The history and iconography relating to the thyroid gland
Knowledge of goitre (which was not known to be a thyroid enlargement until about the 16th century) goes back into antiquity. In 1600 bc, burnt sponge and seaweed was used for the treatment of goitre in China (2). In the fourth century bc, the Ayur Veda, a Hindu system of medicine in India, contained a discussion of goitre (1,2). In Greece, in the days of Hippocrates, goitre was regarded purely as a deformity, and was attributed to the drinking of snow water (2). In ancient Greece, swellings in the region of the thyroid gland (and presumably swellings elsewhere in the neck) were referred to as ‘bronchocoele’ or ‘struma’. Galen (ad 130–200), considered the greatest medical practitioner in antiquity after Hippocrates, regarded the thyroid as a lubricant for the larynx (2). Later, Julius Caesar (2) noted that Gauls had large necks as one of their characteristics. Celsus (25 bc to ad 50) in Rome defined bronchocele (a tumour in the neck, most likely goitre) and he also described cystic goitre, as well as surgery for these lesions (2). At the same time, in Egypt, Egyptian coins showed the presence of goitres, (4) and an Egyptian relief of Cleopatra likewise depicted her with what appears to be a goitre.
Even in these early years several writers (1,2) referred to epidemics of goitre in the Alps, which was a forerunner to a wide literature from this region regarding goitres and their relationship to Alpine culture. The Chinese also were well aware of goitre in those early years, and recommended seaweed for the treatment of goitre as early as ad 340. Much later, the treatment of goitre with desiccated thyroid was advocated as early as ad 1475 by Wang Hei in China (2).
In Switzerland in the 16th century, Paracelsus (5) (1493–1541) recognized the connection between cretinism, endemic goitre, and congenital idiocy. He attributed goitre to mineral impurities in the drinking water. Later in that century and the next century, also in Switzerland, many writers described cretins in Swiss cantons and related them to the presence of goitre (3). In 1656 (6) at St Thomas’s Hospital, London, Thomas Wharton named the lobes of the thyroid, ‘glandulae thyroidiaeae’ because of their anatomical proximity to the thyroid cartilage, and not because of their shape. He felt that the fact that women generally had larger thyroid glands than men was for the purpose of making their necks ‘more even and beautiful’.
During the mid and late medieval period in Europe, goitre and cretinism played a significant part in the social history of middle Europe, particularly in Alpine areas where these conditions were quite prevalent. Indeed, there was a connotation that those people with goitres were somehow inherently evil, and this was reflected in the folk art of the period. Indeed, depictions of goitre and cretinism in art and sculpture at that time were commonplace, and form the subject of an entire volume (3).
The discovery of iodine at the beginning of the 19th century was a landmark event in relation to the thyroid gland. In 1811, Bernard Courtois (1777–1838), a self-taught chemist and dealer in chemicals and manufacturer of saltpetre in Paris, was using vitriol to clean the vats used for making potash from seaweed, when he noted violet fumes. This violet gas condensed into crystals on cooling; he called the crystals substance X. The substance was soon identified as a new halogen element by Sir Humphrey Davy (1778–1829), (7) who happened to be in Paris at the time (despite the ongoing Napoleonic War). As mentioned above, seaweed or burnt sponge had been employed in the treatment of goitre for centuries (2). However, the credit for using iodine itself in the treatment of goitre appears to go to Coindet (1774–1834) (8) of Geneva in 1820, after he had determined that the substance in burnt sponge that acted against ‘bronchocoele’ was actually iodine. In his ‘tincture of iodine’, he used 48 grains of iodine to one ounce of spirit of wine. For adults, he prescribed 10 drops of the tincture in half a tumbler of ‘syrup of capillaire’ and water three times a day, the dose being increased after a few weeks to 15 or even 20 drops. He noted that bronchocoele would usually subside and be destroyed within the space of 6–10 weeks. A few years later, Lugol (1786–1851) in 1829 (2) also recommended and used (what we now call) Lugol’s solution for the treatment of goitre, with considerable success.
With the spread of iodine usage, toxic effects soon appeared, as described by Coindet in 1821, and later by Frederic Rilliet (1814–1861) (9). These ill effects of iodine led to a great deal of anxiety about its use for goitre under any circumstance; for some, it was completely proscribed.
Surgical treatment of goitre had been mentioned by Celsus (25 bc to ad 50) (2). It was also mentioned in the Turkish manuscript of Charaf Eddin in 1465. Johann A. W. Hedenus (1760–1836) (2) reported in 1822 on six cases of successful excision of a goitre for impending suffocation. Joseph Henry Green (1791–1863) reported the removal of the right lobe of the thyroid gland in St Thomas’s Hospital, London, in 1829, but the patient died of sepsis 2 weeks later.
Structure and function
In a paper by T. W. King (1809–47) (10) of Guy’s Hospital, London, there is a description of what was thought to be the secretion of the thyroid as passing into its lymphatics and so into the great veins. King noted that this had been indirectly surmised by Morgagni. He also remarked prophetically that we should be able one day to show that a particular material is slowly formed and partially kept in reserve and that this principle is also supplementary, when poured into the descending inferior vena cava, to important functions in the course of the circulation. Thus he had a conception of the internal secretion by the thyroid. In notes appended to King’s paper, Astley Cooper (1768–1841), a surgeon at the same hospital, agreed with King about this idea.
John Simon (1818–97) (1) in 1844, while assistant surgeon at King’s College Hospital and demonstrator of anatomy at King’s College, London, published a paper on the comparative anatomy of the thyroid. He stated that in addition to its copious vascular supply, it had the structure of a secreting gland. Several decades later, based on thyroidectomies performed on monkeys and other mammals, Victor Horsley (1857–1916) (11) in 1885 supported the generalization of Felix Semon (1849–1921) in 1883 that myxoedema, cretinism, and operative cachexia strumipriva were all due to thyroid deficiency, and not due to chronic asphyxia (as Theodor Kocher, a surgeon in Bern, Switzerland, originally believed) or due to injury of the sympathetic or other nervous structures. Horsley thought that the thyroid controlled the metabolism of mucus, and that the effects of thyroid insufficiency were due to an accumulation of mucus. Others thought that the function of the thyroid was to neutralize or remove poisons, and so thyroid insufficiency was presumed to produce toxaemia. Horsley, in his report to the Clinical Society’s Committee on Myxoedema (1888) divided the effects of complete thyroidectomy on monkeys into (1) the acute effects, which consisted of nervousness, tremor, clonic spasm, contracture, paresis, paralysis, and which came on between the second and the twelfth day (now in retrospect clearly the result of damage to the parathyroid glands) and (2) chronic experimental myxoedema. After Gley’s (12) rediscovery in 1891 of the parathyroid glands, it became evident that the effect of complete removal of the thyroid resulted in myxoedema, and that removal of the parathyroids was responsible for what had previously been called tetania thyreopriva.
The dramatic results of replacement treatment of myxoedema by thyroid preparations by George Murray (1865–1939) (13) (Fig. 188.8.131.52) in the UK in 1891, and Magnus-Levy’s(14) demonstration in France in 1895 that thyroid medication accelerated metabolism, led to the conclusion that the thyroid and its internal secretion had definite powers other than detoxification.
Theodor Kocher (1841–1917)(2) suggested in 1895 that the thyroid might contain iodine. In the same year, Tschirch (2) was unable to establish this point. However, Eugen Baumann (1846–96), (15) apparently quite independently of Kocher’s suggestion, investigated the chemistry of the thyroid, and was much surprised to find iodine. He published his findings in 1896, (15) called the extracted compound that contained iodine ‘thyreo-iodin’, and considered it to be the active principle of the thyroid. This led to the isolation by Kendall (16) in 1914 of an active principle which was initially called thyroxyindole and later thyroxin. In 1926, Harington (1897–1972) (17) proved that it was derived from tyrosine and not, as Kendall thought, from tryptophane, and was found to be a basic substance, now called thyroxine. Thyroxine was subsequently shown by Harington (2) and Salter (2) to be less powerful than desiccated thyroid. It was of interest that Harington was not able to accept the possibility that a principle other than thyroxine might exist to explain the metabolic effects of desiccated thyroid. It was not until 1952 that Gross and Pitt-Rivers (18) discovered triiodothyronine, which proved to be that elusive second principle.
The term cretin is thought by some to derive from Christianus, in that the cretinous patients were ‘incapable of sin’ (2). They were considered as simple, innocent creatures, ‘gens du bon Dieu’ (2). Cretinism was one of the diseases first recognized in early life before it was realized that adults were also affected. The observation that cretinoid conditions occurred in adult life in women occurred much later, and was particularly recognized by Sir William Gull (1816–90) (19) in 1873. He was instrumental in leading the commission (which he initially chaired) to the conclusion that myxoedema was actually due to thyroid deficiency. William Ord (1834–1902) (20) gave the name ‘myxoedema’ to the adult form in 1877 and was the chairman of the commission at the time of the report (1888).
Significant differences were noticed between the adult and the childhood form. In the latter, there was arrest of development in growth both in body and brain. Because cretinism was found more commonly in the deep mountain valleys, there were many theories as to the relationship of air, water, and food, as noted by Hoefer (1614–81), DeSaussure (1740–99), and Malacarne (1744–1816) (1). A Royal Commission in Sardinia (1) in 1848 found that the incidence of cretinism was 28% of the population in the District of Aosta but much lower elsewhere.
Causes of hypothyroidism
The causes of the hypothyroidism were not fully understood throughout the 19th century. W. M. Ord (20,21) described the appearance of the thyroid gland in this condition in 1878, and 13 cases were examined after death in the Report of the Clinical Society of London in 1888. The thyroid showed fibroid atrophy and great diminution in size and weight. There was evidence of chronic inflammation, lymphocytic infiltration, fibrosis, and disappearance of the acini and colloid. However, in 1912, it was Hakaru Hashimoto (1888–1934) (22,23) a surgeon from Fukuoka, Japan, who described four cases of goitre associated with hypothyroidism in which lymphocytic infiltration of the thyroid gland was an important feature. The most common cause of spontaneous hypothyroidism in areas of the world where there is no iodine deficiency is that of (what is now termed) Hashimoto’s thyroiditis or autoimmune thyroiditis. Only much later, in 1956, was autoimmune thyroiditis produced experimentally by Rose and Witebsky in Buffalo, New York, (24) and in that same year, thyroid antibodies were found in the circulation of patients with Hashimoto’s thyroiditis by Roitt and Doniach (25) in the UK. These findings helped to usher in the era of autoimmunity.
Few diseases can have more synonyms and none more eponyms. C. P. Howard (26) collected more than 20 such terms.
Looking back into antiquity, the Persian writer, Sayyid Ismail Al-Jurjani in 1136 (1,2) may have been the first to connect exophthalmos with goitre. Flajani’s (1741–1808) (27) description in 1802 in Ascoli, Italy, failed to associate the goitre, exophthalmos, and palpitations as one disease, and his account failed to attract much attention. Indeed, Antonia Testa’s (1756–1814) (28) reference in 1800 to the coincidence of prominent eyes and a cardiac disorder likewise did not attract much attention. Testa was the professor of medicine and surgery at Bologna and was said to be a learned theorist, but a mediocre clinician. Caleb Hillier Parry (29,30) (1755–1822) of Bath, England observed a case in August 1786, but his description of eight cases of ‘enlargement of the thyroid gland in connection with enlargement or palpitation of the heart’ was not published until 1825, 3 years after his death. His second case, seen in 1802, was of particular interest as it seemed to be precipitated by an acute stress, a factor that still exercises the interest of many observers. He considered that the thyroid was acting as a reservoir for the blood being pumped out by the hyperactive heart. This posthumous report in 1825 still preceded Graves’ publication by a decade.
Robert J. Graves (31,33) (1796–1853) of Dublin, Ireland, gave a clinical lecture at the Meath Hospital in Dublin and subsequently published a short article on ‘palpitation of the heart with enlargement of the thyroid gland’ in 1835. He then included these accounts in textbooks that he later wrote. These texts drew considerable attention to the disorder. This attention was later amplified in 1840 by Karl Adolf von Basedow (1799–1854) (34) of Merseburg, Germany, who described four patients with exophthalmos, goitre, and palpitations; his description eave rise to the phrase ‘the Merseburg triad’. William Stokes (1804–78), a colleague and friend of Graves in Dublin, actually described hyperthyroidism much more fully than Graves in his text, Diseases of the Heart in 1854 (35).
In France, the first description of the disease was provided in 1856 by Jean-Martin Charcot (1825–93), (36) employing the term ‘cachexia exophthalmica’ to describe the condition. Charcot’s older colleague, Armand Trousseau (1801–67) mentioned in a lecture at the Hotel Dieu in Paris in 1860, that iodine, which had been ‘inappropriately’ prescribed for hyperthyroidism had actually caused marked amelioration of the disease (37). Nevertheless, he felt that the use of iodine in toxic goitre was dangerous, and warned against it.
The credit for the precedence for the description of this disease is scarcely resolved to this day. Sir William Osler (38,39) in his third edition of his famous textbook of medicine belatedly gave the credit for the first important description of this disease to Parry. However, Trousseau (37) had been impressed with the books written by Graves (who was highly regarded as an academic physician) and felt that Graves should be given the credit. In mid-Europe, many observers have given that honour to Basedow. Thus although the term Graves’ disease is in common usage in English-speaking countries, Basedow’s disease is generally used in Europe. In Italy, the term, Flajani’s disease is sometimes heard. At international meetings, the term Graves’ disease is most commonly heard.
The cause of Graves’ disease remained unknown, and led to many interesting hypotheses, most notably the importance of psychological factors. Rolleston (1) has summarized the various influences which were thought to be at work in causing this condition. In 1907, Charles Mayo (2) of Rochester, Minnesota, first used the term ‘hyperthyroidism’, to conform to the idea we hold today, namely that the disorder represents an excess of thyroid hormone. In 1910, Kocher (1,2) coined the term ‘Jod-Basedow’ to describe hyperthyroidism precipitated or aggravated by excess iodine. David Marine (2) also suggested that iodine might actually be a treatment for Graves’ disease. A few years later, in 1913, Henry Plummer (1874–1937) (40) was able to separate Graves’ disease from hyperthyroidism related to toxic nodular goitre (Plummer’s disease). In 1924, Plummer and Boothby (41) showed that the preoperative use of iodine greatly simplified the operative management of Graves’ disease.
Treatment of Graves’ disease remained mainly surgical until 1942, when Hertz and Roberts (42,43) introduced radioactive iodine for the diagnosis and treatment of Graves’ disease. The following year, Astwood (44) used thiourea and thiouracil in the medical treatment of Graves’ disease, thus initiating the era of antithyroid drug therapy. In 1956, the year that thyroid autoantibodies were first identified, Adams and Purves (45) in New Zealand described the presence of an abnormal stimulator of the thyroid in Graves’ disease which later proved to be an antibody directed against the thyroid-stimulating hormone receptor (thyroid-stimulating antibody). Thus Graves’ disease, as well as Hashimoto’s thyroiditis, proved to be an autoimmune disorder.
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