- Wilmar M. Wiersinga, M.D.
- Department of Endocrinology F5-171 Academic Medical Center Meibergdreef 9 NL-1105 AZ Amsterdam, The Netherlands Tel: 011-31-20-566-6071 Fax: 011-31-20-566-4440
The full-blown expression of hypothyroidism is known as myxedema. Adult myxedema escaped serious attention until Gull described it in 1874 1 . That it was a state resembling the familiar endemic cretinism, but coming on in adult life, was what chiefly impressed Gull. Ord 2 invented the term myxedema in 1873. The disorder arising from surgical removal of the thyroid gland (cachexia strumipriva) was described in 1882 by Reverdin 3 of Geneva and in 1883 by Kocher of Berne 4 . After Gulls description, myxedma aroused enormous interest, and in 1883 the Clinical Society of London appointed a committee to study the disease and report its findings 5 . The committees report, published in 1888, contains a significant portion of what is known today about the clinical and pathologic aspects of myxedema. It is referred to in the following discussion as the Report on Myxedema. The final conclusions of the 200-page volume are penetrating. They are as follows:
1. That myxedema is a well-defined disease.
2. That the disease affects women much more frequently than men, and that the subjects are for the most part of middle age.
3. That clinical and pathological observations, respectively, indicate in a decisive way that the one condition common to all cases is destructive change of the thyroid gland.
4. That the most common form of destructive change of the thyroid gland consists in the substitution of a delicate fibrous tissue for the proper glandular structure.
5. That the interstitial development of fibrous tissue is also observed very frequently in the skin, and, with much less frequency, in the viscera, the appearances presented by this tissue being suggestive of an irritative or inflammatory process.
6. That pathological observation, while showing cause for the changes in the skin observed during life, for the falling off the hair, and the loss of the teeth, for the increased bulk of body, as due to the excess of subcutaneous fat, affords no explanation of the affections of speech, movement, sensation, consciousness, and intellect, which form a large part of the symptoms of the disease.
7. That chemical examination of the comparatively few available cases fails to show the general existence of an excess of mucin in the tissues adequately corresponding to the amount recorded in the first observation, but that this discrepancy may be, in part, attributed to the fact that tumefaction of the integuments, although generally characteristic of myxedema, varies considerably throughout the course of the disease, and often disappears shortly before death.
8. That in experiments made upon animals, particularly on monkeys, symptoms resembling in a very close and remarkable way those of myxedema have followed complete removal of the thyroid gland, performed under antiseptic precautions, and with, as far as could be ascertained, no injury to the adjacent nerves or to the trachea.
9. That in such experimental cases a large excess of mucin has been found to be present in the skin, fibrous tissues, blood, and salivary glands; in particular the parotid gland, normally containing no mucin, has presented that substance in quantities corresponding to what would be ordinarily found in the submaxillary gland.
10. That following removal of the thyroid gland in man in an important proportion of the cases, symptoms exactly corresponding with those of myxedema subsequently develop.
11. That in a considerable number of cases the operation has not been known to have been followed by such symptoms, the apparent immunity being in many cases probably due to the presence and subsequent development of accessory thyroid glands, or to accidentally incomplete removal, or to insufficiently long observation of the patients after operation.
12. That, whereas injury to the trachea, atrophy of the trachea, injury of the recurrent laryngeal nerves, injury of the cervical sympathetic, and endemic influences, have been by various observers supposed to be the true cases of experimental or of operative myxedema (cachexia strumipriva), there is, in the first place, no evidence to show that, of the numerous and various surgical operations performed on the neck and throat, involving various organs and tissues, any, save those in which the thyroid gland has been removed, have been followed by the symptoms under consideration; that in many of the operations on man, and in most, if not all, of the experimental operations made by Professor Horsley on monkeys and other animals, this procedure avoided all injury of surrounding parts, and was perfectly antiseptic; that myxedema has followed removal of the thyroid gland in persons neither living in nor having lived in localities the seat of endemic cretinism; that, therefore, the positive evidence on this point vastly outweighs the negative; and that it appears strongly proved that myxedema is frequently produced by the removal, as well as by the pathological destruction, of the thyroid gland.
13. That whereas, according to Clause 2, in myxedema women are much more numerously affected than men, in the operative form of myxedema no important numerical difference is observed.
14. That a general review of symptoms and pathology leads to the belief that the disease described under the name of myxedema, as observed in adults, is practically the same disease as that named sporadic cretinism when affecting children; that myxedema is probably identical with cachexia strumipriva; and that a very close affinity exists between myxedema and endemic cretinism.
15. That while these several conditions appear, in the main, to depend on, or to be associated with, destruction or loss of the function of the thyroid gland, the ultimate cause of such destruction or loss is at present not evident.
9.2 DEFINITION AND EPIDEMIOLOGY OF HYPOTHYROIDISM
Hypothyroidism is traditionally defined as deficient thyroidal production of thyroid hormone. The term primary hypothyroidism indicates decreased thyroidal secretion of thyroid hormone by factors affecting the thyroid gland itself; the fall in serum concentrations of thyroid hormone causes an increased secretion of TSH resulting in elevated serum TSH concentrations. Decreased thyroidal secretion of thyroid hormone can also be caused by insufficient stimulation of the thyroid gland by TSH, due to factors directly interfering with pituitary TSH release (secondary hypothyroidism) or indirectly by diminishing hypothalamic TRH release (tertiary hypothyroidism); in clinical practice it is not always possible to discriminate between secondary and tertiary hypothyroidism, which are consequently often referred to as central hypothyroidism. In rare cases, symptoms and signs of thyroid hormone deficiency are caused by the inability of tissues to respond to thyroid hormone by mutations in the nuclear thyroid hormone receptor TR; this condition, known as thyroid hormone resistance (see Ch. 16 ), is associated with an increased thyroidal secretion of thyroid hormones and increased thyroid hormone concentrations in serum in an attempt of the body to overcome the resistance to thyroid hormone. Mutations in other genes involved with extrathyroidal metabolism and action of thyroid hormones in target tissues may also cause a hypothyroid state. Such cases could be labelled as peripheral (extrathyroidal) hypothyroidism. It thus seems more appropriate to define hypothyroidism as thyroid hormone deficiency in target tissues, irrespective of its cause.