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Hypothyroidism Due to Enzyme Defects E Postgrad. med. J. (May 1968) 44, 398-403. Postgrad Med J: first published as 10.1136/pgmj.44.511.398 on 1 May 1968. Downloaded from Hypothyroidism due to enzyme defects E. M. McGIRR JOHN A. THOMSON B.Sc., M.D., F.R.C.P. (Lond., Glasg. and Edin.) M.B., M.R.C.P.(Lond.), M.R.C.P.(Glasg.) Professor of Medicine, Muirhead Chair Senior Registr,ar University Department ofMedicine, Royal Infirmary, Glasgow, C.4 Summary renders them incapable of responding to normal Defects in thyroid hormone production, trans- levels of T4 and T8 in the blood. port and utilization are classified. Whatever the cause the clinical features of Particular attention is given to inherited intra- hypothyroidism are identical. They are, however, thyroidal defects in hormone synthesis which modified by the age of the patient. If hypo- impair thyroid function and lead to goitre thyroidism develops in utero or the early months formation and hypothyroidism. Anomalies in bio- after birth mental retardation as well as physical synthesis may also result from disease or drugs. stunting may result unless the condition is quicky Reference is made to the derangement of recognized and adequate treatment instituted. iodine metabolism that results from iodine de- While the common 'athyroidic' or 'dysgenetic' ficiency and from insufficient TSH. cretin and adult patient with primary hypo- Protected by copyright. Illustrative clinical problems with regard to thyroidism are non-goitrous, the patient whose transport and utilization are quoted, and it is condition is due to enzymatic dyshormono- inferred that they lie in rather neglected areas. genesis is goitrous. Some patients with dyshor- Throughout an attempt has been made to show monogenesis remain euthyroid, while others be- how the clinical problems that are encountered come hypothyroid, presumably depending on the in practice may, by the techniques of investiga- severity of their defect. Most cases are familial tion available to us, be related to the theoretical and where data are sufficient the evidence favours list of defects that are included in the classifi- the opinion that the defects are inherited as cation. simple recessive autosomal characteristics. Cer- tainly such a conclusion is fully justified for the Introduction organification (Fraser, Morgans & Trotter, 1960) The thyroid hormones thyroxine (T4) and tri- and iodotyrosine deiodinase or dehalogenase iodothyronine (T3) play a dominant role in con- Hutchison and McGirr, 1956) defects. http://pmj.bmj.com/ trolling metabolism and are essential for normal The various defects postulated in the synthesis, growth and development in childhood. The clini- transport and utilization of the thyroid hormones cal features and laboratory findings indicative of may be classified as follows. hypothyroidism appear when the amounts of these hormones available to organs, tissues and A. Defects in biosynthesis cells are insufficient. (a) Intrathyroidal defects: these may be due The term dyshormonogenesis implies a dis- to: turbance of normal hormone production. While 1. defective trapping of iodide by the thy- on September 27, 2021 by guest. it may be due to lack of the driving force of roid gland thyrotrophin (TSH), as in pituitary hypothyroid- 2. defective organification and utilization of ism, or to insufficiency of dietary iodine, as in the iodine to form monoidotyrosine (MIT) endemic cretinism, it is especially applied to and diiodotyrosine (DIT) those patients whose condition is due to a defect 3. defective coupling of MIT and DIT to in the intrathyroidal mechanisms, in particular form T3 and T4 to those whose condition is due to an inherited 4. defective deiodination of MIT and DIT anomaly in thyroid hormone synthesis. Theo- with their consequent loss in the urine retically, hypothyroidism may also result from a due to iodotyrosine deiodinase deficiency defect in the mechanism for transporting T4 and 5. defective production of thyroglobulin T3 from the thyroid gland to the peripheral with the formation of an abnormal iodi- tissues, and from a defect in tissue cells which nated protein to 399 Hypothyroidism due enzyme defects Postgrad Med J: first published as 10.1136/pgmj.44.511.398 on 1 May 1968. Downloaded from 6. defective proteolysis of thyroglobulin iodide to penetrate the thyroid cell by passive 7. miscellaneous and ill-defined defects diffusion and so allow sufficient hormone to be (b) Iodine deficiency produced to make the patient euthyroid. (c) Deficient production of TSH Failure of organification was the first defect of and T3 from to be described by Stanbury & Hedge (1950). B. Defects in the transport T4 after the administration of the thyroid gland to the peripheral tissues It is readily detected 1. plasma binding proteins increased radioiodine. The iodine which has been accumu- decreased lated but not utilized to form MIT and DIT is 2. plasma binding proteins easily dischargeable by perchlorate or thiocy- C. Defects in the tissue cells anate. There appears to be a defect in the per- 1. ? deficiency of cellular binding proteins oxidase enzyme system. Failure of organification 2. ? failure of mechanism for transportation may be associated with a high tone nerve deaf- of T4 and T3 across the cell membrane. ness (Pendred's syndrome). Patients with Pen- 3. ? refractory end organ response by the dred's syndrome frequently remain euthyroid. tissues. Defective coupling of MIT and DIT has In this paper we propose in the main to dis- been occasionally and tentatively propounded cuss intrathyroidal defects in thyroid hormone (Stanbury, Ohela & Pitt-Rivers, 1955; Stanbury, synthesis. We shall, however, briefly refer to the 1966). The precise details of coupling are un- other topics where they appear to us relevant to known. It has never been shown to be an enzy- our theme. matic process, and indeed it may depend upon the molecules of MIT and DIT being in the Intrathyroidal defects correct geometric positions on the thyroglobulin The stages involved in the production of T3 molecule. Such an arrangement could well be and T4 are fairly well understood in broad out- upset if the thyroglobulin molecule was abnor- Protected by copyright. line, although the minute details of the processes mal, or if the gland was very iodine deficient involved are not. It is envisaged that iodine is resulting in the molecules of MIT and DIT being trapped by the thyroid probably in the form of too far apart to permit their coupling (Joseph iodide; that iodide is then oxidized to some & Job, 1958). This latter explanation seems un- 'active' form of iodine which is then bound to likely because the coupling process is normal in tyrosine in thyroglobulin to give MIT and DIT; other dyshormonogenetic goitres which are just as that MIT and DIT are then joined together to iodine deficient. Other mechanisms of coupling give To and T4 within the thyroglobulin mole- have been postulated. For example it has been cule. As hormone is required the thyroglobulin suggested that coupling may occur between one is broken down by proteolytic enzymes to re- molecule of DIT and one of diiodophenyl- lease T3 and T4 which pass into the peripheral pyruvic acid (DIIPPA). We ourselves have seen blood. MIT and DIT are also released by a a patient with a presumptive coupling defect with similar mechanism but their iodine is removed a pattern of iodoamino acids in the thyroid con- http://pmj.bmj.com/ by a special enzyme (iodotyrosine deiodinase or sistent with the presence of the pyruvic acid ana- dehalogenase) and is conserved for re-use within logues of the iodotyrosines (Murray et al., 1965a). the thyroid. Recently Surks, Weinbach & Volpert (1967) have Defective iodine trapping is a very rare cause described DIIPPA in the rat thyroid. In practice of goitrous hypothyroidism having been des- most cases claimed to have a coupling defect cribed on only two occasions (Stanbury & Chap- have been examples of goitrous hypothyroidism man, 1960; Wolff, Thomson & Robbins, 1964). in which other known defects of thyroid hor- This defect is diagnosed by demonstrating the mone synthesis have been eliminated. The thy- on September 27, 2021 by guest. absence of significant accumulation of radio- roid glands at operation 48-72 hr after radio- iodine in the thyroid area. The salivary glands iodine administration have been shown to con- also normally trap iodine. In patients with the tain abundant MIT and DIT but little or no trapping defect the salivary glands are also de- T3 or T4. Otherwise the diagnosis has been made fective in this function. The ratio of the radio- on the basis of negative criteria. A more positive activity of a sample of saliva and of plasma diagnostic approach awaits eludication of the obtained simultaneously after a tracer dose of coupling mechanism. radioiodine in them is approximately unity When the iodotyrosine enzyme system is de- whereas in normal subjects it is about 20: 1. fective MIT and DIT escape in large amounts The administration of potassium iodide in phar- from the thyroid gland into the blood and thence macological doses may raise the plasma inorganic into the urine taking their iodine with them. iodide of such a patient sufficiently to permit Individuals with this defect constituted the first 400 E. M. McGirr and John A. Thomson Postgrad Med J: first published as 10.1136/pgmj.44.511.398 on 1 May 1968. Downloaded from group of patients with dyshormonogenesis seen Radioiodine studies give a 'thyrotoxic' pattern by the authors. The precise diagnosis is readily of rapid trapping of 131! and an elevated pro- made by demonstrating that such subjects ex- tein-bound 131I (PB31!I) at 48 hr. The crete in the urine a substantial amount of orally PB81I consists of an abnormal iodinated pro- or intravenously administered M131T or D131T tein which cannot be extracted with butanol: the as iodotyrosine and do not break down these BE'31! is low.
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