61 Goiter

Quis tumidum guttur miratur in Alpibus?

Juvenal, Satire 13, c. A.D. 127

Goiter is an ancient disease that has always been more common in some places than in others. Chi­nese writings show that goiter was known at least by the third century B.C.

Terminology

The word “goiter” (or goitre in Europe) derives from the Latin gutter, but the meaning has shifted from “throat” or “neck” to mean specifically an enlarged thyroid gland. An ancient Greek synonym was bronchocele, a term actually used to describe any enlargement in the neck, although it meant literally a swelling or an outpouching of the trachea. Over time this term also came to mean an enlarged thy­roid (e.g., the English “bronchocele” of the eigh­teenth and nineteenth centuries). Modern synonyms are the Spanish bocio (from Latin, botium), the Ital­ian gozzo, and the German Kropf. The ancient Latin word struma was probably originally used to de­scribe inflamed lymph nodes in the neck, most likely tuberculous, but was later used to denote the normal thyroid gland, and is still so used although it is almost obsolete.

Confusion over names is understandable, as the thyroid gland itself was unknown until the six­teenth century. Leonardo da Vinci may have drawn the thyroid about the year 1500, but the drawing was not published until much later. Andreas Vesa­lius did note “laryngeal glands” in 1543, but not in humans. Nevertheless, by the end of the sixteenth century, Vesalius’s contemporaries and successors had clearly identified the human thyroid gland as a discrete structure: Bartolomeo Eustachi in 1552, Realdo Colombo in 1558, and Giulio Casserio in 1600.

Classification and Diagnosis

Although shown on an occasional autopsy or dissec­tion, the connection between goiter and the thyroid gland was not clear as a concept. Other diseases of the neck confounded the connection in a living pa­tient. The main confounder was scrofula, which in medieval Latin meant “swelling of the glands” and today is still used to connote tuberculous lymph glands (or nodes) in the neck.

Because obvious and severe goiter affecting large portions of a population occurred only in certain regions, the disease in these areas was called en­demic. In these instances the connection to the thy­roid gland was fairly clear. But where only a few individuals in a population had a mass in the neck, it might be called sporadic goiter — because not endemic - or something else. If the mass was not too large, it might move with swallowing and so was called an enlarged thyroid. But if the mass were nodular, firm, and immovable, then it was consid­ered to be probably characterized by tuberculous nodes. This diagnostic confusion persisted until the mid-nineteenth century. Jean Louis Alibert, for ex­ample, classified endemic goiter as a type of scrofula (“endemic scrofula”) found in rural areas (Alibert 1835). Today endemic goiter is arbitrarily defined; it is present, according to some, if more than 10 per­cent of a population is goitrous.

Besides the occasional large and disfiguring goi­ters that were cosmetically distressing and some­times blocked breathing, endemic goiter areas also produced a much smaller number of people who were retarded from birth, both mentally and physically, whose faces were disfigured, and who were some­times deaf and mute. Most but not all had goiter, which was also common in their mothers. They were called cretins, and their disease, endemic cretinism.

Cretinism is probably as ancient a disease as goiter, but descriptions are not as old. Travelers’ observations, again in the Alps, go back to the early thirteenth century, but clinical allusions begin with Paracelsus (Theophrastus Bombastus von Hohen­heim), lecturing about 1527, who connected cre­tinism (or at least "fools”) with goiter. Good descrip­tions begin with Felix Platter, who probably ob­served it in 1562 and who also made the association of cretinism with goiter (Cranefield 1962).

Thus, by the seventeenth century, the concept of goiter as an abnormally enlarged thyroid gland was reasonably well established as was its association with cretinism and with the mountainous alpine ar­eas of Europe. Yet, cretinism in particular was rare outside densely goitrous sites in the Alps, and thus most European physicians never saw it. Just as goiter could be confounded with other neck diseases, so could cretinism with any sort of mental retardation. Thus a certain amount of diagnostic “fuzziness” per­sisted into the nineteenth and twentieth centuries.

Today goiter means only an enlarged thyroid, and any large thyroid is a goiter. The goiter may be Imiformly and diffusely enlarged (“simple” or diffuse goiter), have several lumps in it (multinodular goi­ter), or be only a single nodule, although on closer study many of the latter prove to be multinodular. The standard screening method of the World Health Organization in endemic areas is to assign grada­tions to the disorder. Grade O is no goiter, grade 1 is a goiter that is palpable but not visible, grade 2 is an easily visible goiter, and grade 3 is a very large goiter visible 30 meters away (Stanbury and Hetzel, eds. 1980).

Some goiters are malignant (e.g., thyroid cancer or lymphoma), but the vast majority are benign.

Cretinism is called endemic if it is found in an area of endemic goiter, but is called sporadic if not found in an endemic area; the latter is almost al­ways nongoitrous. Again, entirely different causes underlie the two types. Both goiter and cretinism, whether endemic or sporadic, can be associated with hypothyroidism, although the notion that cretinism is synonymous with childhood hypothyroidism is false. Hypothyroidism is common but not universal in cretinism, and it occurs only occasionally with goiter.

Early Treatment

Goiter of itself is not particularly harmful unless it grows to compress the trachea or causes emotional upset. But when therapy for a large goiter was re­quired, the only solution until the twentieth century was to remove it, or at least part of it, surgically. The problem was that surgery commonly killed the pa­tient, and some surgeons said that such an operation should simply not be done. Others persisted, and by the 1880s were able to remove all or most of a goitrous thyroid with death rates under 1 percent.

E. Theodor Kocher in Berne and the cousins Jacques-Louis and Auguste Reverdin in Geneva were pioneers in this surgery. In 1882-3, however, these Swiss surgeons realized that removing the en­tire thyroid caused symptoms resembling cretinism, but that this did not happen when only part of the thyroid was taken out. Simultaneously in London, Felix Semon proposed that cretins, patients after total thyroid removal, and adults with a mysterious disorder called myxedema (described by William Withey Gull in 1873) all suffered because they lacked thyroid glands.

Etiology

Early Theories

Many theories were generated over the centuries to explain goiter. An ancient idea was that goiter is due to an excess of phlegm descending from the head to the throat. An excessive flexing of the head was seen as the cause by many, including Michelangelo (Mi- Chelagniolo Buonarroti), who suggested it in 1509. Geographic peculiarities were frequently blamed as well, such as high altitude or narrow valleys, as were climatic features such as high humidity, too much sun, and polluted air, proposed by physicians such as Horatio-Benedict de Saussure in 1779 and F. E. Fodere in 1789. Differences in drinking water were also viewed with suspicion, especially cold wa­ter, water made from snow, and water from streams or springs believed to be tainted. Finally, hereditary or constitutional factors were thought important; that idea is attributed to Jacques de Vitry about A.D.1220.

Nineteenth-Century Theories

Dming the nineteenth century, the major theories of the etiology of goiter focused at least in part on some peculiarity of the drinking water, a lack of iodine, an infection of some sort, or some combination of these. Climatic factors had been dismissed when it turned out that goiter can occur in almost any climate, dry or wet, from the Arctic to the equator (Hirsch 1885). High altitude had been rejected as well, for the dis­ease was not limited to mountainous regions; flat­lands had endemic goiter as well.

The long process of linking endemic goiter and cretinism to iodine deficiency began in 1811, when Bernard Courtois discovered the element while mak­ing saltpeter for gunpowder during the Napoleonic Wars. He noticed it as a violet vapor released from the residue of burnt seaweed by sulfuric acid.

In 1818, Jean-Frangois Coindet, a Geneva physi­cian, suggested that because some seaweeds were effective in treating goiter, iodine might be the ac­tive principle. He asked Jean-Baptiste Dumas (then aged 18 and later to become one of France’s most famous chemists) to look for iodine in marine sponge; Dumas did and found it (Thorpe 1902). Coindet then gave iodine, mostly as potassium iodide, to goitrous patients, with good results that were almost immediately confirmed by other Swiss physicians.

An effective therapy, however, does not necessar­ily mean that a disease is due to a deficiency of the therapeutic agent. (Few would suggest, for example, that pneumococcal pneumonia results from penicil­lin deficiency.) Thus although the chemist Jean Bap­tiste Boussingault suggested as early as 1825 that iodine deficiency might be the cause of goiter and recommended the addition of iodine to table salt to prevent it, little came of this suggestion.

A generation later, Jean-Louis Prevost, another Geneva physician, made the same suggestion as Boussingault. But iodine had fallen into disfavor as therapy for goiter because of toxic side effects when given in excess, including (in retrospect) iodine- induced hyperthyroidism. Coindet himself had seen this (he used a dose of 1 to 2 grains of iodine per day) and had cautioned against too high a dose, but to no avail.

In the 1850s, Adolphe Chatin, a French pharma­cist and botanist, using a somewhat better assay for iodine, found the element in freshwater plants and suggested these plants be used to prevent goiter (Chatin 1850a). He went on to measure iodine in water samples from all over France, and in some foods as well, and concluded that a lack of iodine in drinking water in certain areas appeared to be the principal cause of goiter (Chatin 1850b). The follow­ing year, the French Academy of Sciences appointed a committee to study Chatin’s results; its report (Thenard et al. 1852) congratulated Chatin for his work, but viewed the association between a lack of iodine and goiter as unproven.

There were successful trials of iodine prophylaxis of endemic goiter in the nineteenth century, notably in South America in 1835 (Dumas et al. 1851) and in Savoy in the 1840s. Yet success did not encourage further trials, and the question of iodine as a goiter preventive was not pursued.

The rise of the “new pathology” with Rudolph Virchow as its leader in the mid-nineteenth century also interfered with the idea of iodine deficiency as the cause of endemic goiter. During the 1860s Virchow himself felt that excessive growth of a tis­sue, in this case goiter, must be due to some irrita­tion that stemmed from a “positive substance” and not a deficiency (Follis 1960). In France the view persisted that goiter and cretinism were serious prob­lems but that the cause was not iodine deficiency. Rather, an agent toxique special was thought to be responsible (Baillarger 1873).

The reluctance to accept iodine deficiency as a cause of goiter is understandable: There was then no good example of a disease known to be caused by a deficiency. Further, the theory did not explain why only some people in low-iodine areas got goiter while others did not. This problem remains unresolved today.

Later in the nineteenth century, after the discov­ery of the bacterial cause of many diseases, it was postulated that goiter was caused by either a bacte­rium or a bacterial toxin, perhaps in the water. Ed­win Klebs, a pioneer microbiologist, believed he had found such an agent in 1877, and August Hirsch (1885) stated flatly that “endemic goitre and cre­tinism have to be reckoned among the infective dis­eases.” Indeed, the notion that goiter has an infec­tious cause had its twentieth-century adherents at least until mid-century, although the evidence put forth has never been convincing. But while the infec­tious hypothesis has faded, the parallel notion of a toxin in the water, possibly of bacterial origin, is still alive (Gaitan et al. 1983) and warrants serious con­sideration, particularly in areas where there is much goiter despite adequate iodine intake.

Iodine as a therapy in medicine, in contrast to its use solely to treat goiter, caught on rapidly in the decade after its discovery. Beginning in the late 1820s, for example, Jean-G. A. Lugol, another Ge­neva physician whose name is memorialized in the still-used LugoFs solution of iodide-iodine, em­ployed it against any scrofulous disease (Lugol 1829). Its use spread rapidly to include treatment of other conditions, among them rheumatic diseases, almost any pulmonary condition, any disease that involved swelling of a part of the body, and syphilis. Late-nineteenth-century texts on medicine and phar­macology indicate its continued wide use while recog­nizing the hazards of overdosage (Wood 1881; Pepper 1894; Osler 1892). Iodine as therapy for goiter did persist (Inglis 1838; Wood 1881) but only as one of several possible treatments (Pepper 1894; Osler 1896) and was employed without much enthusiasm.

In sum, up to the 1890s there was no resolution of the problem of the cause of endemic goiter or cre­tinism. No clear choice could be made among the drinking water, iodine deficiency, or toxic-infective hypotheses. Prophylaxis of goiter with iodine on a mass scale was not popular and hence not done. Fear of inducing serious side effects if everyone took iodine in salt or food was widespread since, after all, iodine was a known poison. Social and political issues fre­quently arose, similar to those that surround ques­tions of the chlorination or fluoridation of water.

It was in the 1890s, however, that substantial advances began to be made in goiter research. George R. Murray (1891) discovered that a glycerin extract of sheep thyroid cured myxedema (hypothy­roidism). After this, investigators began to look for iodine in the thyroid gland itself. Eugen Baumann (1895), for example, in looking for the active com­pound in the thyroid, made a fairly potent extract. When analyzing that extract, he routinely looked for iodine, not expecting to find it; to his surprise it was there.

Twentieth-Century Theories

From this point research diverged: One path led to the isolation of a specific thyroid hormone, thyrox­ine, by Edward C. Kendall in 1914 (Kendall 1915) at the Mayo Clinic; and another led to studies relating goiter to the iodine content of the thyroid rather than to that of the environment.

David Marine came to Cleveland, Ohio, an area of endemic goiter, in 1905. He was aware of the impor­tance of hyperplasia - the process that leads to goiter - through William Halsted, his teacher at Johns Hopkins Medical School. By 1910, he showed that iodine prevented goiter in brook trout (Marine 1910), and therefore gave it to patients at Cleve­land’s Lakeside Hospital and to children of friends to prevent goiter. In fact, he tried to give it to all school­children in Cleveland, but the school board, led by a goiter surgeon, said it would poison the children. (At the time there was also a controversy over compul­sory smallpox vaccination.) Not until several years later was Marine able to carry out a large-scale study of iodine prophylaxis for goiter. The results were clear-cut: Sixty-five percent of goiters became smaller, whereas this happened in only 14 percent of the control group, and new goiter was largely pre­vented (0.2 percent got new goiter among those treated versus 21 percent for those untreated) (Ma­rine and Kimball 1920). This study provided the impetus, in the United States, for the use of iodized salt, which now contains 0.01 percent potassium iodide.

Even though Marine showed iodine to be both a treatment and a preventive for endemic goiter, he had not proven that these patients were iodine defi­cient. It remained for J. F. McClendon, a nutrition officer in the U.S. Army during World War I, to mea­sure accurately iodine in water and food. He showed not only that there was a correlation between lower iodine in food or water and the presence of human goiter, but also that rats on a low-iodine diet got goiter (McClendon and Williams 1923). He later put together worldwide data to support his thesis that low iodine in the water causes goiter (McClendon 1939); although the data in general did support the idea, close reading shows many exceptions.

By 1924, Michigan, a state with endemic goiter, offered iodized salt to the public after an intense public education campaign; within 12 years goiter prevalence fell from 37 percent to 8 percent and, by 1951, to 2 percent. Ohio, Marine’s own state, never acted. Still, Marine’s statement that “endemic goiter is the easiest known disease to prevent,” though a bit hyperbolic, was finally shown to be reasonably correct.

Over the years since Marine’s study, the average daily iodine intake in the United States has in­creased several times not only because of iodized salt (the label now says that iodine is “a necessary nutri­ent”), but because of the widespread use of pur­chased foods that contain iodine, such as bread and milk. Thus, in the United States, few can today develop iodine deficiency, and, as in countries with similar food sources, goiter is mostly sporadic and occurs either spontaneously or as a result of factors other than iodine deficiency, such as exposure to therapeutic X-rays (DeGroot et al. 1983) or radiation from atomic fallout (Hamilton et al. 1987; Morimoto et al. 1987). Sporadic goiter is also called nontoxic goiter, meaning that the patient is not hyperthyroid. Sporadic goiter can be any of the clinical types (i.e., diffuse or nodular). Yet, some areas of endemic goi­ter persist in the United States, especially in parts of Appalachia, and may be caused by a goitrogen (a substance that causes goiter). Goitrogens certainly exist, but how much they contribute to human goiter is unclear (Delange and Ermans 1976).

Prevention and Treatment

In many other parts of the world, both rich (Scriba et al. 1985) and poor (Prevention 1986), goiter remains endemic (World Health Organization 1960; Stan- bury and Hetzel 1980) with its attendant disfigure­ment, cretinism, and hypothyroidism. It is worth noting that persons in an endemic area could have any of the diseases that cause sporadic goiter, which is one reason why goiter prevalence never falls to zero even with iodine repletion. For some areas this endemia is a major public health problem, and mil­lions of people remain at risk. The disease, when endemic, is almost always associated with low iodine intake and iodine deficiency, and while there re­mains no good explanation as to why some do not develop goiter in areas of low dietary iodine, iodine does prevent the disease. The issue then becomes a social and political one of providing iodine to those in deficient areas and then getting them to take it. As Marine wrote, “Endemic goiter will be prevented only when society decides to do it.”

If a large goiter already exists, however, iodine will likely not be of help and surgery may be needed. On the other hand, thyroid therapy alone can shrink some goiters, as was shown as early as 1894 (Bruns 1894; Reinhold 1894), and prevent recurrence of oth­ers after surgery even if the goiter is cancerous (Mazzaferri and Young 1981). Thus thyroid hormone can be the initial treatment for goiter and should be used after any goiter surgery.

Therapies for endemic and sporadic goiter and cre­tinism are fairly straightforward, although some dis­agree on details of testing or timing. In developed countries they are easy to apply in principle; the major problems are societal and relate to detection and prevention. In less developed countries the pub­lic health aspects are paramount, especially where budgets are limited; prevention of endemic goiter and cretinism is an effective use of funds.

Conclusions

Overall, changes in how goiter was defined pro­gressed erratically. As theories and techniques em­ployed in anatomy and pathology were developed, the concept of “goiter” shifted from the simplistic idea of a swollen neck, to an enlarged thyroid of several types, to a range of different thyroid dis­eases. However, early taxonomies did not disappear but persisted along with the new.

Along with these changes in taxonomy came paral­lel changes in purported causes and the possibilities of prevention. Focusing for the moment only on io­dine, one can demonstrate a continuous link from the Chinese use of seaweed through the European Middle Ages and folk medicine, to the discovery and use of the element in the nineteenth and twentieth centuries. In actuality, however, although empirical “folk” medicines containing iodine were effective against goiter, they were used along with many oth­ers that seem to have had no benefit. Nineteenth­century French physicians may have been “right” in proposing iodine as a treatment for endemic goiter, but they did not convince their colleagues. That io­dine deficiency might cause goiter was confounded by iodine’s use in goiter treatment and prophylaxis; furthermore, the technical inability to measure con­sistently and accurately small amounts of iodine led to persistent and valid controversy. Improvements in the iodine assay in the late nineteenth and early twentieth centuries provided a solid basis for resur­recting earlier beliefs in its effectiveness; moreover, because it was thought that iodine ought to prevent endemic goiter, the studies were done that proved it. But the pendulum then swung to the other extreme, with many researchers believing that iodine was the answer to all endemic goiter. It was not, however, and we now face the scientific challenge of teasing out several probable factors in addition to iodine deficiency that can produce endemic goiter, as well as the political challenge involved in iodine prophy­laxis on a worldwide basis.

In conclusion, sporadic goiter is usually not due to iodine deficiency but is mainly the result of an intrin­sic thyroid disease, often related to genetic, immuno­logic, or enzymatic factors; it is apparently influ­enced by gender, as it is more common in women. Sporadic cretinism (or neonatal hypothyroidism) is almost never caused by iodine deficiency, but is usu­ally the result of failure of the thyroid gland to develop; thus there is no goiter. For this condition, a public health approach, with testing of all newborns, is mandatory to prevent irreversible brain damage.

On the other hand, endemic goiter and cretinism are usually related to a low dietary iodine, although goitrogens, genetic, and immunologic factors may be operative in some locales. Taking iodine cures some and prevents almost all; again a public health ap­proach is essential.

Clark T. Sawin

Bibliography

Alibert, J.-L. 1835. Monographie des dermatoses ou precis theorique et pratique des maladies de la peau, 2d edi­tion. Paris.

Baillarger, J. G. F. 1873. Enquete sur Ie goitre et Ie cre- tinisme. Reviewed in: Gazette Hebdomadaire de Medi­cine et de Chirurgie₁ 2d ser., 10: 807.

Baumann, E. 1895. Ueber das normale Vorkommen von Jod im Thierkorper. Hoppe-Seyler^,s Zeitschrift fur Phy- Siologische Chemie 21: 319-30.

Bruns, P. 1894. Ueber die Kropfbehandlung mit Schild- rtisenfutterung. Deutsche Medizinische Wochenschrift 41: 785-6.

Chatin, A. 1850a. Existence de 1’iode dans les plantes d’eau douce: Consequences de ce fait pour la geog- nosie, la physiologie v6getale, la therapeutique et peut-etre pour 1’industrie. Comtes Rendus Hebdoma- daires de VAcademie des Sciences 30: 352—4.

1850b. Recherches sur 1’iode des eaux douce (suite): De la presence de ce corps dans les plantes et les animaux terrestres. Comtes Rendus Hebdomadaires de VAcad­emic des Sciences 31: 280—3.

Cranefield, P. F. 1962. The discovery of cretinism. Bulletin of the History OfMedicine 36: 489-511.

DeGroot, L. J., et al. 1983. Retrospective and prospective study of radiation-induced thyroid disease. American Journal OfMedicine 74: 852—62.

Delange, F. M., and A. M. Ermans. 1976. Endemic goiter and cretinism: Naturally occurring goitrogens. Phar­macology and therapy [C] 1: 57-93.

Dumas, (J.-B.), et al. 1851. Rapport sur les recherches de M. Ie Dr. Grange, relatives aux causes du cr6tinisme et du goitre, et aux moyens d’en preserver les popula­tions. Comtes Rendus Hebdomadaires de IAcademie des Sciences 32: 611-18.

Follis, R. H., Jr. 1960. Cellular pathology and the develop­ment of the deficiency disease concept. Bulletin of the History OfMedicine 34: 291-317.

Gaitan, E., et al. 1983. In vitro measurement of antithy­roid compounds and environmental goitrogens. Jour­nal of Clinical Endocrinology and Metabolism 56: 767-73.

Hamilton, T. E., et al. 1987. Thyroid neoplasia in Marshall Islanders exposed to nuclear fallout. Journal of the American Medical Association 258: 629-366.

Harington, C. R. 1933. The thyroid gland: Its chemistry and physiology. London. [A historical chapter on goi­ter and cretinism.]

Hirsch, A. 1885. Handbook of geographical and historical pathology, Vol. II. Chronic infective, toxic, parasitic, septic and constitutional diseases, trans. C. Creighton, from the 2nd German edition. London.

Inglis, J. 1838. TreatiseonEnglishbronchocelewithafewre- marks on the use of iodine and its compounds. London.

Kendall, E. C. 1915. The isolation in crystalline form of the compound which occurs in the thyroid: Its chemi­cal nature and physiologic activity. Journal of the American Medical Association 64: 2042—3.

Lee, T. 1941. A brief history of the endocrine disorders in China. Chinese MedicalJournal 59: 379—86.

Lugol, J.-G.-A. 1829. Memoire sur Vemploi de Viode dans les maladies Scrophuleuses. Paris.

Marine, D., and C. H. Lenhart. 1910. On the occurrence of goitre (active thyroid hyperplasia) in fish. Bulletin of Johns Hopkins Hospital 21: 95—8.

Marine, D., and O. P. Kimball. 1920. Prevention of simple goiter in man. Archives of Internal Medicine 25: 661— 72.

Matovinovic, J. 1983. Endemic goiter and cretinism at the dawn of the third millennium. Annual Review of Nu­trition 3: 341—412.

Mazzaferri₁ E. L., and R. L. Young. 1981. Papillary thyroid carcinoma: A 10-year follow-up report of the impact of therapy in 576 patients. American Journal of Medi­cine 70: 511-18.

McClendon, J. F. 1939. Iodine and the incidence of goiter. Minneapolis.

McClendon, J. F, and A. Williams. 1923. Experimental goitre and iodine in natural waters in relation to distribution of goitre. Proceedings of the Society for Experimental Biology and Medicine 20: 286—7.

Merke, F. 1984. History and iconography of endemic goitre and cretinism. Beme-Hingham. [An excellent guide to older works.]

Morimoto, T., et al. 1987. Serum TSH, thyroglobulin, and thyroidal disorders in atomic bomb survivors exposed in youth: 30-year follow-up study. Journal of Nuclear Medicine 28:1115-22.

Murray, G. R. 1891. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. British Medical Journal 2: 796-7.

Needham, J., et al. 1970. Proto-endocrinology in medieval China. In Clerks and craftsmen in China and the West. Cambridge.

Ord, W. M. (chairman). 1888. Report of a committee of the Clinical Society of London nominated December 14, 1883, to investigate the subject of myxoedema. Trans­actions of the Clinical Society of London 21 (Supple­ment): 1—215.

Osler, W. 1892. The principles and practice of medicine, 1st edition. New York.

1896. The principles and practice of medicine, 2d edition. New York.

Pepper, W., ed. 1894. A textbook of the theory and practice of medicine by American teachers, Vol. 2, 1021-2. Philadelphia.

Prevention and control of iodine deficiency disorders. 1986. Lancet 2: 433-4.

Reinhold, G. 1894. Ueber Schilddrusen Therapie bei kropf- Ieidenden Geisteskranken. Miinchener Tnedizinische Wochenschrift 41: 613—14.

Rolleston, H. D. 1936. The endocrine organs in health and disease with an historical review. London. [See espe­cially pp. 192-207.]

Scriba, P. C., et al. 1985. Goitre and iodine deficiency in Europe. Lancet 1: 1289—93.

Stanbury, J. B., and B. S. Hetzel, eds., 1980. Endemic goiter and endemic cretinism: Iodine nutrition in health and disease. New York. [A modern detailed text.]

Thenard, L. J., et al. 1852. Rapport sur les travaux de M. Chatin, relatifs ⅛ la recherche de l^,iode, et sur differ­entes notes ou memoires presentes sur Ie meme sujet, par MM. Marchand, Nidpce, Meyrac. Comtes Rendus Hebdomadaires de VAcademie des Sciences 35: 505­17.

Thorpe, T. E. 1902. Essays on historical chemistry. London. Wood, H. C., Jr. 1881. A treatise on therapeutics, 3d edition.

Philadelphia.

World Health Organization (WHO). 1960. Endemic goitre. Geneva. [Strong on epidemiology with good maps and a short historical chapter.]