias much more rapidly. lodin administered to dogs, sheep, pigs, and human beings often induces involution in a month, and in Lake Erie pike the involution of mild degrees of hyperplasia takes place in twenty-six days (5). In brook trout with extensive thyroid overgrowth and visible goitres involution occurs in forty days. To summarize, it is seen that the ages of the fish held at the hatchery in August, 1913, are seven months, nineteen months, thirty-one months, and forty- three months. The seven months old fry all have active hyperplasia not dif- ferent in degree or extent from the fry of 1909 and 1910. The nineteen, thirty-one, and forty-three months old fish all have completely involuted or colloid thyroids, and the amount and distribution of the thyroid tissue in the nineteen and thirty-one months old fish are the same and represent the degree of thyroid overgrowth reached during the first nine months df life when liver and heart only are fed. The forty-three months old fish had been fed with liver and heart for the first twenty-one months of life, and the thyroids both on gross and microscopical examinations were much larger and more widely distributed than in the nineteen and twenty-one months old fish. DISCUSSION These data afford supplementary proof for several of the con- clusions deduced from the earlier work, and in addition establish an- other simple and certain means for the cure and prevention of goitre in fish. The view previously held by some observers that this disease was closely related to true carcinoma is now only of theoretical interest. WESTERN RESERVE UNIVERSITY 49 since, in addition to the facts already reported, it establishes the fact that the feeding of fresh sea fish also readily arrests the disease. No tissue overgrowth that presents the biological phenomena de- scribed for this disease, which are also identical with those of mam- malian goitre, can be considered malignant. It was urged by some observers that the reaction with iodin could not be utilized as proof that the disease was not cancer since arsenic, mercuric chloride, and colloidal copper were reported to have the same thyroid effects (6). I have not been able to effect these changes with arsenic in canine goitre. I (7) have also failed to modify the growth of the mam- malian thyroid carcinoma by the use of iodin, and from an extensive experience with human thyroid adenomata the conclusion was reached that they also are rarely affected by iodin (8). On the other hand, simple physiological hyperplasias of all animals are readily and invariably modified by iodin. This disease should be classified as endemic goitre or endemic thyroid hyperplasia. One must recognize all degrees of the over- growth in fish, just as in mammals, from the slightest departure from normal, detectable only microscopically, to the most extensive infiltration of the thyroid region and the formation of external goitres. Whether this form of goitre is similar to ordinary goitre in birds and mammals is not known. As mentioned above, they are identical anatomically, physiologically, and pathologically in all their known reactions, but inasmuch as goitre is only the symptomatic manifestations of a nutritional disturbance it is possible that many agents are capable of exciting the thyroid to this single and only known anatomical manifestation of increased activity, compensatory hypertrophy and hyperplasia. From our knowledge of mammalian goitre it would seem prob- able that the thyroid reaction in infectious diseases, puberty, preg- nancy, cretinism, Basedow's syndrome, etc., is not due to the same exciting cause. The fundamental fault in nutrition is probably the same in all, but the immediate exciting agent is probably different. In mammalian goitre the localization in certain districts is most obvious, while in fish and in birds this is not so apparent although it is present. Goitre, however, occurs wherever favorable conditions are created whether in mammals or in the- lower animals. It is therefore the increased susceptibility of mammals to goitre that brings out the localization of endemicity. Fish are very resistant to 50 THE PREVENTION OF SIMPLE GOITRE goitre and only acquire the disease when subjected to conditions in- compatible with prolonged life in mammals. The nearest approach to the etiology of goitre in fish was made when it was shown that food is the major etiological factor. Fish fed exclusively with liver always acquire thyroid hyperplasia, while fish of the same age, breed, and environment readily recover or escape goitre when fed with whole sea fish. It is almost certainly a biochemical reaction, but whether it is due to the presence or absence of some substance normally needed by the organism is not known. A comparison of liver as a food with fish as a food seems to indicate that the liver lacked something normally needed by the developing fish which the diet of fish con- tained. It is also probable that the liver contains some substances in ex- cess, in attempting to utilize which, the animal exhausts other ele- ments necessary for nutrition which are not present in the liver in sufficient amounts. As to the nature of this chemical fault one cannot reasonably speculate. From time to time most of the inor- ganic and many of the organic substances have been specified as etiological factors, but without foundation. Some observers have called it a toxin, but work based upon this hypothesis has added nothing to our knowledge of the etiology. lodin is certainly reduced in fish with thyroid hyperplasia, as in all other animals, and iodin certainly prevents and involutes hyper- plasia, but the conclusion that goitre is due to a deficiency of iodin is not justified since there is considerable evidence to show that some other factor or factors are operating to divert or deplete an otherwise sufficient amount of iodin. On the other hand, the bene- ficial effects of feeding fish may be due to the iodothyreoglobulin that it contains, since only exceedingly small amounts are necessary, and the whole fish including the thyroid gland is used. Sea fish may also contain traces of iodin apart from the thyroid. Therefore much careful work must still be done to exclude iodin as the cause of the beneficial effects. I have made two iodin determinations on mixed specimens of whole butter fish, and two determinations on mixed specimens of fish from which the thyroid areas had been removed. The results are as follows: (1) whole fish, slightest trace; (2) exclusive of thyroid area, no trace of iodin. The possibility of a contagium vivum in fish goitre can, it seems to me, be eliminated since there is not the slightest evidence that it WESTERN RESERVE UNIVERSITY 51 is either contagious or infectious. It obeys none of the laws which we associate with true infectious processes. No evidence of natural or acquired immunity has been obtained, though different species of fish exhibit different degrees of resistance (carp, trout). Gaylord (9) has reported the finding of evidences of immunity, but this evidence does not exclude the following important factors: (1) Age is an important factor in all animals; the young are more susceptible to goitre and the old tend toward spontaneous recovery. (2) When the active hyperplasia involutes to the colloid state it is more difficult to produce again active hyperplasia (a) because of the increased age of the animal, and (b) because of the increased factor of safety due to the increased number of thyroid follicles over what obtains normally. For example, if a dog has fifty grams of col- loid thyroid it is more difficult, apart from any age factor, to induce active hyperplasia in it than if the dog has three grams of normal thyroid; but other things being constant, three grams of colloid will undergo hyperplasia as readily as three grams of normal thyroid. (3) The food is probably the most important factor in determining the onset or cessation, progression or regression of the hyperplasia. (4) Water supply has some influence on the resistance of fish to active hyperplasia, reduced and much used water favoring, and large amounts lessening it. (5) The different Salmonidae vary greatly in their susceptibility. I have seen none that were not susceptible, but the brown trout and rainbow trout in my experience have been more resistant than the silver salmon or brook trout. The water supplied to this hatchery has little if anything to do with the development of goitre, since the fish have never developed the disease unless the single factor of overfeeding with the highly abnormal diet of liver and heart is also operating. The following observations bearing on the relation of water to the etiology and spread of goitre may be mentioned: (1) Within the hatch house are twenty-one troughs,-twelve hatch troughs and nine nursing troughs. The twelve hatch troughs receive water directly from the spring, while the nine nursing troughs receive the water from the twelve hatch troughs. Every summer these troughs are used to hold extra fry. They are kept remarkably clean, yet all the fry have shown equally marked thyroid overgrowth in each of the years that they have been examined. Fish living outside the troughs and ponds (hence not directly fed with liver), whether above, below, or between the troughs and ponds, never develop active hyperplasia, 52 THE PREVENTION OF SIMPLE GOITRE although in most instances they have some degree of colloid goitre, showing that they had once been confined in the troughs or ponds and that, after escaping, the hyperplasia involutes. (2) The 1913 distribution of the fish made another observation possible. In house II (text-figure 1) there are 3,000 nineteen months old fish which have been fed with fish for the past ten months; all these fish have colloid glands. While above in house I and below in house III there are seven months old fry which have been fed only with liver and heart muscle and all have well marked active thyroid hyperplasia. There is also some evidence that liver when fed in excessive amounts is a more potent stimulus than when fed in small amounts, as the fish living in the runways between the houses also obtain small particles of liver which float through the screens but do not develop active hyperplasia. Plehn (9) has reported greater variations in the occurrence and distribution of the disease in a fish hatchery than they could account for purely on the basis of external changes. They suggest that these variations point to in- fection. I have also seen wide variations in its occurrence in dif- ferent hatcheries and even in the same hatchery, but feel that all the variations could be accounted for on the basis of one or more of the following factors: (1) food, (2) water supply, (3) age, and (4) species of fish. Some observers have applied the term epidemic goitre to this form of goitre in fish. This is wrong. There is nothing acute or localized in its occurrence or distribution. It ap- pears wherever fish are overfed with liver or other incomplete foods. It extends over the entire time of such feeding and all fish are affected. Goitre has been present in this hatchery for the past twenty-five years and, in my opinion, it will remain as long as fish of any age are fed with liver. Treatment and Prevention.-Trout living in their normal envi- ronment and partaking of their normal food do not develop goitre, hence in the treatment and prevention our efforts should be directed toward imitating natural conditions as far as possible. However, as with many other animals it has been found possible to alter these natural environmental conditions within extremely wide limits with- out seriously impairing their health. Goitre is one of the serious diseases that has developed in testing the range of adaptability. The infectious diseases of fish, as of mammals, are better known and methods for the cure and prevention have been studied longer. WESTERN RESERVE UNIVERSITY 53 Goitre belongs to the group of diseases dependent upon nutritional disturbances, and our knowledge of the food requirements of ani- mals generally and of fish in particular is as yet in its infancy. It has been conclusively shown that the feeding of the highly artificial and incomplete diet of liver and heart muscle is the major factor in the causation of fish goitre, and the first essential in treat- ment is to provide some other food that meets the animal's require- ments. A natural food of trout is fish and the experiments of the past two years show that when sea fish is fed to these trout exist- ing goitre is cured and the development of goitre is wholly prevented. The feeding of fish with hard fine bones or with large heavy scales is associated with risks mentioned above. The fish stomach is adapted for the ingestion of relatively large food boli, and food should be fed in as large masses as they will take since digestion is a continuous process in fish. This would probably solve the bone question and would tend to control overfeeding. Some sort of chopper should be devised instead of hashers, since hashers mince the food and allow of too rapid digestion and, therefore, too long intervals of stomach inactivity. Coarse fish, like sharks, rays, etc., might be utilized. Sea fish, therefore, makes a perfect food as far as the cure and prevention of goitre are concerned. Overfeeding must be guarded against. Definite amounts of food should be fed but once a day with a fast day each week comparable to the fast day maintained among the carnivores at Zoological Gardens. No obser- vations have been made as to the minimum amounts of sea fish nec- essary to involute or prevent hyperplasia, but judging from the rapidity of the involution when the food is changed to fish only, it would appear that the daily feeding with fish was not necessary to cure or prevent the hyperplasia. It might be beneficial to alternate between fish and liver or between fish and other foods daily or weekly. Overcrowding is dependent on the water supply and the food. It is a highly important factor as regards the general health of the fish, the prevention of traumata and infectious diseases, the oxygen supply, etc., but is only a minor factor in the production of goitre. Cleanliness likewise is a secondary factor in goitre, but is of great importance in the prevention of other diseases and as a general hygienic measure cannot be neglected. Modification of pond con- struction with this in view would greatly simplify the cleaning and sanitary problems. lodin in minute traces has also been found to THE PREVENTION OF SIMPLE GOITRE 54 prevent and cure goitre. Indeed it is a specific therapy for goitre but does not relieve other untoward manifestations of an incomplete food. Gaylord (6) has reported that arsenic and mercuric chloride also effect similar changes in fish thyroid hyperplasia. Our obser- vations with arsenic in canine goitre were negative and in any event the action of arsenic and mercuric chloride is not comparable to the action of iodin on the thyroid. CONCLUSIONS 1. Goitre in fish is a non-infectious, non-contagious, sympto- matic manifestation of a fault in nutrition, the exact biochemical nature of which has not been determined. 2. Feeding the highly artificial and incomplete diet of liver is the major etiological factor in bringing about this fault of nutrition which is at once corrected by feeding whole sea fish. ' 3. Water plays no essential part in the etiology, transmission, or distribution of the disease in the fish of this hatchery. BIBLIOGRAPHY 1. Marine, D., and Lenhart, C. H., Observations and Experiments on the So Called Thyroid Carcinoma of the Brook Trout (Salvelinus fontinalis) and Its Relation to Endemic Goitre, Jour. Exper. Med., 1910, xii, 311; 1911, xiii, 455. 2. Baumann, E., Ueber das Thyrojodin, Munchen, med. Wchnschr.,1896, xliii, 309. 3. Hunt, R., and Seidel, A., Studies on Thyroid. The Relation of Iodine to the Physiological Activity of Thyroid Preparations, Bull., Hyg. Lab., U. S. P. and M.-H. S., 1909, No. 47. 4. Watson, C., The Influence of a Meat Diet on the Thyroid Gland in the Second Generation of Meat Fed Rats, Jour. Physiol., 1906, xxxiv, p. xxix. 5. Marine, D., and Lenhart, C. H., On the Occurrence of Goitre in Fish, Bull. John^ Hopkins Hosp. 1910, xxi, 95. 6. Gaylord, H. R., Ueber die therapeutische Wirkung der Metalle auf Krebs, Berl. klin. Wchnschr., 1912, xlix, 2017. 7. Marine, D., and Johnson, A. A., Experimental Observations on the Effects of the Administration of lodin in Three Cases of Thyroid Carcinoma, Arch. Int. Med., 1913, xi, 288. 8. Marine, D., Benign Epithelial Tumors of the Thyroid Gland, Jour. Med. Re- search 1912-13, xxvii, 229. 9. Plehn, M., Ueber Geschwiilste bei niederen Wirbeltieren, Travaux de la deuxieme conference internationale pour V etude du cancer, Paris, 1910, 221; reviewed by Gaylord, H. R., ibid., p. 787. WESTERN RESERVE UNIVERSITY 55 [Reprinted from the Journal of Experimental Medicine, Vol. XIX, No. 4, 1914.] THE RAPIDITY OF THE INVOLUTION OF ACTIVE THY- ROID HYPERPLASIAS OF BROOK TROUT FOLLOW- ING THE USE OF FRESH SEA FISH AS A FOOD.* David Marine, M. D. (From the H. K. Cushing Laboratory of Experimental Medicine of Western Reserve University, Cleveland.) In a recent paper (1) the effect of certain foods on the produc- tion and prevention of goitre in brook trout (Salvelinus fontinalis) was described and it was shown that a continuous diet consisting only of hog's liver and heart1 quickly (in one to two months) in- duces well marked thyroid hypertrophy and hyperplasia, and that when hashed fresh sea fish alone was substituted, further hyper- plasia was prevented, and any existing thyroid hyperplasia involuted to its colloid or quiescent state. In the present communication will be given data concerning the rapidity of the involution following the substitution of the fish diet, and the time limits within which it is completed, and also, for com- parison, the time limits of the involution induced by other means in Lake Erie pike, in brook trout, and in mammals (dogs). The fish used in these observations were taken from the regular stock hatched about January 15, 1913, and distributed to the ponds about July 1. They had, therefore, in common with the entire 1913 hatch, been fed with finely divided hog's liver for the first few months (four to five), and after that with a mixture of heart muscle and liver. I arbitrarily chose fish from pond 8,2 since complete ex- aminations made in August of all the 1913 hatch, both those living in the troughs and those in the ponds, showed approximately the same degree of thyroid hyperplasia. The experiments were conducted as follows: On September 28, 1913, the food of all the fry of 1913 was changed to fresh butter fish (Stromateus triacanthus) given once daily except for the weekly fast day. Eight fish were taken from pond 8 on this date as con- * Received for publication, February 7, 1914. 1 The food is but one of a complex of interacting factors, among which are over- crowding, and relatively insufficient water supply, with its diminished oxygen and excess of excreta contents. The food, however, is believed to be the major single factor. 2 For the plan of the hatchery see page 40. 56 THE PREVENTION OF SIMPLE GOITRE trols, and four fish were removed every seventh day for sixty-three days following.. The data are presented in the following tabulation. The eight fish taken as controls at the beginning of the experi- ment have uniformly hyperplastic thyroids listed as "marked hyper- plasias," comparable and similar in all essentials to those present in the fry of corresponding ages in 1909, 1910, 1911, and 1912. The strain of fish and the food (hog's liver and heart) have also re- mained constant during these years. The distribution of the thy- roid tissue is approximately the same in all the forty-four fish used. In all cases the thyroid follicles have filled the thyroid area about the aorta and between the 1st and 3rd gill arches, have extended up to the pharyngeal mucosa, have invaded the bone and muscles, and in most cases have extended through to the skin adjacent to the ven- tral attachments of the 1st and 2nd gill arches. Specimens taken seven days after the feeding of fish was insti- tuted show slight but distinct changes in the thyroid toward involu- tion. The follicular spaces are more distinct and contain some stainable colloid. The epithelium is slightly changed, and the stroma and vascularity appear unmodified, and, according to the arbitrary standards I have used, such a histological appearance would be designated "colloid-moderate-marked hyperplasia." The fourteen day specimens are listed as "colloid-moderate hy- perplasias," i. e., the stainable colloid is more abundant, the fol- licular spaces better defined, and the epithelium has shrunken from high columnar to low columnar. The twenty-one day specimens show still further accumulations of colloid in the follicles, and the lining epithelium has shrunken to the cuboidal form. These specimens are listed as "colloid-early hyperplasias." Specimens removed twenty-eight days after the fish feeding was instituted show still further shrinking of the epithelium, and the colloid content is now nearly uniform and homogeneous. Vacuoles are still present at the colloid-epithelium junction. By the use of less rigid standards than I have adopted, these thyroids could be classified as completely involuted rather than as "colloid-early hyperplasias." By comparing the follicles with those of normal fish or with those seen in the subsequent specimens of this series, however, it is evident that the involution is not complete. The specimens taken after thirty-five days of fish feeding are listed as "complete involutions"; that is, the lining epithelium is low cu- WESTERN RESERVE UNIVERSITY 57 Pond No. Age in months. Date taken. Food and length of time fed. Condition of thyroid. Remarks. Extent of overgrowth. Classification. 8 8+ Sept. 28, 1913 Hog's liver for 1st 4 mos. of life; then hog's liver and heart Entire subpharyngeal area infiltrated, including bone and muscle Marked hyperplasia This is an example of 8 controls. All have approximately the same degree of hyperplasia.3 Colloid absent. 8 8+ Oct. 5, 1913 Whole butter fish only, beginning Sept. 28, 1913, 1 wk. Entire subpharyngeal area infiltrated, including bone and muscle C o 11 o i d-moderate- marked hyperplasia (beginning involu- tion) This is an example of 4 speci- mens examined. All have ap- proximately the same thyroid condition. Colloid appears in follicles. 8 8+ Oct. 12, 1913 Butter fish only for 2 wks. Thyroid area filled, extend- ing to pharyngeal mucosa, in bone and muscle Colloid-moderate hy- perplasia (involut- ing) This is an example of 4 speci- mens examined. All have ap- proximately the same thyroid condition. Colloid in fair amounts in all follicles. Epi- thelium low columnar. 8 9 Oct. 19, 1913 Butter fish only for 3 wks. Entire subpharyngeal area filled, extending to phar- yngeal mucosa and skin and gills, in bone and muscle Colloid-early (invol- uting) This is an example of 4 speci- mens examined. All have ap- proximately the same thyroid condition. Colloid in all fol- licles fairly homogeneous. Epithelium cuboidal. 8 9+ Oct. 26, 1913 Butter hsh only for 4 wks. Entire subpharyngeal area filled, extending to phar- yngeal mucosa, bone, and muscle Colloid-early ( a p - proximating pure colloid) This is an example of 4 speci- mens examined. All have ap- proximately the same thyroid condition. Colloid dense, near- ly uniform. Follicles more separate and stroma more prominent, due to shrinkage of blood supply and size of fol- licles. Epithelium cuboidal. 3 Complete examinations of all the fry at the hatchery were made m August, and all were found to have thyroid hyperplasia (Marine, D., Jour. Exper. Med., 1914, xix, 70). TABLE I. 58 THE PREVENTION OF SIMPLE GOITRE Pond No. Age in months. Date taken. Food and length of time fed. Condition of thyroid. Remarks. Extent of overgrowth. Classification. 8 9+ Nov. 2, 1913 Butter fish only for 5 wks. Entire subpharyngeal area filled, extending to phar- yngeal mucosa, to bone, muscle, and gills Colloid goitre (com- plete involution) This is an example of 4 speci- mens examined. All have ap- proximately the same thyroid condition. Colloid dense, uni- form. Follicles separate. Epi- thelium low cuboidal. 8 9+ Nov. 9, 1913 Butter fish only for 6 wks. Entire subpharyngeal area filled, extending to phar- ynx mucosa, bone, and muscle Colloid goitre (com- plete involution) This is an example of 4 speci- mens examined, all showing same thyroid condition. 8 10 Nov. 16, 1913 Butter fish only for 1 wks. Entire subpharyngeal area filled, extending to skin, pharyngeal mucosa, bone, and muscle Colloid goitre (com- plete involution) This is an example of 4 speci- mens examined, all showing same thyroid condition. 8 10+ Nov. 23, 1913 Butter fish only for 8 wks. Entire subpharyngeal area filled, in bone and muscle Colloid goitre (com- plete involution) This is an example of 4 speci- mens examined, all showing same thyroid condition. 8 10+ Nov. 30, 1913 Butter fish only for 9 wks. Entire thyroid area filled, extending to pharyngeal mucosa, to bone, and muscle Colloid goitre (com- plete involution) This is an example of 4 speci- mens, all showing same thy- roid condition. TABLE I (Continued). WESTERN RESERVE UNIVERSITY 59 boidal. The stainable colloid is homogeneous, and nearly uniform in all follicles. The follicles are smaller and more widely separated from each other, while the stroma is correspondingly more promi- nent. The capillaries about the follicles are less prominent. The distribution of the follicles is, of course, the same as that attained during the growing actively hyperplastic stage, i. e., in bone and muscle with extension to the skin and pharyngeal mucosa. The specimens examined on the 42d, 49th, 56th, and 63d days respectively are nearly identical with those of the 35th day. There is probably some further involution in the last specimens, as evi- denced by a slight increase in the staining density of the colloid and in the flattening of the lining epithelium. This is also true of nor- mal thyroid follicles, and has occasioned much discussion as to what is the normal type. In a tissue like the thyroid epithelium, which is capable of such marked hypertrophy and hyperplasia, as well as marked involution, one must adopt somewhat arbitrary groups, within which variations between certain narrow limits are not taken into account. The time in which complete involution of these relatively mild degrees of thyroid hyperplasia occurs, following the use of butter fish in this particular environment and strain of brook trout, is about thiry-five days. As was shown in a previous paper (1), the thyroid gland, once involuted, remains in this colloid or involuted stage as long as the fish are fed with this food. No further growth of the thyroid takes place under these conditions. Thus the thy- roids of the three and two year old brook trout at this hatchery have the same amount of thyroid tissue with the same distribution of follicles that was attained during the first ten months of their lives, at which time the change of food was instituted. lodin involutes the hyperplasias more rapidly than butter fish. In Lake Erie pike with mild degrees of thyroid hyperplasia it was found (2) that iodin involuted them in from sixteen to eighteen days. In the experiments of 1909 (3) it was found that the thyroid of twenty months old brook trout with extensive hyperplasia involuted in from twenty to twenty-five days following the daily addition of traces of iodin to the water. In the iodin experiments of 1910 (4) it was found that involution took place in about forty days in twenty-nine months old brook trout with large and often slightly ulcerated goitres, while in forty-one months old emaciated brook 60 THE PREVENTION OF SIMPLE GOITRE trout with extensively infected and ulcerated external goitres heal- ing and involution were complete at the sixty-second day. In mam- mals the involution with iodin is of course more rapid (5). In young dogs with uncomplicated simple hyperplasias, the involution is usually complete in from fourteen to eighteen days. As the whole butter fish contains appreciable amounts of iodin4 one may ask whether this effect of fish as food is merely the well known iodin action, and the somewhat longer involution time only the manifestation of a very dilute solution. In the absence of any data against this view, I prefer tentatively to consider it an iodin effect rather than to postulate another explanation in favor of which there are at present no direct data. Experiments are now in prog- ress which it is hoped will shed some light on this question. BIBLIOGRAPHY. 1. Marine, D., Further Observations and Experiments on Goitre (So Called Thyroid Carcinoma) in Brook Trout (Salvelinus fontinalis). III. Its Prevention and Cure, Jour. Exper. Med., 1914, xix, 70. 2. Marine, D., and Lenhart, C. H., On the Occurrence of Goitre ^Active Thyroid Hyperplasia) in Fish, Bull. Johns Hopkins Hosp., 1910, xxi, 95. 3. Marine and Lenhart, Observations and Experiments on the So Called Thyroid Carcinoma of Brook Trout (Salvelinus Fontinalis), and Its Relation to Ordinary Goitre, Jour. Exper. Med., 1910, xii, 311. 4. Marine and Lenhart, Further Observations and Experiments on the So Called Thyroid Carcinoma of the Brook Trout (Salvelinus fontinalis), and Its Relation to Endemic Goitre, Jour. Exper. Med., 1911, xiii, 455. 5. Marine and Lenhart, Effects of the Administration or the Withholding of lodin-Containing Compounds in Normal Colloid or Actively Hyperplastic Thyroids of Dogs, Arch. Int. Med., 1909, iv, 253. 4 lodin in fish, birds, and mammals is, for the most part, contained in the thyroid glands, although traces of iodin have been found in certain fish oils, as, for example, cod liver oil, where presumably contamination with thyroid was avoided. Using the modified Baumann and the Hunter methods, I have not been able to recognize traces of iodin in whole amphioxus and in butter fish (Strornatcus triacanthus') and weak fish (Cynoscion rcf/alis) from which the thyroid areas had been removed. A. T. Cameron (Biochem. Jour., 1913, vii, 466; Jour. Biol. Chern., 1914, xvi, 465) has published the finding of relatively large amounts of iodin in the thyroids of rays and dog fish. Thus in Raia clai'ata he found the mean iodin content to be 0.438 per cent, cf dried gland, while in Scyllium canicula he found a mean content of 1.16 per cent, of dried gland. I have made the following iodin estimations in butter fish: (1) With whole butter fish in 1 gm. amounts rz: possible trace. (2) With whole butter fish in 5 gm. amounts = trace, unmeasurable. (3) With butter fish, exclusive of the thyroid area, in 1 gm. amounts - no trace. (4) With butter fish, exclusive of the thyroid area, in 5 gm. amounts - no trace. WESTERN RESERVE UNIVERSITY 61 [Reprinted from the Journal of Laboratory and Clinical Medicine. 1917, iii, 40-48.] THE PREVENTION OF SIMPLE GOITRE IN MAN* A Survey of the Incidence and Types of Thyroid Enlargements in the Schoolgirls of Akron (Ohio), from the 5th to the 12th Grades, Inclusive-The Plan of Prevention Proposed. By David Marine, M.. D., and O. P. Kimball, B. S., Cleveland, Ohio. Simple goitre in animals is probably the easiest of all known diseases to prevent. Simple goitre includes all the thyroid enlarge- ments seen in the lower animals and those thyroid enlargements seen in man, except cases properly classified as exophthalmic goitre. Many cases with simple goitre later develop exophthalmic goitre. In brief, simple goitre includes all those thyroid enlargements formerly classi- fied as endemic, epidemic and sporadic. The periods when it most frequently develops are (1) fetal, (2) adolescent, and (3) during pregnancy. Anatomically a wide range of changes may be present, depending on the species of animal and on the stage (duration) of the disease. In man and fowls one more commonly sees the form characterized by an abundance of colloid material-the so-called "cystic or colloid goitre" of older writers, while in goitre of dogs, sheep, cattle, pigs, fish, etc., the accumulation of colloid material is seen only in the late, regressive or quiescent stages. Again in man the adenomatous form is very common and is exceedingly rare if present at all in the lower animals. It will not be possible to review all the experimental data on which the assertion, that simple goitre in animals is an easily pre- ventable disease, is based. Certain of the more important facts bearing on the subject will be summarized as an introduction to the discussion of the means proposed to attempt the prevention of simple goitre in man. 1. The developmental stage of all goitres is characterized by an increased blood flow, an increase in the size and number of epithelial cells, a decrease in the stainable colloid of the follicular spaces and a marked absolute decrease in the iodine content. The decrease in iodine precedes the cellular changes. 2. Similar thyroid changes (compensatory hyperplasia) invaria- * From the H. K. Cushing Laboratory of Experimental Medicine, Western Reserve University, Cleveland, Ohio. Aided by a grant from the Committee on Therapeutic Research of the Council on Pharmacy and Chemistry of the American Medical Association. 62 THE PREVENTION OF SIMPLE GOITRE bly occur in the remaining portion of the gland when a sufficient portion of the entire gland is removed. The amount of gland it is necessary to remove in order to cause compensatory hyperplasia varies somewhat with the species of animal, definitely with the age, the diet, and the presence of iodine. 3. The administration of exceedingly small amounts of any salt of iodine thus far tried in any manner completely protects the re- maining thyroid against compensatory hyperplasia, even after the removal of three-fourths of the normal gland in cats, dogs, rabbits and rats, fowls and pigeons. Halsted1 and Hunnicutt2 reported a series of partial thyroidectomies in dogs in which they failed to ob- tain the hypertrophy or hyperplasia of the remaining portion and, therefore, concluded that Halsted's earlier and justly classic experi- ments3 on the production of compensatory hyperplasia by partial removal were not due to thyroid removal, but to something else, possibly infection. Their failure to obtain compensatory hyperplasia in the second series was really due to the presence of available iodine either from the absorption of iodine painted on the skin or from con- tact with other dogs, or from inhalation of volatilized iodine from other dogs carrying iodine, or from other sources in the rooms. 4. If most of the thyroid gland is removed before or in the early stages of pregnancy and rigid steps are taken to exclude avail- able iodine, the pups at birth will have enlarged thyroids, as first shown by Halsted,3 while if available iodine is present, the pups will have normal thyroids.4 5. We have repeatedly found that a milligram of iodine given at weekly intervals is sufficient to prevent thyroid enlargement, al- though other pups of the same litter, living in the same kennel, and eating the same food, regularly developed goitre. 6. The thyroid gland has an extraordinary affinity for iodine, as can readily be shown by perfusion experiments in vitro or by in- jecting small amounts-5 to 20 mg. KI.-into the circulation.5, 0 Ex- perimentally then the proof is sufficiently complete to demonstrate the underlying principles of goitre prevention in animals and the ease with which they can be applied. From the practical standpoint, the first instance of preventing goitre on a large scale was accidental and in connection with the sheep raising industry of Michigan. Prior to the discovery of salt deposits around the Great Lakes, the future of the industry seemed hopeless, but with the development of WESTERN RESERVE UNIVERSITY 63 the salt industry and its use by the sheep growers, goitre rapidly de- creased. The salt contains appreciable quantities of both bromine and iodine and in places these elements are extracted on a commer- cial scale. The second instance of goitre prevention on a large scale was in brook trout. Some years ago the development of goitre in artificially raised members of the salmon family became alarming and many plants were abandoned on account of the disease. After considerable work, which led to the conclusion that the disease was simple goitre, we were able to completely prevent the disease in several hatcheries, by the use of very small amounts of tincture of iodine added to the water.7 Later the attempt was made to substitute whole sea fish for part or all of the diet, which, likewise, proved to be, from the practical point of view, a cheaper and simpler method of complete prevention.8 Similar preventive work with farm stock is being carried out under our direction in some of the valleys of British Columbia, where goitre was so prevalent that farmers were unable to raise hogs, cattle, horses, and chickens on account of myxe- dema (cretinism). Similar work in the prevention of goitre in hogs was recently reported by Smith.9 He was able to completely pre- vent fetal myxedema by the use of potassium iodide to the mother during pregnancy. He, however, used quantities far in excess of those necessary to prevent goitre and myxedema. Tn spite of this knowledge of the ease and simplicity of goitre prevention in the lower animals, we know of no instance where the attempt has been made to systematically prevent or control the disease in children in large communities, especially those of the Great Lakes Basin, where goitre is so prevalent. Locally, we have been carrying out preventive treatment for the past six years at the Lakeside Hospital Medical Dispensary and have urged local physicians to do so in their private practices. A great deal has been accomplished in this way, but as ir is a public health matter the most practical and economic method would be to utilize the Public School System and the Board of Health. When the Medical Inspection of Schools is more or less independent of the Board of Health, it would be carried out through the Medical Director of Schools. This year it has been possible to begin such work on a large scale in the city of Akron, through the cooperation of the Superintendent of Schools, the Board of Educa- tion, and the County Medical Society. It was decided for the present to limit the prophylactic work to the girl pupils, since adolescence is the most important goitre THE PREVENTION OF SIMPLE GOITRE 64 developing period and since at this period it occurs about six times more frequently in girls than in boys. The plan now in operation was arranged from the standpoint of simplicity, practicability, economy, and the possible scientific value of the data obtained. Changes will doubtless be made as the work progresses. First a census of the condition of the thyroid gland was taken of all girls between the 5th and 12th grades in- clusive and the findings recorded on individual cards, of which the following is a copy: No. Date Name School Age Weight Physical Development Grade Class Standing T onsils-Adenoids Thyroid 1 Simple 2 Adenomas . 3 Thyroid-tract 4 Duration Remarks The thyroid examinations of all pupils were made by a single examiner in order to make the standards used constant and the data obtained uniform. It is planned to take the census each year in the same way. For the prophylactic treatment we have selected sodium iodide on the grounds of economy and ease of administration. Regarding the amounts that should be given, we have no data except those from animal experimentation. As has been pointed out repeatedly, ex- ceedingly small amounts of iodine are needed. One milligram of iodine given weekly, by mouth, is ample to prevent goitre in dogs. In all our dispensary experiments with children we have used either syrup of hydriodic acid or syrup of ferrous iodide, in 1 c.c. doses, daily for two to three weeks, repeated twice yearly, and have recom- mended their use to clinicians solely because they were the only U. S. P. preparations sufficiently dilute to offset the tendency to use too large amounts. We have, therefore, arbitrarily selected to use 2 gm. sodium iodide, given in 0.2 gm. doses each school day, for each pupil in the 5th, 6th, 7th, and 8th grades; and 4 gm. given in 0.4 gm. doses each school day for each pupil in the 9th, 10th, 11th, and 12th grades. These amounts will be given twice annually about the first of May WESTERN RESERVE UNIVERSITY 65 and December, at the schools by the teachers or nurses. Bottles were distributed to the several schools, containing the solutions (0.2 gm. Nai in 5 c.c. H2O and 0.4 gm. in 5 c.c. H2O) in sufficient amounts to give each pupil electing to take the prophylactic treatment a total of 50 c.c. A record was made both of those who took the treatment and of those who did not. All pupils will be examined annually and the thyroid conditions recorded. These amounts of sodium iodide provide approximately 1700 (1692) mg. of iodine for each pupil of the 5th, 6th, 7th, and 8th grades and approximately 3400 (3384) mg. for the 9th, 10th, 11th, and 12th grades. When one recalls that 25 to 30 mg. saturates the normal thyroid of 20 to 25 gm. and that the thyroid has an extraordinary affinity for iodine, it seems like a prodigious waste and we believe it is. The amounts used at the start were purposely made excessive to provide for any unknown factors and will probably be materially reduced. Analysis of the Thyroid Examinations.-Three thousand eight hundred and seventy-two girls of the 5th, 6th, 7th, 8th, 9th, 10th, 11th, and 12th grades were examined and the general result is given in the following tabulation. Table I. NORMAL SLIGHT ENLARGE- MENT MODERATE ENLARGE- MENT MARKED ENLARGE- MENT ADENOMAS THYROID- TRACT (persistent) Total 1688 1931 246 7 39 594 Per cent. 43.59 49.88 6.35 0.18 1.01 13.4 Condition of Thyroid Gland. The thyroid glands were examined from the standpoint of normals, slight, moderate, and marked enlargements, adenomas, per- sistent thyroglossal tracts and the pupils for gross manifestations of myxedema, and exophthalmic goitre. No obvious case of either myxedema or exophthalmic goitre was found. Under normal we have included all glands, (a) which are not visible as a bulging of the skin across the trachea, (b) having a barely detectable band of thyroid tissue across the trachea on palpation and (c) absence of well-defined thyroglossal stalk (so-called pyramidal process). Those cases with enlarged thyroids have been divided into three arbitrary groups (1) slight, (2) moderate and (3) marked enlarge- ment. Under slight enlargement we have grouped those cases with 66 THE PREVENTION OF SIMPLE GOITRE (a) visible bulging of the skin over the thyroid isthmus (except in the very stout children) and (b) a widened and thickened isthmial band or mass on palpation. If the isthmus can not be seen or felt, it can be felt by having the child swallow, while the finger or thumb is held against the trachea just below the cricoid cartilage. Under moderate enlargement we have grouped those with gross deformity-bulging of the neck laterally from the enlarged lobes and marked bulging of the skin anteriorly from the enlarged isthmus. In approximately 93 per cent the right lobe was larger than the left, which is about the usual, percentage. Under marked enlargement we have grouped those cases with excessive deformity. One thousand six hundred and eighty-eight, or 43.59 per cent, of all pupils examined were classed as normal; 1931, or 49.88 per cent, were classed as slightly enlarged; 246, or 6.35 per cent, were classed as moderately enlarged (none of which had been operated upon) ; 7, or 0.18 per cent, were classed as markedly enlarged, of which two had been operated upon. This gives as totals 2184, or 56.41 per cent with enlarged thyroids and 1688, or 43.59 per cent, with normal thyroids. In 39 cases, or 1.01 per cent, adenomas, single or multiple, were detected. The smallest was approximately 2 cm. in diameter and the largest about 6 cm. These figures are of little value, since they include only the large superficial and favorably located ones. The thyroglossal tract when present is very readily detected, either slightly to the right or left of, and rarely in, the midline. Only those which extended to the base of the thyroid cartilage were included. In many it was palpable to the hyoid bone. The very small pyramidal processes ending below the cricoid cartilage were not included. Five hundred ninety-four, or 13.4 per cent, of the cases had well-defined thyroid stalks. Physiologically the pres- ence of thyroid tissue in the line of descent of the embryologic thyroid anlage indicates that the gland had undergone enlargement in intrauterine life, whereas normally the tract undergoes absorp- tion beginning according to His10 in the second month. The presence of large amounts of thyroid tissue about the foramen cecum-the so-called lingual thyroid-or of large masses between the hyoid bone and thyroid cartilage-so-called infrahyoid thyroids -are of the same significance. Excluding the rare congenital defects in the thyroid anlage, the amount of thyroid tissue in the line of descent of the thyroid gland may be used to determine the WESTERN RESERVE UNIVERSITY 67 degree of normality of the thyroid gland in intrauterine life and as first pointed out by Streckeisen11 it is an excellent index for determ- ining the extent and degree to which a given district is affected with simple goiter. At Basel he found about 79 per cent of the cases coming to postmortem examination had persistant thyroglossal stalks. If the district is extremely goitrous and the mothers are not fed iodine during pregnancy, practically all children should have large persistent thyroglossal tracts. If the district is non- goitrous (e. g., sea coast regions) very few children will have per- sistent thyroglossal tracts. Following the analysis further, the condition of the thyroid in relation to grades is shown in Table II and in relation to age, in Table III. Table II. Grades 5 6 7 8 9 10 11 12 O % No. of Cases % No. of Cases % No. of Cases % O £ . 05 o rt ZU % O " o zu % o . w o rt zu % 05 . tn 0 zu % Normal Slightly 410 51.77 354 45.90 269 40.0 206 40.47 191 42.92 124 40.00 76 36.02 58 36.02 Enlarged Moderately Enlarged Markedly Enlarged 350 44.20 388 50.33 360 53.49 271 53.24 215 48.31 155 50.00 112 53.08 80 49.70 31 1 3.90 0.13 29 3.76 43 1 6.39 0.14 31 1 6.09 0.20 38 1 8.54 0.23 30 1 9.68 0.32 23 10.90 21 2 13.04 1.24 Totals Adeno- 792|20.45* 771 19.91 673 17.38 509 13.15 445 11.5 310 8.0 211 5.45 161 4.16 mas** 3 0.13 3 0.13 7 0.32 6 0.28 8 0.36 6 0.28 5 0.22 1 0.04 Condition of Thyroid Arranged by Grades. * Percentage of total pupils examined 3872. ** Adenoma percentage figured from the total enlarged thyroids 2184. Table III. Age 10-12 12-14 14-16 16-18 18-20 No. of Cases % No. of Cases % No. of Cases % No. of Cases % No. of Cases % Normal Slightly 530 56.08 521 41.32 460 40.35 156 34.44 21 28.77 Enlarged Moderately 394 41.69 680 53.92 578 50.70 235 51.88 44 60.27 Enlarged Markedly Enlarged 21 2.22 59 1 4.68 0.08 98 4 8.6 0.35 60 2 13.24 0.44 8 10.96 Totals Adenomas 945 2 24.41* 0.01** 1261 11 32.56 0.52 1140 18 29.44 0.84 453 8 11.70 0.39 73 1.89 Condition of Thyroid Arranged According to Ages. *Percentage of total pupils. ** Percentage of total enlarged thyroids. 68 THE PREVENTION OF SIMPLE GOITRE The most rapid increase in the number of slight enlargements occurs between the 5th and 8th grades. This corresponds very closely with the rapid increase, between the 10th and 14th years. The average age of the 5th grade pupils was 10 years. Less than 2 per cent of the 5th grade were under 10 years and they were tabulated in the 10 to 12 age group. The age group 18 to 20 contains less than 2 per cent of the total pupils, and while tabulated for the sake of completeness, the per- centages are doubtless higher than the normal average for this age and properly belong to a special group with lower mental activity. The relation of thyroid enlargement to retarded mental development is an important subject, but our available data do not permit of further discussion at present. DISCUSSION The most valuable and accurate data of the incidence of goiter in America can be obtained from examinations of the public school population, because, in the first place it covers the most important ages when goiter develops; secondly, it gives the most complete census; and thirdly, no additional expense or additional effort is necessary. Up to the present time no organized and systematic effort has been made in this country to study the incidence of goiter in the school populations of large communities, even in the Great Lakes Basin-the largest and most densely populated of all goiter districts of North America. The report by Hall12 of the examination of 3339 students at the University of Washington is the most extensive available in American literature. Of the 2086 men with the average age of 20 years and 5 months, he found 374, or 17.93 per cent, with enlarged thyroids; 272, or 13.03 per cent, classed as perceptible; 92, or 4.43 per cent, classed as medium; and 10, or 0.48 per cent, classed as large. Of the 1253 women, with the average age of 19 years and 3 months, he found 388, or 30.98 per cent, with enlarged thyroids; 294, or 23.45 per cent, classified as perceptible; 85, or 6.79 per cent, classed as medium; and 9, or 0.7 per cent, classified as large. These figures demonstrate clearly the prevalence of goiter in the northwestern states. The group is too selective and the ages too advanced to give an average incidence percentage, because (a) the greatest incidence occurs during puberty, (b) a certain percentage of enlargements recede below the level of clinical detectability spon- WESTERN RESERVE UNIVERSITY 69 taneously and (c) a small percentage would have receded because of iodine feeding. In the Great Lakes Basin, Olsen13 reports the examination of 606 women and 193 men, presumably between the ages of 18 and 60, at Chicago. Among the women, he found an average of 17.87 per cent affected and among the men 6.72 per cent. The figures emphasize the frequency of thyroid enlargements, though they are very much lower than would be obtained from a similar number of examinations during the school age, on account of the factors of spontaneous or induced regression of the thyroid enlargements and of migrations from nongoitrous districts, which his figures neces- sarily include. In Europe the statistics of Schittenhelm and Weichardt14 deal with the incidence of goiter in the school populations of certain districts of Bavaria, where goiter is prevalent. Using very liberal standards, they report incidences as high as 77 and 89 per cent of the school population affected. In the Vosges mountains of eastern France and Alsace, MacAuliffe15 has recently reported the examination of 2311 children between the ages of 2 and 15 years. He found 288, or 12.5 per ■cent, affected. A comparison of our data with the data cited above is not possible. We use a much more rigid standard of normal, both clinically and anatomically. Anatomically, the strictly normal gland does not exceed 0.5 gm. thyroid per kilo of body weight, though many European writers, especially those in the Alpine goiter districts, allow as much as 1.0 gm. per kilo. In dogs, the normal thyroid gland does not exceed 0.3 gm. per kilo. Clinically, in the normal gland the isthmus can barely be felt, but the lateral lobes can not be felt. The question of the production of exophthalmic goiter by the use of iodine may be mentioned briefly. Some Swiss writers, like Oswald16 take the extreme view that iodine should never be used in goiter, because of the danger of producing exophthalmic goiter. Pineles17 and Kocher18 take the more moderate ground that iodine should be given cautiously to neurotic individuals with goiter. Our experience has led us to the conclusion that the risk of inducing manifestations of exophthalmic goiter from the use of iodine in physiologic doses is exceedingly small, even in those cases with large hyperplastic thyroids; i. e., the kind of thyroid enlargement which would permit of the most rapid formation and excretion of 70 THE PREVENTION OF SIMPLE GOITRE the iodine-containing hormone. The extent to which iodides are used in general medicine and surgery and the rarity of the develop- ment of signs of exopthalmic goiter is the best index of the danger. Iodine is usually employed in immensely large doses; 0.2 to 0.4 gm. Nai daily for 2 weeks would offer a great excess over the amounts necessary to saturate even the largest thyroids and probably much smaller amounts would suffice in man, as it has been proved to do in the lower animals. While the danger of causing symptoms of exophthalmic goiter probably varies with the size and degree of active hyperplasia, all authors agree that the important factor in determining such symp- toms lies outside the thyroid, either in the nervous system, or some gland like the adrenal, and antedates any thyroid changes. Klose19 has reported the production of exophthalmic goiter in nervous fox terrier dogs, by the injection of sodium or potassium iodide in 0.6 gm. doses per kilo. Those experiments were soon discredited by the work of Bordenhewer20. No one else has suggested any danger from the use of iodides in the case of nongoitrous individuals, except the well-known acute iodism, which affects a small percent- age of people, and, so far as known, is not related to thyroid activity. Cases with definite manifestations of exophthalmic goiter should not be given iodine, although there are cases (or better, stages) of the disease which are distinctly benefited by iodides. The use of desiccated thyroid has well-known dangers after adolescence-mainly because of the large doses used. Both econ- omically and practically, it would not be suitable for general use, as a prophylactic agent. SUMMARY In a complete census of the condition of the thyroid gland in the girls from the 5th to 12th grades of the school population of a large community in the Great Lakes goiter district, it was found that 1688, or 43.59 per cent had normal thyroids; 2184, or 56.41 per cent, had enlarged thyroids; and 594, or 13.4 per cent, had well- defined persistent thyroglossal stalks. The community lies near the southern edge of the goiter district and it is suggested that communities near the lakes would show a higher incidence. The method of prophylaxis proposed is in operation. WESTERN RESERVE UNIVERSITY 71 1 Halsted, W. S.: Reconsideraticn of the Question of Experimental Hypertrophy of the Thyroid Gland, and the Effect of Excision of This Organ Upon Other Ductless Glands. Am. Jour. Med. Sc., 1914, cxlviii, 56. 2 Hunnicutt: Absence of Hyperplasia of Remainder of Thyroid in Dog After Piecemeal Removal of This Gland. Autotransplantation of Thyroid in Partially Thyroidecto- mized Animals. Am. Jour. Med. Sc., 1914, cxlviii, 207. 3 Halsted, W. S.: Experimental Study of Thyroids of Dogs. Johns Hopkins Hosp. Report, 1896, i, 373. 4 Marine and Lenhart: Effects of the Administration or the Withholding of lodin-Con- taining Compounds in Normal, Colloid, or Actively Hyperplastic Thyroids of Dogs. Some Experiments on Prenatal Thyroid Hyperplasia in Dogs, etc. Arch. Int. Med., 1909, iv, 253. 5 Marine and Feiss: The Absorption of Potassium lodid by Perfused Thyroid Glands and Some of the Factcrs Modifying It. Jour. Pharm. and Exper. Therap., 1915, vii, 557. 0 Marine and Rogoff: The Absorption of Potassium lodid by the Thyroid Gland in Vivo Following Its Intravenous Injection in Constant Amounts. Jour. Pharm. and Exper. Therap., 1916, viii, 439. 7 Marine and Lenhart: Observations and Experiments on the So-called Thyroid Carcin- oma of Brook Trout (Salvelinus Fontinalis) and Its Relation to Ordinary Goiter. Jour. Exper. Med., 1910, xii, 311. 8 Marine: Further Observations and Experiments on Goiter (So-called Thyroid Carci- noma) in Brook Trout (Salvelinus Fontinalis). Ill Its Prevention and Cure. Jour. Exper. Med., 1914, xix, 70. 9 Smith, G. E.: Fetal Athyreosis. A Study of the lodin Requirements of the Pregnant Sow. Jour. Biel. Chern., 1917, xxix, 215. io His, W.: Der Tractus Thyreoglossus und Seine Beziehungen zum Zungbein. Arch. f. Anat. u. Physiol. (Anat. Abtheilung), 1891, 26-32. 11 Streckeisen: Beitrage zur Morphologei der Schilddriise. Virchow's Arch. f. path. Anat., 1886, xiii, 131, 215. 12 Hall, D: The Prevalence of Goiter in the Northwest, Based on the Examinations of 3339 Students Entering the University of Washington. Northwest Medicine, 1914, vi, 189, 371. 13 Olsen, E. T.: Goiter, Its Prevalence in Chicago, as shown by the Examination of 800 Individuals. Illinois Med. Jour., Springfield, 1915, xxvii, 16. 14 Schittenhelm, A., and Weichardt, W.: Der Endemische Kropf mit Besonderer Berfick- sichtigung des Vorkommens in Konigreich Bayern J. Sprenger, Berlin, 1912. 15 MacAuliffe, L.: Goitre, cretinisme et myxedeme dans les Hautes-Vosges. Bull, de l'Acad. de med., Paris, Ixxv, 127. !o Oswald: Die Gefahren der Jodbehandlung. Correspondez., Bl. f. Schweizer Aerzte, 1915, xlv, 641. 17 Pineles: Ueber die Empfindlichkeit des Kropfes gegen Jod. Wien. klin. Wchnschr., 1910, xxiii, 353. 18 Kocher: Ueber Jod Basedow. Arch. f. klin. Chir., 1910, xcii, 1166. 19 Klose: Experimentelle Untersuchungen fiber die Basedow'sche Krankheit. Arch. f. klin. Chir., 1911, xcv, 649. 20 Bordenhewer: Erzeugt lodeinspritzung Morbus Basedow? Arch. f. klin. Chir., 1912, xcvii, 729. BIBLIOGRAPHY. WESTERN RESERVE UNIVERSITY 73 THE PREVENTION OF SIMPLE GOITER IN MAN* SECOND PAPER O. P. Kimball, M. D„ and David Marine, M. D CLEVELAND In Article I1 we gave a brief review of the experimental work on which the assertion is based that simple goiter is probably the easiest of all known diseases to prevent. We gave a survey of the incidence and types of thyroid enlargement in the schoolgirls of Akron (Ohio) from the fifth to the twelfth grades, inclusive, and the plan of prevention used. The plan in operation was arranged from the standpoint of simplicity, practicability, economy and the possible scientific value of the data obtained. First, a census of the condition of the thyroid gland was taken of all girls between the fifth and twelfth grades, inclusive, and the findings recorded on individual cards. This card will be used throughout the whole series of observations, the condi- tion of the thyroid noted each year and a record of all treatment kept on the back of the card. No • Date Name School Age Weight Physical Development Grade Class Standing Tonsils-Adenoids Thyroid .1 Simple 2 Adenomas 3 Thyroid-tract 4 Duration Remarks It was- planned that the thyroid examinations should be made by a single examiner in order to make the standard used constant, and the data obtained uniform. At the time of the first examina- tion, however, it was clearly foreseen that Dr. Marine would be called to military duty. Therefore, in order that the junior author should be trained to examine and classify the cases in the November examination as nearly as possible precisely in the same way as was done in the April examination, the April examination was made by * From The H. K. Cushing Laboratory of Experimental Medicine, Western Reserve University. Reprinted from the Archives of Internal Medicine, 1918, xxii, 41-44. 1 The Prevention of Simple Goiter in Man, Journal of Laboratory and Clinical Medi- cine, 1917, 3, 40. 74 THE PREVENTION OF SIMPLE GOITRE both authors conjointly. It is obvious that much of the value of observations of this kind must depend on the uniformity of the methods and classification. The thyroid glands were examined from the standpoint of Nor- mals, Slight, Moderate and Marked Enlargements, Adenomas, Per- sistent Thyroglossal Tracts, and the girls for gross manifestations of myxedema, or exophthalmic goiter. No obvious case of either myx- edema or exophthalmic goiter has been found. Under Normal we have included all glands (a) which are not visible as a bulging of the skin across the trachea; (b) having a barely detectable band of thyroid tissue across the trachea on pal- pation, and (c) absence of a well defined thyroglossal stalk (so- called pyramidal process). The cases with Enlarged Thyroids have been divided into three arbitrary groups: (1) Slight, (2) Moderate and (3) Marked En- largement. Under Slight Enlargement we have grouped those cases with (a) visible bulging of the skin over the thyroid isthmus (except in very stout children), and (b) a widened and thickened isthmial band or mass on palpation. If the isthmus can not be seen or felt, it can be felt by having the child swallow while the finger or thumb is held against the trachea just below the cricoid cartilage. Under Moderate Enlargement we have grouped those with gross deformity, bulging of the neck laterally from the enlarged lobes and marked bulging of the skin anteriorly from the enlarged isthmus. Under Marked Enlargement we have grouped those cases with excessive deformity. Analysis of Thyroid Examinations.-In April, 1917, 3,872 girls of the fifth to twelfth grades, inclusive, were examined and the general results are given in Table 1. In November, 4,415 girls of the fifth to twelfth grades, inclusive, were examined and the new records are given in Table 1. The new records each year will be classed in this table. Slight Moderate Marked Normal Enlargements Pupils % Pupils % Enlargements Pupils % Enlargements Adenomas Pupils % Pupils % April, 1917 Nov., 1917* . 1,688 43.59 1,931 49.88 831 47.00 820 46.20 246 6.35 121+ 6.80 7 0.18 29 1.01 TABLE 1.-Condition of Thyroid Gland * Fifth grade girls and girls who entered the Akron schools since April, 1917. + This number is greater than it would be if only fifth grade pupils were examined; two large schools, one a high school, accidently destroyed all records of those girls not taking treatment, and therefore had to be recorded as new records. WESTERN RESERVE UNIVERSITY 75 For the prophylactic treatment we selected sodium iodid on the grounds of economy and ease of administration. Regarding the amounts that should be given, we had no data except from animal experimentation, and as we have pointed out repeatedly, exceedingly small amounts of iodin are effective. In all our dispensary work with children we have used either syrup of hydriodic acid or syrup of ferrous iodid, in 1 c.c. doses daily for two or three weeks, re- peated twice yearly. The dosage is much less than the therapeutic dose of iodids in other instances in which they are so extensively used, and there can be no reasonable doubt that the action is very different. We, therefore, arbitrarily selected to use 2 gm. sodium iodid, given in 0.2 gm. doses each school day, for each pupil in the fifth, sixth, seventh and eighth grades; and 4 gm. in 0.4 gm. doses each school day for each pupil in the ninth, tenth, eleventh and twelfth grades. These amounts were given in May, 1917, but in November, 1917, we gave 2 gm. to each pupil from the fifth to twelfth grades, inclusive, since this amount in the year's use gave such definite re- sults. As was pointed out in the previous paper, it was thought likely that the dose would be materially reduced. This amount (2 gm.) will be given again in April, 1918. The treatment is given at the school by the teacher or principal and the number of doses recorded. A record is kept, both of those who take the treatment and of those who do not, and all pupils are to be examined annually and the thyroid conditions recorded. A complete reexamination of all girls from the fifth to twelfth grades was made in November, 1917. There were 1,772 new records (Table 1). These include (a) this year's fifth grade; (&) pupils of all grades above the fifth entering Akron schools since April, 1917, and (c) all the girls in two schools (not taking treatment) whose records had been accidentally destroyed (see footnote, Table 1). All those previously examined were classed either as taking prophylactic treatment or not taking prophylactic treatment. The results are summarized in Table 2. It will be seen that not a single pupil in whom the thyroid was normal last year and who took iodin, showed any enlargement, while of those not taking iodin, 26 per cent, showed definitely enlarged thyroids-some moderately large goiters. Even more than a pro- phylactic action is shown in the results-just one third of the goiters 76 THE PREVENTION OF SIMPLE GOITRE Pupils Taking Prophylactic Treatment Pupils % Pupils Not Taking Prophylactic Treatment Pupils % Thyroids remained normal . 283 100.0 637 74.0 Increased from normal to slight goiter.. 0 0.0 259 26.0 Small goiters (unaltered) . 287 66.0 759 87.0 Small goiters (disappeared) . 141 33.5 10 1.2 Small goiters (increased) 2 0.5 103 11.8 Large goiters (unaltered) 34 66.7 106 95.5 Large goiters (decreased) 17 33.3 5 4.5 Total . 764 1,879 Total number of girls examined. . 4,415 TABLE 2.-Summary marked "small goiters" disappeared; and one third of those marked "moderate goiters" showed a decrease of 2 cm. or more. Accord- ingly, a distinct therapeutic effect is clearly demonstrated. It was suggested by some physicians that we would have many cases of iodid rash. We spoke of this possibility in every school and asked the principal and teachers to look for symptoms and call the attention of the school nurse and physician to every possible case. There were more than a thousand girls who took the full treatment, and only five developed any noticeable rash. None of these gave any trouble and the condition lasted only three or four days. Four of the girls continued the treatment and paid no attention to it, while the fifth asked to be excused from further treatment and the rash promptly cleared up. As to the possibility of producing symptoms of Basedow's dis- ease by giving iodin (in small doses) to a large number of girls indiscriminately, we can say that we have not seen a single instance in which any sign of such an effect was produced. The earnestness with which the school girls have taken up the prophylaxis of goiter is encouraging for the practical application of this work. It is entirely elective on the part of the girls, and last year 1,080 girls finished the treatment. This year approximately 2,000 girls are taking the treatment. WESTERN RESERVE UNIVERSITY 77 SUMMARY 1. Simple goiter can be prevented by the administration of small amounts of iodin. 2. One third of the cases of uncomplicated simple goiter dis- appear or are markedly decreased by the use of a small amount of iodin, given internally. 3. There is no danger of producing a toxic condition ("Base- dow's disease"). 4. A very small proportion of the cases (at most 0.5 per cent.) may develop an iodid rash, which promptly clears up on stopping the treatment. We wish to thank Prof. H. V. Hotchkiss (Superintendent of the Public Schools), the Board of Education and the Principals of the several schools; through whose excellent organization and system, as well as the interest in the problem, the work was made possible. WESTERN RESERVE UNIVERSITY 79 [Reprinted from The Journal of the American Medical Association, Dec. 20, 1919, Vol. 73, pp. 1873 and 1874.] THE PREVENTION OF SIMPLE GOITER IN MAN* THIRD PAPER O. P. Kimball, M. D., J. M. Rogoff, M. D., and David Marine, M. D. CLEVELAND This report is based on the reexamination of the girls in the public schools of Akron, Ohio, in grades from the fifth to the twelfth, inclusive, made from Nov. 26 to Dec. 3, 1918-nineteen months after beginning the prophylactic use of iodin. The first report1-a survey of the incidence of thyroid enlargements (goiter) -was based on the examination made in April, 1917. The second report2 gave the results of the examination in November, 1917- seven months after beginning the prophylactic use of iodin. The same classification of the condition of the thyroid has been used as in previous examinations, namely: normal, slight, moderate and marked enlargements, adenomas and persistent thyroglossal tracts.3 The pupils were further examined for gross manifesta- tions of exophthalmic goiter and myxedema. No obvious case of either of these diseases was detected. The results of these examinations are given in Table 1. For comparison and reference, the figures of the original sur- vey in April, 1917, and of the second examination in November, 1917, are added. The subjects included in this table are all new admissions to the public schools and presumably had not previously received iodin. Owing, however, to the very extensive use of iodin in some form, both by the public and the profession, it is probable that some of these pupils had had iodin for one reason or another, but no attempt was made to detect such cases. lodin administered in any form markedly affects the thyroid. ANALYSIS OF THE RECORDS OF NEW PUPILS * From the H. K. Cushing Laboratory of Experimental Medicine, Western Reserve University. * Aided by a Grant from the Committee on Therapeutic Research of the Council on Pharmacy and Chemistry of the American Medical Association. 1 Marine, David, and Kimball, O. P.: Prevention of Goiter in Man, J. Lab. & Clin. M. 3:40-43 (Oct.) 1917. 2 Kimball, O. P., and Marine, David: Prevention of Goiter in Man, Second Paper, Arch. Int. Med. 22:41-44 (July) 1918. 3 Persistence of the thyroid tract is the best evidence of enlargement of the thyroid during fetal life. 80 THE PREVENTION OF SIMPLE GOITRE The figures in the first line represent the results of the original survey of all girls in grades from the fifth to the twelfth, inclusive. The figures in the second line represent: (1) incoming fifth grade girls; (2) girls entering other grades of the public schools between April and November, 1917, and (3) girls of two schools that acci- Date Exam- ined Total Exam- ined Total New Cases Normal Pupils , Enlargements- Slight Moderate Marked Ade- nomas No. % No. % 'No. % No. % No. % April, 1917 3,872 3,872 1,688 43.5 1,931 49.9 246 6.3 7 0.2 39 1.0 Nov., 1917 4,415 1,772 831 47.0 820 46.2 121 6.8 Nov., 1918 4,277 1,873 1,037 55.4 779 41.6 53 2.8 4 0.2 6 0.3 TABLE 1.-ANALYSIS OF THE RECORDS OF NEW PUPILS dentally lost the records of those not taking the prophylactic treat- ment. The figures in the third line represent only girls in the incoming fifth grade and girls entering other grades. The progressive increase in the percentage of normal thyroids (43.6, 47 and 55.4 per cent.) for the three periods is due to the preponderance of fifth grade girls in the second and third groups. Fifth grade girls average 10 years of age and are for the most part below the age of the greatly increased incidence of thyroid enlarge- ment. The same method as outlined in the first paper and modified in the second paper was used, i. e., 2 gm. of sodium iodid were given in 0.2 gm. doses for ten consecutive school days, repeated each autumn and spring. The results are given in Tables 2 and 3. For reference and comparison, the figures for the November. 1917, ex- amination are added. The most striking fact brought out is that not a pupil in whom the thyroid was normal at the November, 1917, examination, and who took iodin, showed any thyroid enlargement; while of those not taking iodin, 15.9 per cent, showed definite enlargement. This effect is similar to that noted in last year's examination. As was noted last year, a distinct therapeutic effect is again observed in that the glands of 38.1 per cent, of the pupils with slightly enlarged glands decreased following the use of iodin, while of the glands of those listed as not taking iodin 27.8 per cent, showed a decrease in size. This difference is much less than that found last year and suggests that many pupils with slight goiter were taking iodin privately. EFFECT OF PROPHYLACTIC TREATMENT WESTERN RESERVE UNIVERSITY 81 Thyroids Thyroids Enlarged from Normal Slightly Enlarged A Moderately and Markedly Enlarged Total Number Normal Enlarged Unaltered Decreased Increased Unaltered Decreased Date No. % ' No. %' No. % No. % No. % No. % No. % November, 1917 764 283 37.0 0 0.0 287 37.6 141 18.4 2 0.3 34 4.4 17 2.2 November, 1918 1,121 469 41.8 0 0.0 354 31.6 218 19.4 0 0.0 29 2.6 51 4.5 Date Total Number Thyroids Remaining Normal Thyroids Enlarged from Normal to Slightly r Enlarged Slightly Enlarged Moderately and Markedly Enlarged Unaltered Decreased Increased Unaltered Decreased 'No. % No. % No. % ' No. % ' No. % No. % No. % November, 1917 1,879 637 33.9 259 13.8 759 40.4 10 0.5 103 5.5 106 5.6 5 0.3 November, 1918 1,283 496 38.7 94 7.3 424 33.1 170 13.2 17 1.3 52 4.1 30 2.3 TABLE 3.-RECORDS OF PUPILS NOT TAKING PROPHYLACTIC TREATMENT TABLE 2-RECORDS OF PUPILS TAKING PROPHYLACTIC TREATMENT 82 THE PREVENTION OF SIMPLE GOITRE The same therapeutic effect is also noted in those with moderate and marked enlargements, and again the percentage differences between those taking and those listed as not taking iodin is less than last year's figures. The main effects of the administration of iodin observed dur- ing the second year are similar to those noted during the first year. The danger of iodism or of exophthalmic goiter from the use of such amounts of iodin as were given is shown to be neglible. SUMMARY 1. Simple goiter in man may be prevented on a large scale. 2. The method used is practical and economical, and can be recommended as a public health measure in goiter districts. 3. Two gm. of sodium iodid given twice yearly, as we have indicated, seems adequate. Copyright 1919 American Medical Association, 535 N. Dearborn St., Chicago WESTERN RESERVE UNIVERSITY 83 [Reprinted from The Archives of Internal Medicine, 1920, xxv, 661-672.] THE PREVENTION OF SIMPLE GOITER IN MAN* David Marine and O. P. Kimball CLEVELAND FOURTH PAPER In previous publications1 we have outlined the plan of preven- tion, presented the data of the incidence of thyroid enlargements as determined by annual surveys of all new pupils in the Akron public schools, and the results of the prophylatic use of sodium iodid for nineteen months. The present paper deals with the data obtained at the fourth general examination made October 13-17, 1919, together with summaries and conclusions based on observations extending over a period of thirty months. ANALYSIS OF THE RECORDS OF NEW PUPILS The general data of the clinical condition of the thyroid gland are given in Table 1. For comparison and reference the figures for the three previous examinations are also given. The pupils included in this table are new admissions to all grades from the fifth to the twelfth, inclusive, and presumably had not previously received iodin. The figures in the first line represent the results of the original survey of all girls in grades from the fifth to the twelfth, inclusive. The figures in the second line include (1) incoming fifth grade girls, (2) girls entering grades above the fifth grade, and (3) girls of two schools that accidently lost the records of those not taking the treatment. The figures in the third and fourth lines include (1) incoming fifth grade girls and (2) girls entering grades above the fifth. The progressive increase in the percentage of normal thyroids (43.6, 47.0, 55.4 and 65.4) and the corresponding progressive decrease in the percentage of enlarged thyroids whether taken together (56.4, 53.0, 44.6 and 34.5) or as separate groups (slightly enlarged, moderately enlarged and mark- edly enlarged) are due to the increasing preponderance of fifth grade girls in the second, third and fourth groups. This is also * From the Department of Experimental Medicine, Western Reserve University. * Aided by a Grant from the Committee on Therapeutic Research of the Council on Pharmacy and Chemistry of the American Medical Association. 1 Marine, D., and Kimball, O. P.: The Prevention of Simple Goiter in Man, J. Lab. & Clin. Med. 3:40, 1917. Kimball, O. P., and Marine, D.: The Prevention of Simple Goiter in Man (Second paper), Arch. Int. Med. 22:41 (July) 1918. Kirriball, O. P., Rogoff, T. M., and Marine, D.: The Prevention of Simple Goiter in Man (Third Paper), J. A. M. A. 73:1873 (Dec. 20) 1919. TABLE 1.-.Analysis of the Records of New Pupils Date Exam- ined Total Cases Exam- ined Total New Cases Normal Slight Enlarge- ments Moderate Enlarge- ments Marked Enlarge- ments Adenomas Num- ber Per Cent. Num- ber Per Cent. Num- ber Per Cent. Num- ber Per Cent. Num- ber Per Cent. April 1917 3,872 3,872 1,688 43.6 1,931 49.9 246 6.3 7 0.2 39 1.0 November 1917 November 1918 4,415 4.277 1,772 1,873 831 1,037 47.0 55.4 820 779 46.2 41.6 121 53 6.8 2.8 4 0.2 6 0.3 October 1919 5,520 2,162 1,415 65.4 679 31.4 67 3.1 1 0.05 1 0.05 TABLE 2.-Summary of Age Incidence-New Pupils Date of Examina.- tion Total New Cases Age 10-12 12 - 14 14 - 16 . 16 - 18 18 - 20 Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of. . Cases Per Cent.. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. April 1917 3,872 945 24.4 ' 1,261 32.6 1,140 29.4 453 11.7 73 1.0 November 1918 1,873 2,162 706 40.9 590 31.5 406 21.7 94 5.0 17 ' 0.9 October 1919 4.4.8 678 31.4 401 18.6 102 4.7 12 0.5 TABLE 3.-Relation of Age to Thyroid Condition-New Pupils-1917 - ■ or Age 10 - 12 12 14 14 - 16 16 - 18 18-20 Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Normal 530 56.1 521 41.3 460 40.3 156 34.4 21 28.8 Slightly enlarged. Moderately en- 394 41.7 680 53.9 578 50.7 ■ 235 _ 51.9 44 60.3 larged Markedly en- 21 2.2 59 4.7 98 8.6 60 13.2 8 11.0 larged 1 0.1 4 0.3 2 0.4 TABLE 4.-Relation of Age to Thyroid Condition-New Pupils-1918 Age 10 - 12 12 - 14 14-16 .16-18 18 - 20 Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Normal 491 64.2 295 50.0 214 52.7 39 41.5 9 52.9 Slightly enlarged. 267 34.8 276 46.8 168 41.4 49 52.1 6 35.3 Moderately en- larged 8 1.0 19 3.2 24 5.9 6 6.4 2 11.8 Markedly en- larged 0 0.0 0 0.0 0 0.0 0 0.0* 0 0.0 85 WESTERN RESERVE UNIVERSITY TABLE 5.-Relation of Age to Thyroid Condition-New Pupils-1919 Age 10-12 12 - 14 14-16 - 16 - 18 18 20 Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Num- ber of Cases Per Cent. Normal 743 76.7 419 61.8 199 49.6 53 51.9 7 58.3 Slightly enlarged. Moderately en- 215 22.2 239 35.3 170 42.4 43 42.2 5 41.7 larged Markedly en- 11 1.1 20 2.9 31 7.8 6 5.9 0 0.0 larged... 0 0.0 0 0.0 1 0.2 0 0.0 0 0.0 TABLE 6.-Analysis of Records of New Pupils-Negroes-1919 Age 10 - 12 12 - 14 14 - 16 Number of Cases Per Cent. Number of Casec Per Cent. Number of Cases Per Cent. Normal 5 50.0 7 53.9 Slightly enlarged 4 40.0 5 38.5 3 75.0 Moderately enlarged..... 1 10.0 1 7.6 1 25.0 shown in Table 2, where all new pupils are grouped according to ages. Fifth grade pupils average from 10 to 11 years of age, and approximately 95 per cent, are included in the age group from 10 to 12. Details of the relation of age to the clinical condition of the thyroid are given in Tables 3, 4 and 5. For reference and comparison the original survey of all pupils (April, 1917), is given in Table 3, while in Tables 4 and 5 are given the results of the surveys of new pupils for 1918 and 1919, respectively. It should be emphasized, that in the 1917 examination 43.9 per cent, of the girls in the 10-12 years age group had enlarged thyroids; that in the 1918 examination 35.8 per cent, had enlarged thyroids; and that in the 1919 examination 23.2 per cent, had thy- roid enlargements. This is important from the standpoint of the age at which the prophylactic treatment should be started. When this work was begun, no data of this kind were available, and the fifth grade was arbitrarily chosen as the lower limit, because our limited facilities made it necessary to confine our efforts to what seemed to be the most important age periods. We have seen only 86 THE PREVENTION OF SIMPLE GOITRE forty instances of moderately enlarged glands and no instance of marked enlargement in the 10-12 year age group, and as very striking therapeutic effects are seen in these slight hyperplasias it makes little difference in the ultimate result. If, however, one had to depend entirely on prevention it would be necessary to begin at an earlier age. There appears to be no noteworthy difference in the incidence of thyroid enlargements between white and colored children. The data are, however, insufficient for any definite conclusion. The data on the twenty-seven colored children are given in Table 6. The prophylactic treatment as carried out for the past two years consists of the administration of 2 gm. sodium iodid, given in 0.2 gm. doses daily, for ten consecutive school days, repeated each spring and autumn. The general data of those, pupils not taking the treatment are given in Table 7, and of those taking the treatment in Table 8. Only pupils with two or more consecutive examinations have been included in the tabulations. A considerable number of pupils, both taking and not taking the treatment, have been omitted because they missed one examination, although other- wise their records were complete. Two thousand, three hundred and five pupils are included in the tabulation of those not taking EFFECT OF PROPHYLACTIC TREATMENT TABLE 7.-Record of Pupils Not Taking Prophylactic Treatment Time Under Obser- vation, Moe. Normal Slightly Enlarged Moderately Enlarged Unaltered Increased Unaltered Increased Decreased Unaltered Increased Decreased No. % No. % No. % No. % No. % No. % No. % No. % 6 47 50.0 47 50.0 93 69.4 36 26.9 5 3.7 16 69.6 7 30.4 0 0.0 12 420 75.5 136 24.5 251 70.3 35 9.8 71 19.9 17 65.4 8 30.8 1 3.8 18 103 65.2 55 34.8 108 74.5 18 12.3 19 13.1 11 57.9 3 15.8 5 26.3 24 135 76.7 41 23.3 106 79.7 8 6.0 19 14.3 9 60.0 3 20.0 3 20.0 30 205 75.1 68 24,9 140 73.7 30 15.8 20 10.5 4 66.7 0 0.0 2 33.3 treatment, and 2,190 in the tabulation of those taking treatment. Further, it was necessary to tabulate the results with reference to the length of time under observation. As the prophylactic treat- ment was given at intervals of six months, we have used this interval as the unit and grouped the pupils according to the periods under observation, 6, 12, 18, 24 and 30 months respectively. Only the results of three groups (normals, slightly enlarged, and moderately enlarged) are included because the fourth group (markedly en- WESTERN RESERVE UNIVERSITY 87 larged) is too small. A comparison of the two tables brings out striking differences between those not taking and those taking iodin. These differences are manifested both in prevention of enlargement and in a decrease in the size of existing enlargements, i. e., thera- peutic effect. Prevention.-This effect is shown in the columns marked "un- changed" and "increased." Taking the totals for the five six month periods (Table 9) the following results were obtained. Of those that were normal at the first examination and did not take iodin, 347, or 27.6 per cent., have enlarged thyroids, while of those that were normal at the first examination and took iodin as outlined, two, or 0.2 per cent., have enlarged thyroids. These two instances of en- largement were investigated. The first pupil, M. T., age 16, had her thyroid examined and classified as normal May 2, 1917, Oct. 17, Time Under Obser- vation, Mos. Normal Slightly Enlarged Moderately Enlarged Unaltered Increased Unaltered Increased Decreased Unaltered Increased Decreased No. % No. % No. % • No. % No. % No. % No. % No. % 6 17 94.4 1 5.6 54 69.2 1 1.3 23 29.5 9 81.8 0 0.0 2 18.2 12 344 99.7 1 0.3 187 45.5 0 0.0 224 54.5 10 23.8 0 0.0 32 76.2 18 73 100.0 0 0.0 72 52.3 1 0.7 64 46.7 7 28.0 0 0.0 18 72.0 24 184 100.0 0 0.0 72 37.9 1 0.5 117 61.6 2 7.7 0 0.0 24 92.3 30 288 100.0 0 0.0 92 28.5 0 0.0 231 71.5 1 2.6 0 0.0 38 97.4 TABLE 8.-Record of Pupils Taking Prophylactic Treatment TABLE 9.-Summary-Records of Pupils Taking and Not Taking Prophylactic Treatment Taking Not Taking Totals Per Cent. Totals Per Cent. Normal: Unchanged 906 99.8 910 72.4 Increased 2 0.2 347 27.6 Slightly Enlarged: Unchanged 477 41.9 698 72.8 Increased 3 0.3 127 13.3 Decreased 659 57.8 134 13.9 Moderately Enlarged: Unchanged 29 20.3 57 64.0 Increased 0 0.0 21 23.6 Decreased 114 79.7 11 12.4 Total 2,190 2,305 1918 and Dec. 3, 1918. At the examination Oct. 15, 1919, it was classified as slightly enlarged. This girl had taken 2 gm. of sodium iodid during each of the five possible periods, May, 1917, November, 1917, May, 1918, December, 1918 and May, 1919. A special exami- nation was made Jan. 13, 1920. The enlargement of the thyroid 88 THE PREVENTION OF SIMPLE GOITRE was verified. The enlargement was acquired as opposed to con- genital, as shown by the absence of a pyramidal process or thyro- glossal tract. The tonsils were markedly enlarged, nearly meeting in the midline when the mouth was widely opened. They were abnormally hyperemic, and on direct questioning the pupil stated she was subject to recurrent tonsillitis. There was also slight en- largement of the lymphoid tissue at the base of the tongue and in the nasopharynx. The general impression was that of a neurotic individual with general lymphoid hyperplasia. The second girl, aged 15, had. her thyroid first examined and classified as normal Nov. 27, 1918. At the examination Oct. 16, 1919, it was classified as slightly enlarged. This girl had taken 2 gm. sodium iodid during each of the two available periods, Novem- ber, 1918 and May, 1919. A special examination was made Jan. 13, 1920, and the thyroid enlargement was verified. Careful inspec- tion revealed the presence of Hutchinson teeth, depressed nasal arch and interstitial keratitis. We considered the case one of neglected congenital syphilis. Passing to Group 2, or those classified as having slightly en- larged thyroids at the first examination, it is seen among those not taking the prescribed treatment that 127, or 13.3 per cent., under- went further enlargement, while of those taking the prescribed treatment, three, or 0.3 per cent., underwent further enlargement. Two of these three pupils were again examined Jan. 13, 1920. One, R. R., aged 14, was examined May 2, 1917, Oct. 12, 1917 and Nov. 26, 1918, and the thyroid classified as slightly enlarged, and at the examination Oct. 16, 1919 the gland was classified as moderately enlarged. This girl had taken the prescribed treatment only during the last three available periods, May, 1918, November, 1918 and May, 1919. A special examination was made Jan. 13, 1920, and the thyroid enlargement verified. In this case also the tonsils were enlarged and the seat of recurrent infections. The second case, V. S., aged 11, was examined Oct. 22, 1917 and Nov. 27, 1918, and the thyroid classified as slightly enlarged. At the third examination, Oct. 16, 1919, it was classified as moderately enlarged and the special examination Jan. 13, 1920, verified this finding. This girl had taken the prescribed treatment during the four available per- iods, November, 1917, May, 1918, December, 1918, and May, 1919. Superficial inspection failed to reveal the existence of any associated WESTERN RESERVE UNIVERSITY 89 pathologic condition as was found in each of the first three cases mentioned. The fifth girl was not present for the special examina- tion. These five cases are the only instances out of 2,190 pupils taking iodin that showed enlargement. For the group with slightly enlarged thyroids taking iodin, 447, or 41.9 per cent., remained unchanged, while of those not taking iodin, 698, or 72.8 per cent., remained unchanged. Passing to the third group, or those classified as having mod- erately enlarged thyroids at the first examination, it is seen that of those taking iodin, twenty-nine, or 20.3 per' cent., remained un- changed, while of those not taking iodin, fifty-seven, or 64.0 per cent., remained unchanged; of those taking iodin none increased, while of those not taking it, twenty-one, or 23.6 per cent., increased. Curative or Therapeutic Effect.-Although of secondary im- portance, the results are just as striking as those above described under prevention. These results are shown in the column marked "decreased." Of those pupils whose thyroids were classified as slightly enlarged at-the first examination, and who took iodin, 659, or 57.8 per cent., definitely decreased in size, while of those not taking the prescribed treatment, 134, or 13.9 per cent., decreased. Passing to the group whose thyroids were classified as moderately enlarged at the first examination, 114, or 79.7 per cent., of those taking iodin showed definite decreases. In some the decrease in size was most striking and hardly to be believed had we not had actual measurements and descriptions of the condition previously. The reduction in several cases was as marked as one sees in the thyroid enlargement of young dogs, sheep or cattle following the use of iodin. It means that with similar anatomic conditions, i. e., uncomplicated hyperplasias of the thyroids, the degree of reaction is similar. Or- dinarily, one does not obtain the striking therapeutic effect on human thyroid enlargements that is seen in animals. This, as pointed out in previous papers, is due, in large part, to the duration of the enlargement, the presence of adenomas, cysts, degenerations, hem- orrhage, etc., which are common in all long standing human goiters, while very uncommon in the lower animals at the ages when these animals are usually observed. The therapeutic effect is a very im- portant supplement to prevention and makes it possible to begin prophylactic treatment in older pupils with the same practical result than would otherwise be possible. 90 THE PREVENTION OF SIMPLE GOITRE Our observations on the prevention of simple goiter in man have extended over a period of thirty months. The disease is as easily prevented in man as in fish or in domestic animals. Of 2,190 pupils taking 2 gm. sodium iodid twice yearly, five have shown enlargement of the thyroid, while of 2,305 pupils not taking the prophylactic, 495 have shown enlargement of the thyroid. Of 1,182 pupils with thyroid enlargement at the first examination and who took the prophylactic, 773 thyroids have decreased in size, while of 1,048 pupils with thyroid enlargement at the first examina- tion and who did not take the prophylactic, 145 thyroids have de- creased in size. These figures demonstrate in a striking manner both the preventive and the therapeutic effects. There is an error in the above figures in that many pupils listed as not taking iodin have taken iodin in one or another form outside the school jurisdic- tion. No attempt has been made to detect or estimate this error. In the practical application of the preventive treatment, one must keep in mind the three periods when simple thyroid enlarge- ments most commonly occur, viz., (1) fetal, (2) adolescence and (3) pregnancy. (1) Prevention of goiter in mother and fetus is as simple as that occurring during adolescence. Practically, it would seem that it is a charge or responsibility of individual members of the medical profession supplemented with public education. (2) The prevention of goiter of adolescence, on the other hand, should be a public health measure under state, county or municipal control. The existing systems of organization of the schools, public and private, is sufficient to handle all the details with- out additional aid or expense. Education of the pupils would be combined with the actual administration so that after leaving school they could continue the treatment, if necessary. Physicians in in- dustrial medicine could render an important service in this field- Thyroid enlargement is approximately six times as frequent in girls- as in boys. It is a social economic question each community must decide whether it will include both sexes. Likewise, as to the age- of beginning and stopping the use of iodin. In this climate probably the maximum of prevention, coupled with the minimum of effort,, would be obtained by giving it between the ages of 11 and 17 years- DISCUSSION WESTERN RESERVE UNIVERSITY 91 As applied to our schools it would mean beginning with the fifth grade. Manner and Form of Administration.-As previously stated, iodin is taken up by the thyroid gland when given by mouth, by inhalation, or by external application. Weith2 reports favorable therapeutic effects from inhalation of iodin as carried out by sus- pending a wide mouthed bottle containing a 10 per cent, tincture of iodin in the school room. Waste and lack of control of amounts taken are the most obvious objections. Similar objections hold in case of external application. Some form of oral administration seems most practical and economical. The addition of iodin or a salt of iodin to the water supply as we have done in preventing goiter in fish might be considered. There are obvious objections to such a plan. It would entail enormous waste. It is applicable only when there are installations, i. e., in towns and cities, and depending on the chemical impurities in water interactions might throw out the iodin. The most feasible oral method would seem to be the individual administration of definite small amounts, either in solution or as tablets. The cheapest salt, sodium iodid, could be given in either form. Manufacturing pharmacists state that sodium iodid could be prepared very cheaply in tablet form protected from the action of water and light. For private use, the well known U. S. P. preparations, syrup of ferrous iodid and syrup of hydriodic acid are excellent. Amounts of lodin to be Used.-An ounce of syrup of ferrous iodid or hydriodic acid given over a period of from two to three weeks and repeated twice yearly would seem ample. As a public health measure, we have used 2 gm. of sodium iodid given over a period of two weeks and repeated twice yearly. This dosage has prevented enlargement of the thyroid in more than 99 per cent, of the children in this mildly goitrous district. It is our opinion that much smaller amounts would suffice for healthy children and healthy pregnant women, provided the period of taking was prolonged, i. e., 1 gm. sodium iodid distributed over a month would accomplish as good thyroid effects as 2 gm. given over a period of two weeks. The prevention of thyroid enlargement in individuals with other diseases or residing in extremely goitrous districts, as in some glacial valleys of Alaska and British Columbia; certain districts in the Alps and Himalayas, might require larger amounts of iodin 2 Weith: Goiter and lodin in the School, Cor.-Bl. f. schweiz. Aerzte 49:1474, 1919. 92 THE PREVENTION OF SIMPLE GOITRE for normals than above indicated. Our data of the clinical condition of four of the five cases that enlarged during the administration of 2 gm. of sodium iodid, twice yearly, suggest that in infections (chronic catarrhal or suppurative tuberculosis, syphilis, etc.) and possibly also in conditions like chlorosis, osteomalacia, lymphatism and exophthalmic goiter, such amounts might not control the thyroid growth. In such conditions there may be a greatly increased demand for the thyroid hormone or the organism's ability to store iodin in the thyroid may be impaired. There is a great deal of clinical evidence for the first view and none at present in support of the second. Effect of lodin on the Thyroid Gland.-This is manifested in two ways (1) on the iodin store and (2) on the histologic condition. Both of these effects have been fully described in previous papers.3 Effect on the Store: If the thyroid gland is not saturated with iodin (i. e., contains less than 4 mg. per gm. of dried gland) it is taken up readily by the cells following its administration in any form and in any manner thus far studied. An increase in the iodin content of thyroid may be demonstrated in a few seconds following the injection of a soluble salt into the circulation.4 lodin thus taken up is held by the cells until elaborated into the physiologically active hormone, when any excess is excreted into the follicular spaces and stored in the so-called colloid. Two factors then are concerned in the storage of iodin in the thyroid: (a) the capacity of the gland cells to take up and elaborate the hormone and (b) the capacity of the colloid material to store the product. It is evident, then, that to obtain maximum thyroid effects from a minimum amount of iodin, it should be administered in amounts not to exceed the capacity of the cells at any given time to handle it. As has been shown, the elaboration of the hormone proceeds slowly5 in the most active thyroids. Also when one recalls that from 4 to 5 mg. of iodin per gm. of dried gland, or from 25 to 30 mg., is the total 3 Marine, D.: On the Occurrence and Physiological Nature of Glandular Hyperplasia of the Thyroid (Dog and Sheep) Together with Remarks on Important Clinical Human Problems, Bull. Johns Hopkins Hosp. 18:359, 1907. Marine, D., and Lenhart, C. H.; Colloid Glands (Goiters): Their Etiology and Physiological Significance, Bull. Johns Hopkins Hosp. 20:131, 1909. Marine, D., and Lenhart, C. H.: Effects of the Administra- tion or the Withholding of lodin Containing Compounds in Normal, Colloid or Actively Hyperplastic Thyroids of Dogs, Arch, Int. Med. 4:253, 1909. Marine, D.: Quantitative Studies on the in vivo Absorption of lodin bv Dogs' Thyroid Glands, J. Biol. Chern. 22:547, 1915. 4 Marine, D., and Rogoff, J. M.: The Absorption of Potassium lodid by the Thyroid Gland in vivo Following Its Intravenous Injections in Constant Amounts, J Pharm. & Exper. Therap. 8:439, 1916. 5 Marine, D., and Rogoff, J. M.: How Rapidly Does the Intact Thyroid Gland Elaborate Its Specific lodin Containing Hormone? J. Pharm. & Exper. Therap. 9:1, 1916. WESTERN RESERVE UNIVERSITY 93 storage capacity of a normal thyroid, it is clear that small amounts of iodin (a few mg.) given daily for a long period of time (a month or more) would produce optimum thyroid effects. In the school work, a compromise was found necessary, increased amounts and decreased time of administration. Effect on Histology of the Thyroid: It has been shown that the minimum amount of iodin store necessary to maintain normal or quiescent thyroid structure is quite constant for mammals.6 In the dog, sheep, human and pig thyroid it is approximately 1 mg. per gm. of dried gland, and immediately the percentage is reduced below the minimum, hypertrophic and hyperplastic changes begin .and continue until the store of iodin has again been raised above the minimum requirements, when involution takes place. This cycle may be repeated many times in the same individual under natural or experimentally controlled conditions. In young dogs, with active hyperplasia, involution is usually complete in from fourteen to twenty-one days after beginning the administration of iodin. The histologic features of this involution have been described in detail in other papers. Untozvard Effects.-No obvious case of exophthalmic goiter has developed, although such cases have been carefully looked for. An occasional instance of iodin idiosyncrasy (iodism), amounting to less than 0.5 per cent, of the cases, was noted. Most of the cases were very mild and the girls did not stop the treatment. As an untoward effect it is negligible. Observations on the prevention of simple goiter in man on a large scale have extended over a period of thirty months. The results show that it may be prevented very simply and cheaply in normal individuals. While thyroid enlargements of adolescence are more common, they are not more important than those occurring in mother and fetus. Prevention of adolescent goiter is properly a public health problem, while the prevention of fetal and maternal thyroid enlargements is largely a responsibility of individual phy- sicians. The presence of pathologic conditions may modify the result of the prophylactic treatment in individual cases. While such instances are rare they are important and merit detailed reports. SUMMARY 6 Marine, D., and Williams, W. W.: Relation of lodin to the Structure of the Thyroid Gland, Arch. Int. Med. 1:349, 1908. Marine, and D., and Lenhart, C. H.: Further Observations on the Relation of lodin to the Structure of the Thyroid Gland in the Sheep, Dog, Hog and Ox, Arch. Int. Med. 3:66, 1909. WESTERN RESERVE UNIVERSITY 95 [Reprinted from The Journal of the American Medical Association, Oct. 1, 1921, Vol. 77, pp. 1068-1070.] THE PREVENTION OF SIMPLE GOITER IN MAN* David Marine, M. D., New York, and O. P. Kimball, M. D., Cleveland. Simple or endemic goiter is one of the most benign and insid- ious diseases of man and animals. The sum total of its ravages throughout all ages and in all lands is still unrealized by the public generally, notwithstanding the numerous reports of commissions appointed for its study. Those who live on the sea coasts fortun- ately have no need to be concerned and those who lived in goiter districts-before the days of extensive travel-grew accustomed to look on goiter as natural and normal. Indeed, in many districts of the world, it is still looked on as a mark of beauty. Simple goiter includes all those thyroid enlargements in man and animals formerly grouped as endemic, epidemic, sporadic and physiologic. It must be sharply distinguished from exophthalmic goiter, with which it has no necessary association or etiologic rela- tionship. Exophthalmic goiter, so far as is yet definitely known, occurs spontaneously only in man, while simple goitre occurs in all animals having the ductless thyroid. Exophthalmic goiter is not notably associated with districts, while with simple goiter this is most characteristic. Exopthalmic goiter occurs more frequently in the highly developed and civilized races, while in simple goiter race is not a factor. Simple goiter may develop sporadically in any place (even at sea. as reported on one of Captain Cook's voyages), but it is preeminently associated with certain regions or districts. The distribution of these districts of endemic goi- ter throughout the world was fully described by Hirsch, in 1860. The actual incidence of goiter within a given district is still quite unknown. With the information at present available, how- ever, one can distinguish between mildly and severely goitrous districts. As compared with certain other districts, for example, the Alps and the Himalaya regions, our most important districts, namely, the Great Lakes Basin and the Cascade Mountain regions * From the Laboratories of Western Reserve University, Cleveland, and Montefiore Hospital, New York. * Read before the Section on Pharmacology and Therapeutics at the Seventy-Second Annual Session of the American Medical Association, Boston, June, 1921. * This investigation has been made with the assistance of a grant from the Committee on Therapeutic Research, Council on Pharmacy and Chemistry, American Medical Associa- tion. 96 THE PREVENTION OF SIMPLE GOITRE of Oregon, Washington and British Columbia, would be classified as mildly goitrous. The mildness or severity of a district may be determined by the incidence of myxedema or cretinism-a fact known to Morel and expressed in his famous dictum, "Goiter is the first halting place on the road to cretinism" (Le goitre est la premiere etape sur le chemin qui conduit au cretinisme). The ultimate cause of simple goiter is totally unknown, not- withstanding a relatively large amount of study. The immediate cause is a lack of iodin. The enlargement, therefore, is a symptom and may result from any factor which increases the iodin needs of the organism, as in certain types of infection, or which interferes with the normal utilization of iodin; or it may result from actual experimental deprivation of iodin. The conception that it is due to a contagium vivum in the sense that this term is ordinarily used may be abandoned. Water has been associated as an etiologic factor by all peoples as far back as history goes. The American Indians (Barton) and the natives of Central Africa (Livingston) seem to have been as strongly convinced of the relation of water to the dis- ease as was Hippocrates. If water is a factor, it would seem that it is the absence rather than the presence of some substance, which is to be considered, since goiter is associated with the purest of waters, chemically and bacteriologically as, for example, in Portland, Ore., and in Seattle and Tacoma, Wash., where there has been a rapid increase in goiter since these cities began to take their water supplies from the Cascade Mountains. After consideration of all the various substances, agents and theories that have been put forward as having a role in the etiology of goiter, we at present must fall back on the view that thyroid hyperplasia (goiter) is a compensatory reaction arising in the course of a metabolic disturb- ance and immediately depending on a relative or an absolute deficiency of iodin. ETIOLOGY PATHOLOGIC ANATOMY Anatomically, a wide range of changes may be present, depend- ing on the species of animal and on the stage (duration) of the disease. It always begins with a decrease in the colloid material and a hypertrophy of the epithelial cells, at first cuboidal, later columnar, with infoldings and plications. In man and fowls, the WESTERN RESERVE UNIVERSITY 97 stage most commonly observed is characterized by an abundance of colloid material--the so-called cystic or colloid goiter of the older writers-while in dogs, sheep, cattle, pigs, fish, etc., the accu- mulation of colloid is seen only in the late regressive or quiescent stages. In man, the adenomatous form (struma nodosa) is very common, but it is exceedingly rare in all the lower animals. These adenomas, in all probability, arise from fetal cell rests. The stimu- lus which initiates the growth of the cell rests (adenomas) and that which initiates the growth of the more differentiated thyroid tissue are probably identical. These growths have many of the attributes of tumor, in that their growth may not be arrested by iodin administration or by the natural physiologic compensation. No accomplishment in preventive medicine has a firmer physio- logic and chemical foundation than that underlying goiter preven- tion, and, as the work of prevention is based on certain of these facts, the more important may be reviewed: 1. The active principle of the thyroid is a very stable organic compound of iodin, first recognized by Baumann, in 1895, and recently (1916) isolated in crystalline form, by Kendall. 2. The developmental stage of all goiters is characterized by an increased blood flow, an increase in the size and number of epithelial cells, a decrease in the stainable colloid, and a marked absolute decrease in the iodin store. The decrease in the iodin store precedes the cellular hypertrophy and hyperplasia. 3. Similar changes (compensatory hyperplasia) invariably occur in the remaining portion of the gland, when a sufficient portion of the entire gland is removed. The amount of gland it is necessary to remove in order to cause compensatory hyperplasia varies some- what with the species of animal, definitely, with the age, diet, and the presence or absence of iodin. 4. The administration of exceedingly small amounts of any salt of iodin in any manner completely protects the remaining thyroid against compensatory hyperplasia, even after the removal of three fourths of the normal gland in cats, dogs, rabbits, rats and fowls. Halsted and Hunnicutt reported a series of partial removals in dogs in which they failed to obtain compensatory hyperplasia, while Loeb has recently reported a series of partial removals in guinea-pigs in which iodin failed to prevent the compensatory hyper- EXPERIMENTAL PHYSIOLOGY 98 THE PREVENTION OF SIMPLE GOITRE plasia, although desiccated thyroid still protected. He concluded that regeneration was physiologically different from spontaneous hyperplasia or simple goiter. The explanation for Halsted's results was probably that the animals were in contact with a source of iodin, while the most probable explanation for Loeb's results is that he removed too much thyroid, since, as shown by Marine and Lenhart, in 1909, iodin will not protect even in dogs if more than three fourths of the gland is removed, while desiccated, thyroid will protect the animal against thyroid regeneration even after the removal of as much as nine tenths. 5. If most of the thyroid gland is removed before or in the early stages of pregnancy, and rigid precautions are taken to exclude iodin, the young at birth will have enlarged thyroids, as first shown by Halsted in dogs; while, if iodin is available, the young at birth will have normal thyroids. 6. A milligram of iodin, given at weekly intervals, has been found sufficient to prevent thyroid hyperplasia in pups. 7. Thyroid tissue has an extraordinary affinity for iodin, as has been demonstrated in in vitro perfusions of surviving thyroids, and also by injecting intravenously small amounts of some soluble salt of iodin into the intact animal. 8. If the iodin store in the thyroid is maintained above 0.1 per cent., no hyperplastic changes, and therefore no goiter, can develop. The foregoing experimental data seem to us sufficiently com- plete to demonstrate the underlying principles of goiter prevention, and the ease with which they may be applied. The first instance in which these facts were utilized in the prevention of goiter on a large scale occurred in 1909 and 1910. Working with endemic goiter in brook trout, Marine and Lenhart were able to demonstrate that iodin added to the water in a concentration not exceeding 1 : 1,000,000 arrested or prevented the development of thyroid hyperplasia (goiter). Since, then, the method has been successfully applied on a large scale by several observers in the prevention of goiter in cattle, sheep, pigs and poultry. To our knowledge, the prevention of human goiter was not attempted on any large or practical scale until 1917, when we began work with the school population of the city of Akron, although in Cleveland it had been strongly urged and had been used by some WESTERN RESERVE UNIVERSITY 99 physicians for several years. Briefly, the method as applied to man consisted in the administration of 2 gm. of sodium iodid in 0.2 gm. doses, distributed over a period of two weeks, and repeated each autumn and spring. This amount of iodin is excessive, and far beyond the needs of the individual or of the ability of the thyroid to utilize and store it. One gram distributed over a longer period would be better. The form or mode of administration of iodin is of little consequence. The important thing is that iodin for thyroid effects should be given in exceedingly small amounts, and it is believed that most of the untoward effects recorded are due to the excessive doses employed, or, more concretely, to the abuse of iodin. The results of our two and one-half years' observations on schoolgirls in Akron are as follows: Of 2,190 pupils taking 2 gm. of sodium iodid twice yearly, only five have developed enlargement of the thyroid; while of 2,305 pupils not taking the prophylactic, 495 have developed thyroid enlargement. Of 1,182 pupils with thyroid enlargement at the first examination who took the prophy- lactic, 773 thyroids have decreased in size; while of 1,048 pupils with thyroid enlargement at the first examination who did not take the prophylactic, 145 thyroids have decreased in size. These figures demonstrate in a striking manner both the preventive and the curative effects. Klinger has recently (1921) reported even more striking curative results in the schoolchildren of the Zurich district. He worked with school populations in which the incidence of goiter varied from 82 to 95 per cent., while our maximum incidence in Akron was 56 per cent. With such a high natural incidence of goiter, his observations necessarily deal more with the curative effects. Thus of 760 children, 90 per cent, were goitrous at the first examination. After fifteen months' treatment with from 10 to 15 mg. of iodin weekly, only 28.3 per cent, were goitrous, of a total of 643 children reexamined. The foregoing results were obtained in adolescents. There are two other periods in life when simple goiter frequently develops, namely, (1) in fetal life and (2) during pregnancy. While the thyroid enlargements developing around the age of puberty are more common, they are not more important than those developing during pregnancy and fetal life. The higher birth mortality of infants with congenital goiter is well known. The thyroid enlarge- ment of both mother and fetus may be prevented by giving 2 gm. of 100 THE PREVENTION OF SIMPLE GOITRE sodium iodid, or its equivalent in iodin in any other form, during the first half of pregnancy. UNTOWARD EFFECTS The dangers of giving iodin, in the amounts indicated, to children and adolescents are negligible. Exophthalmic goiter and iodism are the two important conditions to be looked for. No case of exophthalmic goiter developed in the series reported by Klinger or by us, although in both instances such cases were carefully looked for. Much has been written of iodin-exophthalmic goiters, but a study of the case reports reveals the fact that they resulted from the use of excessive (according to physiologic standards) amounts of iodin, or of desiccated thyroid. In adults, the possibility of aggravating a mild exophthalmic goiter or even the production of the syndrome in susceptible individuals must be considered. Again, the risk is slight. lodin should not be given in any frank case of exophthalmic goiter unless the patient can be daily observed, and then it should be administered only in milligram doses. Iodism was observed in eleven cases among the schoolchildren of Akron during the two and one-half years of observation. Most of these cases were very mild, and the girls did not stop the treatment. Klinger did not observe a single instance in sixteen months' observation on more than 1,000 children, although iodism was carefully looked for. SUMMARY Simple or endemic goiter in man may be prevented as cheaply and as simply as in the lower animals, by the administration of 3 to 5 mg. of iodin twice weekly, over a period of a month, and repeated twice yearly. Klinger in Switzerland has reported as striking, and nearly as extensive, results as those obtained by us in Akron. In young individuals, with goiter of recent development, the curative effects of exceedingly small amounts of iodin are as marked as one sees in the goiter of animals. There are no dangers worthy of consideration associated with the administration of the quantities of iodin used by Klinger or by us. Simple or endemic goiter most commonly develops during (1) fetal life, (2) around the age of puberty, and (3) during pregnancy, and we believe that any plan which provides for its control during these three periods of life will practically eliminate endemic goiter. Goiter in the mother and fetus can be prevented as simply as that WESTERN RESERVE UNIVERSITY 101 of adolescence, but, practically, it would seem that it is a responsi- bility of individual physicians, supplemented by public education. The prevention of goiter of childhood and adolescence should be a public health measure, best administered through the schools in order to combine the important additional factor of education. Beginning with the period of puberty, goiter occurs approximately six times as frequently in females as in males. The question, there- fore, whether general prophylaxis should include both males and females would depend to some extent on whether the particular district was mildly or severely goitrous; hence the need for accurate surveys. The age of beginning and stopping the use of iodin would depend to some extent on race and climate. In the United States, probably the maximum of prevention coupled with the minimum of effort would be obtained by giving iodin between the ages of 11 and 17 years. The prevention of goiter means vastly more than eliminating cervical deformities. It means, in addition, the prevention of those forms of physical and mental degeneration, such as cretinism, mutism and idiocy, which are dependent on thyroid insufficiency. Further, it would prevent the development of thyroid adenomas, which are an integral and essential part of endemic goiter in man. and due to the same stimulus. These multiple, circumscribed benign growths have many of the attributes of tumor, one of which is that their growth once initiated is frequently not controlled by iodin, as are all simple hyperplasias. The terminal metamorphoses are far more serious than those of simple hyperplasia, since, in addition to hemorrhage, necroses, cyst formation, etc., probably 90 per cent, of the malignant tumors of the thyroid arise from these adenomas. If the prevention of goiter is good preventive medicine, it is better preventive surgery. With so simple, so rational and so cheap a means of prevention at our command^ this human scourge, which has taken its toll in misery, suffering and death throughout all age*, can and should be controlled, if not eliminated. Copyright, 1921 American Medical Association, 535 N. Dearborn St., Chicago WESTERN RESERVE UNIVERSITY 103 [Extract from the American Journal of the Medical Sciences, May, 1922, No. 5, vol. clxiii, p. 634.] THE PREVENTION OF SIMPLE GOITRE IN MAN.1 By O. P. Kimball, M. D. CLEVELAND CLINIC, CLEVELAND, OHIO To understand why anyone should undertake a goiter survey of a whole community for the purpose of establishing a principle of prevention by a simple and practical method, it is necessary to study the literature of goiter with this idea in view. For the literature, while rich in statements regarding the distribution of goiter, the pathology of the thyroid gland, methods of medical and surgical treatment, hereditary tendencies and etiology, has little indeed to offer regarding the prevention of goiter. A survey for merely determining the incidence of goiter in the different localities and cities of this portion of the Great Lakes basin would have been unnecessary. There is an abundance of scientific data giving in general the geographic distribution of endemic goiter throughout the world. Surveys of various communities in Europe have been made and the scientific data of the last century have so emphasized the sociologic and economic importance of endemic goiter, cretinism and deaf-mutism that national commissions have been appointed by some of the countries of Europe to study this problem for the purpose of finding some method of relief. For ten years preceding the beginning of our work in Akron, Marine and Lenhart, working in the department of experimental medicine of the Western Reserve University, had been showing the ease with which endemic goiter could be prevented. The results of laboratory experiments and demonstration in animals, however convincing, must be applied to man for final proof of their prophy- lactic or therapeutic value. The prevention of goiter in man was yet to be proven. Therefore, with Dr. David Marine, I undertook to establish in man the applicability of the work of Marine and Len- hart as summed up in their statement that "simple goiter is the easiest of all known diseases to prevent." Definition and History of Endemic Goiter. The term goiter means hypertrophy of the thyroid gland. The term as used in this paper refers only to what is known as simple or endemic goiter and does not include the so-called exophthalmic goiter. 1 Presented as a thesis for the degree of Master of Arts in Medicine, Western Reserve University, June, 1921. - 104 THE PREVENTION OF SIMPLE GOITRE The incidence of simple goiter is so high and so continuous for generations, in certain districts of the world where all kinds of domestic animals as well as humans are involved, that it has come to be considered as characteristic of or endemic in that district. The study of the history of this disease is like studying the history of the human race. The Arthorva Veda, an ancient Hindu collection of incantations dating from 2000 b. c., contains extensive forms of exorcisms for goiter. Caesar mentions the frequent occurrence of big neck as one of the peculiar characteristics of the Gauls. The origin of the term cretin shows the familiarity of the early Romans with this disease. They originated this expression of contempt by calling the myxedematous idiots Christians. The Swiss physician Paracelsus (1493-1541) was the first to emphasize the relationship between goiter and cretinism, and the earliest positive information concerning the latter disease dates from this author. In 1793 appeared Fodere's essay on "Goiter and Cretinism in the Maurienne and Aosta Valley," and in 1800 his Treatise on Goiter and Cretinism. During the last century there have been numerous publications on endemic goiter and cretinism, one of the most exhaustive of which is by A. Hirsch, in his study of the Historical and Geographical Relations of Goiter. About the middle of the last century the governments of the European countries began to see the economic and sociologic im- portance of this problem. In 1848 the Sardinian government appointed a commission to study the cause of endemic goiter and find some method of relief. In 1864 the French government appointed a similar commission, which reported in 1874 that at least 500,000 people in France were suffering from goiter and that there were over 120,000 cretins and cretinoid idiots. This commission seemed to establish as a scientific fact the popular idea that goiter is a water-borne disease. In 1908 Switzerland created a goiter commission, and since then Italy has created a similar commission to study the cause and prevention of endemic goiter. Distribution. The extent to which goiter prevails throughout the world is seldom appreciated. Few countries are free from endemic districts, and we find the so-called sporadic cases of goiter in every section and among every nationality in the world. But there are localities in which the incidence of goiter is so extremely high that they have been known for ages as endemic goiter districts. The best known of these districts is in southern Europe, or, more WESTERN RESERVE UNIVERSITY 105 specifically, the Alps mountain region, comprising southeastern France, southern Germany, all of Switzerland, northern Italy and southern Austria. In Asia practically all of the Himalaya district is an endemic goiter belt, with a very high incidence in northern India and parts of southern and western China and eastern Mon- golia. In South America goiter is endemic throughout most of the Andes region, with probably the highest incidence of both goiter and cretinism on the Peruvian plateau and in parts of western Brazil. In North America goiter is endemic in the whole of the Great Lakes' basin, in the basin of the St. Lawrence and in the northwest Pacific region. In each of these large endemic regions there are localities in which the incidence of goiter is much higher than in the surrounding territory, and in such districts all of the domestic animals are affected. In some of these smaller districts the incidence of goiter has been determined with sufficient accuracy to be mentioned here. For example, as we have stated above, in 1874 the Goiter Com- mission of France estimated that in that country there were 500,000 goitrous people and 120,000 cretins and cretinoid idiots; statistics furnished by Kocher show that 80 to 90 per cent of the school children of Berne were goitrous; in his recent reports Klinger states that in some of the schools of Zurich, where he is carrying out methods of goiter prevention, 100 per cent of the children are goit- rous. In southern Bavaria, according to the statistics of Schitten- helm and Weichardt, who base their conclusions on examinations of school children, the incidence of goiter is as high as from 77 to 89 per cent of the total population. In Switzerland and in certain provinces of Italy, France and Austria the problem of endemic goiter, cretinism and deaf-mutism has been recognized as of sufficient economic importance to demand investigation by their respective governments. We are told that on the Gobi Desert and the plateau of Thibet the incidence of goiter is very high, and that among the various tribes of southeastern Mongolia a third of the population is goitrous. McCarrison carried out some of his researches and made several surveys in Himalayan India. He states that in some of the villages of this section it is difficult to find a man, woman or child who is not suffering from the deformity. He estimates that not less than 20 per cent of the total population of Gilget, in northern India, suffer 106 THE PREVENTION OF SIMPLE GOITRE from goiter, and that among a population of 70,(XX) he found 200 cretins. The frequency of goiter in North America has been known in a general way for more than a century. In 1800 Barton wrote an excellent monograph on the occurrence of goiter among the Ameri- can Indians living along the shores of Lakes Ontario and Erie. Other goiter centers among the Indians of the Rocky Mountain States have been described by Munson. Adami pointed out the frequency of goiter in the St. Lawrence Valley, and speaks of French Canadian villages in this district in which there was scarcely a family without one or more goitrous members. Osler has empha- sized the frequency of goiter in Ontario. Marine finds the disease widely disseminated all along the Great Lakes, where it occurs not only in humans but also in animals, especially dogs and sheep. In a report to the Commission of Conservation of Canada in 1918, Shepherd states that the incidence of goiter is very high in British Columbia and Alberta, and that in some localities of these large states most of the domestic animals are affected. Incidence of Goiter in the United States. Efforts to determine the incidence of goiter in different sections of the United States have been made but no accurate survey of a whole community had been reported previous to our work in Akron. In 1913 Clark examined 13,836 school children in eleven counties of West Virginia and found 1234 cases of goiter-9 per cent of the number examined. In Virginia the same worker examined 6432 school children and found 817 cases of goiter, or 12 per cent of the number examined. In Huntington 50 per cent of the girl students were found to be affected. In the Virginia survey less than 0.1 per cent of the goiters found were among boys. The report of Hall of 3339 students at the University of Washington is indicative of the incidence of goiter in the North- western States. This writer found enlarged thyroids in 18 per cent of 2086 men whose average age was twenty years and five months, and in 31 per cent of the 1253 women examined whose average age was nineteen years and three months. In Chicago, Olson examined 606 women and 193 men, with ages ranging from eighteen to sixty years. Among the women 18 per cent had well-developed goiters, and 7 per cent of the men were affected. WESTERN RESERVE UNIVERSITY 107 During 1917 and 1918, when so many of our young men were in camp, an opportunity was offered to determine the incidence of goiter among young men and to compare the incidence of goiter in different sections of the country. Thus from Camp Lewis, Wash- ington, Kerr reported the examination of 21,182 recruits, with the finding of 1276 large or well-formed goiters. The percentage of unquestionable goiters compared to the number of recruits from each state was as follows: Washington, 11 per cent. Oregon, 8.6 per cent. Idaho, 7.3 per cent. North Dakota, 6.6 per cent. Utah, 5.5 per cent. Minnesota, 5.1 per cent. Wyoming, 3.7 per cent. South Dakota, 2 per cent. Nevada, 1.1 per cent. Colorado, 0.5 per cent. Brendel and Helm, studying the same problem at Camp McDowell, California, conclude that goiter is endemic in Washing- ton and Oregon. Smith, at Jefferson Barracks, Missouri, reports that in the examination of 65,507 men there were found 1074 cases of simple goiter, or an incidence of 1.63 per cent of the total number examined. These recruits represented fifteen different central and western states. These findings only emphasize in a general way the fact that goiter may be considered as distinctly endemic in certain sections of the United States. The Physiology of the Thyroid. In order to appreciate the principle of goiter prevention one must review briefly the biochem- istry and function of the thyroid gland. Early in the sixteenth century Paracelsus emphasized the re- lation between endemic goiter and cretinism. In 1825 Parry's descriptions of cases of goiter or enlargement of the thyroid gland in connection with enlargement of the heart with palpitation and exophthalmos were published. In 1835 appeared Graves's descrip- tion of the clinical complex of exopthalmic goiter, with enlargement of the thyroid as one of the cardinal symptoms. Basedow's descrip- tion of the same syndrome appeared in 1840. But none of these observers interpreted their findings in terms of the function of the thyroid. The first important observations of the functions of the 108 THE PREVENTION OF SIMPLE GOITRE thyroid were published in 1874 by Sir William Gull. At this time the clinical complex of myxedema (Gull's disease) was described in detail, and this clinical picture was interpreted as in some way associated with a lack of function of the thyroid. Gull's observations and interpretation of the etiology of myx- edema were confirmed in 1880 and 1881 by Kocher and Reverdin, who had observed the results of the total removal of goitrous thyroids. Kocher gave to the clinical syndrome resulting from complete thyroidectomy the name of cachexia strumipriva. Rever- din called it operative myxedema. In 1877 Ord designated the disease as myxedema, because he thought he had recognized a mucoid change in the subcutaneous tissue. Sir Victor Horrsley verified the findings of these observers' by his researches on experi- mental myxedema in monkeys. As a result of these observations, Murray and McKenzie in 1891 gave glycerinated thyroid extract to a myxedematous patient and obtained definite therapeutic results. Magnus-Levy, in 1895, showed that heat production was markedly reduced in cases of myxedema and that thyroid feeding raised it, thus establishing the essential or at least the major function of the thyroid as we know it today. The early Greeks treated goiter by the internal administration of the ash of burned sea-sponges, not knowing that the substance was rich in iodides. lodin was first knowingly used in the treat- ment of goiter by Coindet in 1820. From that time iodin was used very extensively and stood alone in goiter therapy for seventy-five years before the discovery by Baumann, in 1895, that iodin was a normal constituent of the thyroid gland. Our knowledge of the chemistry of the thyroid progressed rapidly after Baumann's dis- covery. In 1901 Oswald showed that the iodin is bound with the globulin and is contained for the most part in the colloid. In 1907 Marine emphasized the fact that iodin is necessary for the normal function of the thyroid, and also that in active hyperplasia of the thyroid the iodin store is reduced. The later experiments of Marine and Lenhart have established the following facts relative to the importance of iodin in the chemistry, function and histologic anatomy of the thyroid: 1. lodin is a constituent of the normal thyroid of all animals with the ductless thyroid. As shown by their experiments on the rapidity of absorption of iodin by the thyroid, its elaboration into the active hormone and by alkaline hydrolysis, as introduced by WESTERN RESERVE UNIVERSITY 109 Kendall, iodin exists in the thyroid in an active and inactive form. That is, the elaboration of the hormone goes on slowly from the inactive iodin collected from the blood. The excess of physiologi- cally active iodin is for the most part stored in the "colloid" or globulin of the alveoli, and it is believed that colloid serves merely as the vehicle or means of storing the excess of this remarkably active substance in a harmless manner. The store of iodin then normally consists of inactive iodin for the most part in the cells and of active iodin for the most part in the colloid or thyroglobulin. 2. This store of iodin shows wide variations in any series of animals. These variations reach their maximum in the so-called goiter districts and their minimum in non-goitrous districts. 3. Further, these variations in iodin store have been shown to have an intimate relation with the histology of the gland. Thus in all species of animals with the ductless thyroid the iodin store is decreased in the hyperplasias. This decrease is proportional to the degree of hyperplasia. In mammals, e. g., dog, sheep, ox, pig, rabbit, cat and man, it has been shown that normal thyroids have the highest percentage of iodin, averaging 0.2 per cent, with extremes of 0.1 and 0.5 per cent, of the dried gland. 4. It has been further shown that as soon as the store of iodin falls below 0.1 per cent active hypertrophic and hyperplastic changes in the thyroid begin. In other words, no functional hyper- plasia and therefore no goiter can develop, at least in the mammals above mentioned, if the iodin store in their thyroids is maintained above 0.1 per cent. 5. This iodin store may be rapidly and markedly increased by the administration of exceedingly small quantities of iodin in any known form and through a great variety of means, as inhalation, enteral and parenteral administration, cutaneous application, etc., and as indicated above, marked histologic changes are at the same time brought about in hyperplastic glands, namely, the arrest of the hypertrophy and the involution or return of the thyroid cells to their resting form. The active iodin compound found in the thyroid, beginning with its discovery by Baumann in 1896, and the successive attempts to isolate it, has been known as iodothyrin, iodo-thyro-globulin (Baumann and Roos), thyroidin (Oswald) and thyroxin (Kendall). In 1915 Kendall succeeded in isolating this iodin-containing hormone 110 THE PREVENTION OF SIMPLE GOITRE in crystalline form and has determined its structural formula. He believes it to be tri-iodo-indol-propionic acid. In 1895 Magnus-Levy indicated that the thyroid, in some way, controlled the rate of oxidation in the tissues. He showed that in myxedema the rate of metabolism was much lowered and that by feeding thyroid the rate could be raised. Also, he was the first to demonstrate that as regards metabolism exophthalmic goiter was the opposite to myxedema. This work has been confirmed from many sources as regards experimental and spontaneous myxedema. And as regards exophthalmic goiter, it has so developed that at present the rate of metabolism is the best available basis for classi- fication. In a recent publication on The Physiology of the Thyroid, Marine states that "The thyroid has to do in some important way with internal respiration or the utilization of oxygen by the tissues. Indeed, this is the only known function of the thyroid." The Prevention of Goiter. Before 1896 Halsted had shown that if a portion of the thyroid is removed or destroyed the remainder undergoes hyperplasia. Marine and Lenhart found that this compensating hyperplasia could be prevented if the remainder of the thyroid was kept saturated with iodin. This was true in dogs as long as at least one-sixth of the gland was left, but if more than five-sixths were removed a compensatory hyperplasia followed even though iodin was given. This important observation pointed directly to iodin as the means for the prevention of thyroid hyper- plasia (goiter). One of the first practical applications of the principle of preven- tion of goiter and myxedema accidentally followed the discovery of salt in Michigan and its more extensive use (as crude salt) in the sheep industry of this state at a time. when the industry was being crippled by endemic goiter. This crude salt was afterward found to be rich in iodin. The first definite application of the use of iodin in the prevention of goiter on a large scale in animals was the prevention of goiter in brook trout. This disease had been the cause of much trouble and expense. The so-called thyroid carci- noma in brook trout had become so serious at many private, state and government hatcheries that the question of abandoning the industry was being discussed. An investigation of the causation and a study of methods of prevention was undertaken by Marine and Lenhart in conjunction with the Pennsylvania State Fish Com- WESTERN RESERVE UNIVERSITY 111 mission during the years 1909, 1910, and 1911. Their conclusions as to the etiologic factors producing goiter and the practical method of its prevention were definite and convincing. The important factors which in this instance caused endemic goiter were (1) overfeeding with an artificial food and (2) overcrowding. These investigators showed that goiter could be prevented in young fish under the same environmental conditions which produced goiter by adding a very small amount of iodin to the food or water, or it could be prevented by changing the diet and remedying the overcrowding. The results of this practical research have been far reaching. In addition to the experimental work above mentioned the treatment of goiter with iodin at the dispensary at Lakeside Hospital had been followed for the past ten years. Also the maternity dis- pensary of Lakeside Hospital had not only been using iodin in the treatment of goiter but had been using it as a prophylactic measure during pregnancy. To most of the men in touch with the goiter clinic at Lakeside or the school of medicine the prevention of goiter was no longer an experiment but an accomplished fact. Therefore at the beginning of our work in Akron the possibility of goiter prevention had been clearly demonstrated by animal experimentation, but only a very limited application of methods of prevention had been made in man. No subject in preventive medi- cine had a sounder or more scientific basis for its practical applica- tion to man on a large scale than the prevention of endemic goiter. Yet there was considerable criticism and opposition which had to be overcome. This criticism centered about the possible untoward effects of iodin, especially the dangers of producing exophthalmic goiter. Etiology and Endemic Goiter. Before anyone can fully com- prehend the fundamental principles underlying the method of prevention which we have used, he must have some conception of the factors causing the disease. There have been many theories as to the cause of goiter, most of which are only of historic value and will not be taken up here. At present there are a few who consider goiter as a primary disease or idiopathic enlargement of the thyroid gland. McCarrison considers it a water-borne infectious disease, the exciting factor of which is a contaguim vivum, and suggests that it belongs to the colon group of bacteria. Shepherd, also, in his 112 THE PREVENTION OF SIMPLE GOITRE report in 1918 on the occurrence of goiter in Canada, concludes that it is a water-borne infectious disease, directly comparable to typhoid. However, most of the scientific investigators of this country look upon goiter as a deficiency disease. Marine has been empha- sizing this point since 1907. As has been pointed out: 1. lodin is essential to the normal thyroid activity. 2. From a purely biochemical standpoint any substitution for iodin destroys the physiologic activity of the thyroid hormone. 3. From the histologic point of view glandular hyperplasia of the thyroid is due to a deficiency of iodin. 4. The physiologic action produced by thyroid extract is always proportional to the iodin content. 5. In animal experimentation if the iodin content is main- tained at or above one tenth of 1 per cent no anatomic changes toward goiter formation can take place. These facts, with our results in preventing goiter in school girls by simply keeping the thyroid saturated with iodin. make the infec- tious theory at once untenable. These facts lead to the conclusion that the immediate or exciting cause of endemic goiter (hypertrophy of the thyroid gland) is a lack of iodin in the organism. This lack of iodin may be relative or absolute. The remote or fundamental cause of goiter is quite unknown. Practical Application of the Principle of Goiter Prevention. In the practical application of the principle of prevention we chose the public schools for two reasons: (a) The children are in the adolescent age, the most important period in the development of goiter; (b) the public school group furnishes the best census of goiter in any community and makes it possible to carry out, through the school organization, the most expedient, economic and practical plan of prophylaxis and education. In October, 1916, we explained the principle of the prevention of goiter to the superintendent of schools of Akron, Dr. H. V. Hotchkiss. He promised the full support of all the school auth- orities if the local medical society would sanction the work. After this idea had been explained to the Summit County Medical Associa- tion this body, in a regular session, voted to send the following message to the school board: "The idea of prevention of goiter as outlined can do no harm and may do good. We are in favor of seeing it carried out." The school board authorized the super- WESTERN RESERVE UNIVERSITY 113 intendent to call upon Dr. Marine and myself to make a survey of goiter among the school children of Akron and carry out any plan of prevention we saw fit. In April, 1917, an examination for thyroid enlargement was made of all the girls from the fifth to the twelfth grades inclusive. The boys were not examined because of the* relative infrequency of goiter in boys. The result of each examination was recorded on a special individual card, which on one side had a space for the pupil's name, school, age, grade and the tabulations of four thyroid exami- nations. On the back of this card was space for the record of eight series of prophylactic treatments, which were recorded by the teacher giving the treatment. This goiter card was attached to the school record of each pupil and was transferred with the pupil when- ever transfer to another school was made. In no other way could we have kept track of so many cases over so long a time. The details' regarding this examination and the plan for carry- ing out the treatment were then published. Only the resultant figures will be given here. 3872 girls were examined, with the following results: Normal thyroids, 1688, or 43.6 per cent. Slightly enlarged thyroids, 1931, or 49.9 per cent. Moderately enlarged thyroids. 246, or 6.3 per cent. Markedly enlarged thyroids, 7, or 0.2 per cent. Among these there were 39 adenomas, or 1 per cent. In April, 1917, the first prophylactic treatment was administered to more than 1000 girls who had elected to take it. No girl was urged and no one was permitted to take it unless she had a written permit from a parent. In November, 1917, a second examination of all girls from the fifth to twelfth grades inclusive was made, in all 4415 cases, 1772 of which were new records. Of the 2643 old records 764 had taken the prophylaxis during the preceding six months and 1879 had not. As was published then there was not a single case in which a normal thyroid increased if the pupil was taking iodin, while among those not taking iodin 26 per cent, of those marked normal at the first examination showed definite enlargement-some already having developed moderately large goiters. Even more than a prophy- lactic action was shown by the results-just one-third of the "small goiters" had disappeared and one-third of the "moderate goiters" had decreased 2 cm. or more. 114 THE PREVENTION OF SIMPLE GOITRE In November, 1918, a third examination of 4277 girls was made. In October, 1919, 5520 individual examinations were recorded, and during the entire period 9967 different girls were reported. Effect of Prophylactic Treatment. The prophylactic treatment as carried out for the past three years in the Akron schools consists of the administration of 2 gm. of sodium iodide, given in 0.2 gm. doses daily for ten consecutive school days, repeated each spring and autumn. The general data of the pupils not taking the treat- ment are given in Table I, and of those taking the treatment in Table II. Only pupils who have had two or more consecutive examinations have been included in these tabulations. A consider- able number of pupils, both of those who have been taking the treatment and of those who have not been taking the treatment have been omitted because they missed one examination, although otherwise their records were complete; 2305 pupils are included in the tabulation of those not taking treatment and 2190 in the tabula- tion of those taking treatment. Furthermore, properly to interpret the results, it was necessary to take into consideration the length of time each pupil had been under observation. As the prophylactic treatment was given at intervals of six months we have used this interval as the unit and grouped the pupils according to the periods each had been under observation, i. e., six, twelve, eighteen, twenty-four or thirty months. The results of only three groups, those with normal, slightly enlarged and moderately enlarged thyroids, are included because the fourth group, those with markedly enlarged thyroids, is too small. A comparison of the two tables brings out striking differences between those not taking and those taking iodin. These differences are manifested both in prevention of enlargement-prophylactic effect- and in a decrease in the size of existing enlargements-therapeutic effect. Prevention. The preventive value of the treatment is shown in the column marked "unchanged" and "increased." Taking the totals for the periods of six months each the following results were obtained. Of those that were normal at the first examination and did not take iodin, 347, or 27.6 per cent, had enlarged thyroids, while of those that were normal at the first examination and took iodin as outlined, 2, or 0.2 per cent, had enlarged thyroids. These two instances of enlargement were investigated. The first pupil, aged sixteen years, had her thyroid examined WESTERN RESERVE UNIVERSITY 115 TABLE I.-RECORD OF PUPILS NOT TAKING PROPHYLACTIC TREATMENT. Time under obser- vation, mos. Normal. Slightly enlarged. Moderately enlarged. Unaltered. Increased. Unaltered. Increased. Decreased. Unaltered. Increased. Decreased. No. Fer cent. No. Per cent. No. Per cent. No. Per cent. No. Per cent. No. Per cent. 'No. Per cent. No. Per cent. 6 ,47 50.0 47 50.0 93 69.4 36 26.9 5 3.7 16 69.6 7 30.4 12 420 75.5 136 24.5 251 70.3 35 9.8 71 19.9 17 65.4 8 30.8 1 3.8 18 103 65.2 55 34.8 108 74.5 18 12.3 19 13.1 11 57.9 3 15.8 5 26.3 24 135 76.7 41 23.3 106 79.7 8 6.0 19 14.3 9 60.0 3 20.0 3 20.0 30 205 75.1 68 24.9 140 73.7 30 15.8 20 10.5 4 66.7 0 2 33.3 TABLE II.-RECORD OF PUPILS TAKING PROPHYLACTIC TREATMENT. Time under obser- vation, mos. Normal. Slightly enlarged. Moderately enlarged. Unaltered. Increased. Unaltered. Increased. Decreased. Unaltered. Increased. Decreased. No. Per cent. No. Per cent. No. Per cent. No. Per cent. No. Per cent. No. Per cent. No. Per cent. No. Per cent. 6 17 94.4 1 5.6 54 69.2 1 1.3 23 29.5 9 81.8 2 18.2 12 344 99.7 1 0.3 187 45.5 224 54.5 10 23.8 32 76.2 18 73 100.0 72 52.3 1 6.7 64 46.7 7 28.0 18 72.0 24 30 184 288 100.0 100.0 72 92 37.9 28.5 1 0.5 117 231 61.6 71.5 2 1 7.7 2.6 24 38 92.3 97.4 TABLE III.-SUMMARY OF RECORDS OF NOT TAKING PROPHYLACTIC 1 F PUPILS TAKING AND TREATMENT. Taking. Not taking. Totals . Per cent. Totals. Per cent. Normal: Unchanged .... . 906 99.8 91Q 72.4 Increased 2 0.2 347 27.6 Slightly enlarged: Unchanged .... . 477 41.9 698 72.8 Increased 3 0.3 127 13.3 Decreased . 659 57.8 134 13.9 Moderately enlarged: Unchanged .... . 29 20.3 57 64.0 Increased 21 23.6 Decreased . 114 79.7 11 12.4 Total . 2190 - 2305 - and classified as normal on May 2, 1917, October 17, 1918, and December 3, 1918. At the examination on October 15, 1919, it was classified as slightly enlarged. This girl had taken 2 gm. of sodium iodide during each of the five possible periods, May, 1917, Novem- ber, 1917, May, 1918. December, 1918, and May, 1919. A special examination was made on January 13, 1920, when the enlargement of the thyroid was verified. That this enlargement was acquired rather than congenital was shown by the absence of a pyramidal 116 THE PREVENTION OF SIMPLE GOITRE process of the thyroglossal tract. The tonsils were markedly en- larged and abnormally hyperemic. On direct questioning we were informed that the pupil was subject to recurrent attacks of tonsillitus. There was also slight enlargement of the lymphoid tissue at the base of the tongue and in the nasopharynx, and the general impression was that of a neurotic individual with general lymphoid hyperplasia. The second girl, aged fifteen years, had her thyroid first ex- amined and classified as normal on November 27, 1918. At the examination on October 16, 1919, it was classified as slightly en- larged. This girl had taken 2 gm. sodium iodide during each of the two available periods, November, 1918, and May, 1919. A special examination was made January 13, 1920, when the thyroid enlarge- ment was verified. Careful inspection revealed the presence of Hutchinson teeth, depressed nasal arch and interstitial keratitis. We considered the case as one of neglected congenital syphilis. Of the cases classed as having slightly enlarged thyroids at the first examination and not taking the prescribed iodin, 127 or 13.3 per cent, underwent further enlargement, while among those taking the prescribed treatment only 3, or 0.3 per cent, underwent further enlargement. Two of these 3 were reexamined on January 13, 1920, and the previous finding verified. One of these was another case of chronic infection of the tonsils with recurrent attacks of ton- sillitis during the last year. In the second girl superficial inspec- tion failed to show any pathologic condition to account for the enlargement. The third girl was not present for examination. These 5 cases were the only instances that showed enlargement of the thyroid out of 2190 pupils. Of the 2305 cases not taking iodin, 495 showed thyroid enlargement. Of the group with small goiters taking iodin 659, or 57.8 per cent, returned to normal, while of the same group not taking iodin at school, 134, or 13.9 per cent, returned to normal. However, we know that there is an error in the last figure, for many cases not taking iodin under the school jurisdiction were taking it in some form from their physician. No attempt has been made to detect or estimate this error. In the practical application of the preventive treatment one must keep in mind the three periods when simple thyroid enlargements most commonly occur, namely (a) fetal period; (&) adolescence; (c) pregnancy. (a) The prevention of goiter in the mother and the fetus is as simple as the prevention of goiter which develops during adoles- WESTERN RESERVE UNIVERSITY 117 cence. Practically it would seem that the prevention of goiter during these periods, i. e., (fl) and (c) is properly the responsibility of in- dividual members of the medical profession supplemented by educa- tion of the public. (&) The prevention of goiter in the adolescence period, on the other hand, should be a public health measure under state, county or municipal control. The existing systems of organization of the schools, both public and private, are sufficient to handle all the details without additional aid or expense. Education of the pupils could be combined with the actual adminstration of iodin, so that after leaving school they could continue the treatment if necessary. In industrial medicine physicians could render an important service in this direction. As thyroid enlargement is approximately two and a half or three times as frequent in girls as in boys,* each community must decide whether it will include both sexes in prophylactic measures, as it must also decide regarding the ages when the use of iodin should begin and end. In this climate probably the maximum of prevention, coupled with the minimum of effort, would be ob- tained by the administration of iodin between the ages of eleven and seventeen years. As applied to our schools this would mean be- ginning with the fifth grade. Method and Form of Administration. As has been shown, iodin is taken up by the thyroid gland when given by mouth, by inhala- tion or by external application. And it makes very little differ- ence from a scientific point of view what form of iodin is used; the thyroid gland will take up iodin from the most stable compound, i. e., mercuric iodide. Weith reports favorable therapeutic results from the inhalation of iodin secured by the suspension in the school room of a wide-mouthed bottle containing 10 per cent tincture of iodin. It has been suggested by Sloan that in these mildly goitrous districts a mixture of small amounts of sodium iodide in common table salt could be made which would suffice for all iodin therapy. However, we feel that the most satisfactory method is the individual oral administration of definite small amounts of some salt of iodin, either in solution or tablet form. For private use the well-known U. S. P. preparations, syrup of ferrous iodide and syrup of hydrio- dic acid, are excellent. As described above, as a public health * Our earlier statistics indicated that goitre was about six times as frequent in girls as in boys. Further observations have shown that the difference in frequency is not as great as this. 118 THE PREVENTION OF SIMPLE GOITRE measure, we use 2 gm. of sodium iodide over a period of two weeks and repeated twice yearly. This dosage has prevented enlargement of the thyroid in more than 99 per cent of the children in this mildly goitrous district. When one recalls the small amount of iodin required to satur- ate the normal thyroid and the specific affinity of this gland for iodin it is perfectly obvious that only very small amounts are needed. The normal thyroid contains about 5 mgm. of iodin per gram of dried gland; 25 to 30 mgm. is the total storage capacity. From this it is clear that a few milligrams of iodin daily over a longer period (a month or more) would produce optimum thyroid effects. The prevention of thyroid enlargement in individuals with other diseases or in those residing in extremely goitrous districts as in some glacial valleys of Alaska and British Columbia, and in certain districts of the Alps and Himalayas, might require larger amounts of iodin than in normal individuals indicated above. Possible III Effects. As was stated above there was some anxiety among medical men as to the possible ill effects of giving iodin promiscuously. Some men anticipated many cases of exoph- thalmic goiter while others looked for an outbreak of iodide rash. The actual results were better than we had hoped for. In all the cases taking the prescribed 2 gm. of sodium iodide twice yearly there was not a single instance of exophthalmic goiter nor any evidence of a nervous irritability simulating it. In all there were 11 cases of iodide rash, and 6 of these cases were so mild that the girls did not even stop the treatment; 5 cases, however, caused sufficient difficulty for the treatment to be stopped, when the rash cleared up promptly. Both of these possibilities were considered and mentioned in each school. In all there were over 3000 different girls taking the prophylactic treatment, many of whom took it for three years, and among these the total sum of the ill effects was a mild rash in less than 0.4 of 1 per cent. The Possibility of the Elimination of Endemic Goiter through- out the World. Following the publication of the results of our first year's work in Akron the public schools of Kent and Ravenna adopted the same procedure, and in 1919 the Village of Berea began the prevention of goiter through the schools on the same plan. In the spring of 1920 we completed a survey of goiter among the school children of Warren, Ohio, including all boys and girls from the fifth to the twelfth grades inclusive. As the incidence of thyroid enlarge- WESTERN RESERVE UNIVERSITY 119 ment was low-24.4 per cent in girls and 9.5 per cent in boys-we advised the school physician and nurse that we considered it suffi- cient in this vicinity to provide each school with a stock solution of sodium iodide and treat each goiter as soon as it was detected. This method has been in operation in Warren for one year, and is just now being started in Niles. This same method of treatment is being practised in some of the large factories of Cleveland where many young women are employed, and it is being provided in the different factories of the National Lamp Works in eight different cities of the United States. It is interesting to note that in the spring of 1918 Prof. R. Klinger, of Zurich, Switzerland, undertook to carry out the same treatment in the schools there. This was soon started with a different method of administration, but practically the same amounts of iodin as we used in Akron. Tn January, 1921, Klinger published the results of the first sixteen months' treatment, reporting extra- ordinary results, even though he was working in some schools in which the children were 100 per cent goitrous. Klinger's results certainly supply striking confirmation of the results we obtained in Akron. It is even more gratifying to know that recently this same plan of the prevention of goiter has been recommended to the goiter commission of Switzerland, to be carried out as a public health measure throughout the whole state, the most noted endemic goiter nation in the world. The same imagination which developed the practical application of the principle of the prevention of goiter can now see, a few generations hence, the closing of the chapters on endemic goiter and cretinism in every civilized nation in the world. 120 THE PREVENTION OF SIMPLE GOITRE BIBLIOGRAPHY Adami, J. G.: The Etiology and Symptomatology of Goiter, Montreal Med. Jour., 1900, 29, 1-17. Ashmead, A. S.: Note on the Etiology and Natural Cure of Goiter. New York Med. Jour., 1895, Part 1, p. 1344. Barton, B. S.: A Memoir Concerning the Disease of Goiter as it Prevails in Different Parts of North America, 1900. Brendel, E. P., and Helm, H. M.: Goiter among Drafted Men from the Northwest. Arch. Int. Med., 1919, 23, 61. Clark, T., and Pierce, C. C.: Endemic Goiter: Its Possible Relation to Water Supply. Public Health Reports, 1914, 29, 939. Crotti, A.: Thyroid and Thymus, 1918. Dock, G.: Goiter in Michigan. Tr. Assn. Am. Phys., 1895, 10, 101. Gull W.: A Cretinoid State Supervening in Adult Life in Woman. Tr. London Clin. So'c. 1874, 7, 180. Hall, D. C.: The Prevalence of Goiter in the Northwest, Based on the Examination of 3339 Students Entering the University of Washington. Northwest Med., 1914, n.s., 6, 189. Halsted, William S.: Johns Hopkins Hosp. Reps., 1896, p. 373. Hirsch, A.: Handbook of Geographical and Historical Pathology, 1885, 2, 121. Holder, A. B.: Goiter: A New Habitat. New Orleans Med. and Surg. Jour., 1912, 5 254. Horsely, Sir Victor: Prec. Royal Society of London, 1886, 40, 6; 1884-85 , 38, 5. British Med. Jour., 1892, 1, 215, 265 and 1113. Hunziker, H.: Goiter in Switzerland. Corresp.-Blatt f. Schweitzer Aerzte, 1918, 48, 247. Kendall, E. C.: The Active Constituent of the Thyroid: Its Isolation, Chemical Nature and Physiologic Action. Collected Papers of the Mayo Clinic, 1916, 513. The Thyroid Hormone and its Relation to Other Ductless Glands. Endocrinology, 1918, 2, 81. Thyroid Hormone and its Relation to Other Ductless Glands. Endocrinology, 1918, 2, 81. 39, 125. The Physiologic Action of Thyroxin. Endocrinology, 1919, 3, 156. Kerr, William J.: A Preliminary Survey of the Thyroid Gland among 2182 Recruits at Camp Lewis, Washington. Arch. Int. Med., 1919, 24, 347. Klinger, R.: Prevention of Goiter in School Children in Zurich, Switzerland. Schweiz, med. Wchnschr., 1921, 51, 12. McCarrison: Etiology of Endemic Goiter, London, 1911. Marine, D.: The Occurrence and Physiological Nature of Glandular Hyperplasia of the Thyroid, etc. Bull. Johns Hopkins Hosp., 1907, 18, 359. Further Observations on Goiter: Its Prevention and Cure, Jour. Exp. Med., 1914, 19, 70. Quantitative Studies on the In Vivo Absorption of lodm by Dogs Thyroid Glands. Jour. Biol. Chm., 1915, 22, 547. Physiology of the Thyroid Gland. Ohio State Med. Jour., 1920, 16, 735. Marine, D., and Kimball, O. P.: The Prevention of Simple Goiter in Man. Jour. Lab. and Clin. Med., 1917, 3, 40; Arch Int. Med., 1918, 22, 41; Jour. Am. Med. Assn., 1919, 73, 1873; Arch. Int. Med., 1920, 25, 661. Marine, D., and Lenhart, C. H.: Colloid Glands (Goiter): Their Etiology "and Physiological Significance. Bull. Johns Hopkins Hosp., 1909, 20, 131. Further Observa- tions on the Relation of lodin to the Structure of the Thvroid Gland in the Sheep, the Dog, the Hog and the Ox. Arch. Int. Med., 1909, 3, 66. Effects of the Administration or the Withholding cf lodin-containing Compounds in Normal. Colloid or Active Hyperplastic Thyroids of Dogs. Arch. Int. Med., 1909, 4,: 253. The So-called Thyroid Carcinoma in Brook Trout, Jour. Exp. Med., 1910, 12, 311. Further Observations on the So-called Thyroid Carcinoma of the Brook Trout and its Relation to Endemic Goiter, Jour. Exp. Med., 1911, 13, 455. Marine. D., and Williams, W. W.: Relations of lodin to the Structure of the Thyroid Gland. Arch. Int. Med., 1908, 1, 345. Munson, E. L.: The Occurrence of Goiter among the Indians of the United States. New York Med. Jour., 1895, 42, 513. Plummer, H. S.: The Function of the Thyroid, Normal and Abnormal. Collected Papers of the Mayo Clinic, 1916, p. 528. Reclus: Universal Geography, 2, 68; 3, 111; 5, 130. Schittenhelm, A., and Weichardt, W.: Der endemische Kropf mit besonderer Beriick- sichtigung des Vorkommens in Konigreich Bayern. J. Sprenger, Berlin, 1912. Shepherd, F. J.: Enlargement of the Thyroid Gland or Goiter. Report of the Com- mission of Conservation of Canada, December, 1918. Sloan, H. G.: Use of Iodized Table Salt to Prevent Goiter. Ohio State Med. Tour 1921, 17, 172. ' Smith, F. M.: Statistical Study of Simple and Toxic Goiter at the Jefferson Barracks. Jour. Am. Med. Assn., 1919, 72, 471. Springle, J. A.: Goiter: Its Etiology and Incidence in the District of Montreal. Montreal Med. Jour., 1899, 28, 909. Weith: Goiter and lodin in the School. Corresp. Bl. f. Schweiz. Aerzte, 1919 49, 1474. Zueblin: Experimental Pathology of Goiter. New York Med. Jour., 1916, 104, 1186. WESTERN RESERVE UNIVERSITY 121 PROGRESS OF THE WORK TO DATE ON THE PREVENTION OF SIMPLE GOITER. O. P. Kimball In 1917 we sent our first publication to Dr. Klinger, Zurich, Switzerland, with the hope that this method of goiter prevention would be tried there; and early in 1918 work was begun in the schools of Zurich. It was found that in some of these schools 100 per cent of the children were goitrous; and because of the high incidence of goiter in that region in both sexes throughout all ages the prophylactic treatment was given to both boys and girls through all the grades. Our suggestion was accepted-that a few milli- grams of iodin given weekly throughout the year would produce optimum effects. Instead of sodium iodide which we were using, the Zurich authorities employed an organic iodide which is non- hygroscopic, practically tasteless and very stable-a vegetable fatty acid compound which is combined with chocolate and made into tablets, each containing 5 milligrams of iodin. This preparation is pleasant to take and keeps indefinitely. This method has been employed in all the schools of the cantons of St. Gallen, Berne, and Zurich for more than three years, with even more striking results than those obtained by us in this country. A recent report of the Health Commission of the Canton of St. Gallen gives the following statistics: Incidence of goiter among all the school children of the Canton of St. Gallen-January, 1919, 87.6 per cent; January, 1922, 13.1 per cent. On account of the extraordinary results obtained in these three cantons during the past three years, the Goiter Commission of Switzerland last spring recommended that this method of goiter prevention be instituted as a public health measure throughout the entire state, which is the most noted endemic goiter district in the world. During these years the work has been extending in this country. Following the work in Akron the schools in the adjoining counties at Kent and Ravenna adopted the same method of prevention in 1919. The village of Berea, Ohio, also has been administering iodin for the prevention and treatment of goiter through the schools. The same method was used in the schools of Warren, but here iodin was given only to pupils in whom a goiter had started to develop. This 122 THE PREVENTION OF SIMPLE GOITRE method of treatment is being practiced also in some of the large factories in Cleveland in which many girls are employed. In the Cleveland district the school physicians, the Board of Health and the Academy of Medicine have been endeavoring to popularize the idea of goiter prevention. The method used in the schools here is fundamentally the same as that employed in Akron. For the past two years tablets of sodium iodide (sodium iodide gr. 1 with sugar of milk), have been used, but these have not proved very successful. Very few were actually used in East Cleveland, Cleveland Heights and Shaker Heights, and only ten thousand tablets were used last year in all of the Cleveland schools. After studying this particular phase of work in these districts from the viewpoint of the girls, their parents and teachers, and from our own experiences in the work at Akron we find the greatest difficulty is the disagreeable taste of sodium iodide. The psychology of girls of this age is such that a few en- thusiastic objectors can demoralize the entire work in a large school. This year the schools in East Cleveland, Shaker Heights, War- ren, Niles and Findlay, Ohio; Grand Rapids, Mich.; and Ham- mond, Indiana, are using chocolate tablets, each containing 10 milli- grams of iodin in the form of an organic iodide. (The same prepara- tion as used in Switzerland). Each girl takes one tablet a week throughout the year, and we can safely say that for these girls goiter prevention will be one of the most pleasant and efficient parts of their school work. The possibility of harm from the dosage of iodin which we have been using is absolutely negligible. We saw a mild rash in but one per thousand of the cases treated in Akron; and in all the work which has been done in Switzerland not a single case has been seen, although they have been looking for it. Neither in this country nor in Switzerland has a single case of exophthalmic goiter been produced. The prevention of endemic goiter at present is being studied with the hope of its being carried out as a state health problem in several states, especially Michigan, Indiana and West Virginia. In these endemic goiter districts, if every woman would keep her thyroid saturated with iodin during every pregnancy, she would not develop goiter, nor would there be any tendency toward goiter SUMMARY WESTERN RESERVE UNIVERSITY 123 formation in the thyroid of her child. This would save two of the goiter periods in the life of any individual. Then if every girl would keep her thyroid saturated with iodin during adolescence, that is, from the age of 11 to 16 inclusive, none would develop goiter. As to the prevention of goiter in boys, the following facts are pertinent: (1) Goiter is at least two to three times more frequent in girls than in boys. (2) A large majority of goiters in boys are con- genital and could be prevented by the administration of iodin to the mother during pregnancy. (3) While some boys do develop goiter at puberty, or after illness or as the result of some chronic infection, in most cases the goiter will disappear if it is treated promptly and properly. We, feel therefore, that the maximum good from a minimum of effort would be gained by applying the principle of goiter preven- tion to girls as a public health measure. This can best be done through our public school organizations, and education on this subject will insure application of this method of goiter prevention in later life. The prevention of goiter during pregnancy necessarily depends on the medical profession and on the education of the people as a whole. Each family physician and obstetrician should make this an important part of the routine care of every patient; and the diffusion of this knowledge must be such that each expect- ant mother will anticipate such care.