The thyroid gland: a brief historical perspective. (Editorial).

One of the first references to the thyroid gland in Western medicine is in 1656, when it was thought that the main function of the thyroid gland was to lubricate the trachea. (1) It was also believed to have a cosmetic function in women. Paintings going back to ancient Egypt often emphasize the size of the thyroid gland in women. In the early 1800s, the thyroid was thought to be a vascular shunt to divert the blood flow from the brain. In 1811, cancer of the thyroid was the first disease of the thyroid to be described. (2)

Rush (3) reported in 1820 that the thyroid gland is larger in women because it is "necessary to guard the female system from the influence of the more numerous causes of. irritation and vexation of mind to which they are exposed than the male sex." Also in 1820, Hofrichter (4) stated: "If it were indeed true that the thyroid contains more blood at some times than at others, this effect would be visible to the naked eye; in this case women would certainly have long ceased to go about with bare necks, for husbands would have learned to recognize the swelling of this gland as a danger signal of threatening trouble from their better halves."

It is remarkable that the association between an enlarged thyroid gland and the characteristic clinical features of hyperthyroidism was not recognized until 1786, when Parry noted them, (5) but did not publish them until almost 40 years later, in 1825. This publication was followed by the classic descriptions of Graves (6) and von Basedow (7) in 1835 and 1840, respectively. Cretinism was described in 1871. (8) In 1874, Gull noted the clinical changes associated with atrophy of the thyroid gland, (9) and 4 years later, Ord coined the term myxedema because he felt that excessive mucus formation and deposition under the skin were responsible for the characteristic thickening of the subcutaneous tissue. (10)

In 1884, thyroidectomies were successfully performed for the treatment of toxic goiter. (11) In Europe, Theodore Kocher (1841-1917), a Swiss surgeon, performed over 2,000 thyroidectomies with a reported mortality rate of 5%, while in the United States, Charles Horace Mayo became an authority on thyroid surgery. (12) In 1891, Murray obtained a good clinical response in patients with hypothyroidism by injecting them with thyroid extracts. (13) Shortly afterward, Howitz, Mackenzie, and Fox independently found that thyroid extracts were effective when administered orally. (1)

The results of experimental thyroidectomies to elucidate the exact functions of the thyroid gland were misinterpreted because investigators also inadvertently removed the parathyroid glands. (1) Gley, in 1891, was able to differentiate the functions of the thyroid from those of the parathyroid glands. (14) In 1895, MagnusLevy established the effect of the thyroid on the metabolic rate, the low metabolic rate in patients with hypothyroidism, and the fact that the administration of thyroid extracts to these patients and to individuals with normal thyroid function increased their oxygen consumption. (15) Hashimoto's disease was described in 1912. (16)

Edward Kendall, professor of physiological chemistry at the Mayo Clinic, isolated thyroxine in crystalline form in 1915, and established that the crystalline form had the same effects as the thyroid extract from which it was obtained. (17) A decade later, in 1926, Harington defined the chemical formula of thyroxine, and a year later synthesized the hormone. (18,19) Meticulous studies, however, revealed that the calorigenic effect of synthetic thyroxine was less than that of thyroid extracts. The enigma was not resolved until 25 years later, when triiodothyronine ([T.sub.3]) was isolated and synthesized in the early 1950s. (20,21)

The presence of thyroid-stimulating antibodies in Graves' disease was determined in 1956, (22) and that of thyroid antibodies in Hashimoto's disease in 1957. (23) Medullary thyroid carcinoma was recognized as a distinct entity in 1959. (24) The definition of the exact role of the thyroid gland in calcium metabolism had to wait for the discovery of calcitonin in 1961.

The first description of resistance to thyroid hormone was not made until 1967, when two young deaf-mute patients with features of juvenile hypothyroidism were found to have significantly elevated levels of circulating thyroid hormones. (25) Evidence that circulating [T.sub.3] is derived largely from peripheral monodeiodination of thyroxine was not available until 1970. (26) Reports of cases of postpartum thyroiditis with hypothyroidism or thyrotoxicosis were not made until the mid-1970s. (27) The [T.sub.3]-binding receptors were identified in 1972, (28) and their homology to the viral oncogene erbA was recognized in 1986. (29,20) The fact that point mutations in the thyroid-hormone receptor accounted for hormone resistance was established in 1989 and 1990. (31)

The gene for the [beta]subunit of thyroid-stimulating hormone (TSH) was cloned in 1988, (32) and that of TSH receptor in 1989. (33) It was then determined that both loss-of-function and gain-of-function mutations in that receptor accounted for specific types of hypothyroidism and hyperthyroidism. (34) The development of human recombinant TSH further enhanced the diagnosis and treatment of thyroid cancer. (35,36)

Thyroid dysfunction is not uncommon. The diagnosis of many of these conditions is relatively simple, and the prognosis is excellent if managed in a timely manner. Neonatal screening programs for hypothyroidism are now the standard of care, and have shown an incidence of 1 in 3,500 to 4,500 births. (37) A large number of tests, procedures, and algorithms are available to guide the clinician's efforts to diagnose thyroid dysfunction. (38,39) It is hoped that this Featured CME Topic on thyroid dysfunction/disease will be of help.

It gives me great pleasure to introduce Dr. Alan Peiris as the guest editor of this month's Special CME Feature on thyroid dysfunction.

Alan Peiris, MD, PhD, MRCP (UK), is Professor of Medicine, Department of Internal Medicine, East Tennessee State University; Staff Physician, Mountain Home Veterans Administration Medical Center; and Medical Director at the Diabetes Center, Johnson City Medical Center, Johnson City, Tenn.

Ronald C. Hamdy, MD, FRCP, FACP Editor

References

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(2.) Burns P: Observations on the Surgical Anatomy of the Head and Neck. Edinburgh, Scotland, Bryce, 1811, p 207

(3.) Rush, quoted by Haynes RC Jr: Thyroid and antithyroid drugs. Goodman and Gilman's Tile Pharmacological Basis of Therapeutics, 8th Ed. Gilman AG, Rail TW, Niew AS, et al (eds). Pergamon Press, 1990, p 1361

(4.) Hofrichter, quoted by Haynes RC Jr: Thyroid and antithyroid drugs. Goodman and Gilman's Tile Pharmacological Basis of Therapeutics, 8th Ed. Gilman AG, Rall TW, Niew AS, et al (eds). Pergamon Press, 1990, p 1361

(5.) Parry CH: Collections from the Unpublished Papers of the Late Caleb Hillier Parry. London, England, Vol 2, 1825, p 111

(6.) Graves RJ: Clinic lectures. Lond Med Surg J (Part II) 1835; 7:516

(7.) Von Basedow CA: Exophthalmos durch hypertrophie des Zellgewebes in der Augen hohle. Wochenschr Heilk 1840; 6:197

(8.) Fagge CH: On sporadic cretinism occurring in England. BMJ 1871; 1:279

(9.) Gull WW: On a cretinoid state supervening in adult life in women. Tran Clin Soc (Lond) 1874; 7:180

(10.) Ord WM: On myxoedema, a term proposed to be applied to an essential condition in the "cretinoid" affection occasionally observed in middle-aged women. Med Chir Trans (Land) 1878; 61:57

(11.) Rehn L: Uber die extirpation des Kropfs bei morbus Basedowii. Berlin Klin Wocheschr 1884; 21:163

(12.) Guthrie D: A History of Medicine. London, England, Thomas Nelson and Sons, Ltd, 1945, p 329

(13.) Murray GR: Note on the treatment of myxoedema by hypodermic injection of an extract of the thyroid gland of a sheep. BMJ 1891; 2:796

(14.) Gley E: Sur les effets de l'estirpation du corps thyroide. C R Soc Biol (Paris) 1891; 43:551

(15.) Magnus-Levy A: Uber den respiratorischen Gaswechsel unter den Einfluss der Thyroidea sowie unter verschiedenden pathologischen Zustanden. Berl Klin Wochenshr 1895; 32:650

(16.) Hashimoto H: Zur kenntnis der lymphomatoser veranderung der schildruse (struma lymphomatosa). Arch Klin Chir 1912; 97:219

(17.) Kendall EC: The isolation in crystalline form of the compound containing iodine which occurs in the thyroid: its chemical nature and physiological activity. Trans Assoc Am Physicians 1915; 30:420

(18.) Harington CR: Chemistry of thyroxine I. Isolation of thyroxine from the thyroid gland. Biochem J 1926; 20:293

(19.) Harington CR, Barger G: Thyroxine III. Constitution and synthesis of thyroxine. Biochem J 1927; 21:169

(20.) Gross J, Pitt-Rivers R: The identification of 3:5:3'-1 triiodothyronine in human plasma. Lancet 1952; 1:439

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(23.) Doniah D, Roitt IM: Autoimmunity in Hashimoto's disease and its implications. J Clin Endocrinol Metab 1957; 17:1293

(24.) Hazard JB, Hawk WA, Crile G Jr: Medullary (solid) carcinoma of the thyroid: a clinicopathologic entity. J Clin Endocrinol Metab 1959; 19:152

(25.) Refetoff S, DeWind LT, DeGroot LJ: Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter, and abnormally high PBI: possible target organ refractoriness to thyroid hormone.] Clin Endocrinol Metab 1967; 27:279294

(26.) Braverman LE, Ingbar SH, Sterling K Conversion of thyroxine ([T.sub.4]) to triiodothyronine ([T.sub.3]) in athyreotic human subjects.] Clin Invest 1970; 49:855-864

(27.) Ginsberg J, Walfish PC: Postpartum transient thyrotoxicosis with painless thyroiditis. Lancet 1977; 1:1125-1128

(28.) Oppenheimer JH, Koerner D, Schwartz I-IL, et al: Specific nuclear triiodothyronine binding sites in rat liver and kidney. J Clin Endocrinol Metab 1972; 35:330-333

(29.) Sap J, Munoz A, Damm K, et al: The c-erb-A protein is a high affinity receptor for thyroid hormone. Nature 1986; 324:635-640

(30.) Weinberger C, Thompson CC, Ong ES, et al: The c-erbA gene encodes a thyroid hormone receptor. Nature 1986; 324:641-646

(31.) Usala SJ, Tennyson GE, Bale AE, et al: A base mutation of the c-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds. J Clin Invest 1990; 85:93-100

(32.) Wondisford FE, Radovick S, Moates JM, et al: Isolation and characterization of the human thyrotropin beta-subunit gene. differences in gene structure and promoter function from murine species. J Biol Chem 1988; 263: 12538-1 2542

(33.) Parmentier M, Libert F, Maenhaut C, et al: Molecular cloning of the thyrotropin receptor. Science 1989; 246: 1620-1622

(34.) Morris JC: The clinical expression of thyrotropin receptor mutations. The Endocrinologist 1998; 8:195

(35.) Meier C, Braverman LE, Ebner SA, et al: Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma. J Clin Endocrinol Metab 1994; 78:188

(36.) Ladenson PW, Braverman LE, Mazzaferri EL, et al: Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N Engl J Med 1997; 337:888

(37.) Fisher DA: Hypothyroidism. Pediatr Rev 1994; 15:227

(38.) Klee CC, Hay ID: Biochemical testing of thyroid function. Endocrinol Metab Clin North Am 1997; 26:763

(39.) Davey RX, Clarke MI, Webster AR: Thyroid function testing based on assay of thyroid stimulating hormone: assessing an algorithm's reliability. Med JAust 1996; 164:329