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 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 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- 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 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 thyroxine (T4) and tri- and iodotyrosine 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 (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 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 in thyroglobulin to give MIT and DIT; other dyshormonogenetic 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 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. The diagnosis is confirmed by compounds so that iodide is the main excretion examination of the electrophoretic pattern of the product as occurs in normal individuals. The thyroid proteins, and by their ultracentrifugation defect is confirmed by showing that thyroid which reveals the presence of a light-weight tissue obtained at operation is unable to deiodi- iodoprotein. It seems likely that in time more nate added iodotyrosines in vitro. Cases have refined techniques will delineate more clearly the been described in which the thyroid gland was various anomalies that are at present included unable to deiodinate iodotyrosines but the peri- in the broad term, iodoprotein defect. pheral blood was able to do so (Kusakabe & It is at least theoretically possible that the Miyake, 1964). Presumably in this situation some finding of an abnormal iodinated protein may of the iodine liberated by peripheral deiodin- on occasion reflect not the production of an ation can be conserved provided the thyroid abnormal protein but rather be due to a defect enlarges: or, expressed in another way, the need in the proteolytic enzyme system responsible for for more iodine conservation and more frequent breaking down thyroglobulin. Two patients in recycling through the incompetent thyroid to this category have been described by Pittman & make good the loss from the thyroid of the Pittman (1966) and we consider that we have iodotyrosines leads to goitre formation. Further seen one further case in our own clinic. The work in such partial cases is required before such techniques for assessing protease activity in the a speculative explanation can be accepted as thyroid are, however, unsatisfactory. There areProtected by copyright. established. sampling problems too and it has to be remem- Our experience of the iodotyrosine deiodinase bered that the activity of only a small portion or dehalogenase defect has been in the main of the thyroid gland is measured. It seems reason- with two large kindreds (Hutchison & McGirr, able therefore to state that although it is likely 1956; Murray et al., 1965b), one of tinker stock that such a defect exists there is as yet no con- from the West of Scotland and the other, appar- clusive proof of its existence. ently unrelated, from Dumfries. In both these Despite the use of a whole variety of tech- families genetic studies showed that the defect niques available at present for the elucidation was transmitted as an autosomal recessive char- of defects in thyroid metabolism some cases re- acteristic; some of the apparently unaffected main obscure. We (Murray et al., 1966) recently relatives were shown to have minor defects in the reported a family in which goitre was apparently deiodination of MIT. The thyroid gland of one inherited through five generations in an auto- of our patients unconnected with the above fami- somal dominant fashion. All tests available to http://pmj.bmj.com/ lies showed a histological picture indicative of us were applied to the in vivo and in vitro study neoplasia (McGirr et al., 1959). Crooks, Greig of the of these patients with negative & Branwood (1963) have described a similar results. It is debatable whether they should be case. included with dyshormonogenetic cases. The Many patients have been described who pro- goitres were unusual in that even at an early age duce an abnormal iodinated protein. Indeed this they showed unusual calcification. Their histo- is the commonest defect, the did not show the and probably though logy gross generalized on September 27, 2021 by guest. reports of individual groups of workers such as hyperplasia and the pleomorphism usually asso- ourselves tend to be biased by a misleadingly ciated with dyshormonogenetic goitres. Indeed high proportion of one anomaly which by chance the picture was in many ways similar to that comes their way. Several different types of ab- seen in a long-standing non-toxic goitre in an normal iodoprotein have been reported. Instead elderly individual. of normal thyroglobulin these patients produce Dyshormonogenesis though seen in its most a protein which runs on paper electrophoresis in typical form in the group of cases we have dis- the position of serum albumin or even in ad- cussed is not an exclusive feature of inherited vance of the albumin band-pre-albumin. In intrathyroidal defects in hormone biosynthesis. some cases more than one type of abnormal Blocks of hormone synthesis with goitre forma- protein is present (Murray et al., 1965a). These tion and with or without the features of hypo- patients usually present with familial goitre and thyroidism may result from goitrogens, whether are as likely to be euthyroid as hypothyroid. naturally occurring or iatrogenic. In certain dis- Hypothyroidism due to enzyme defects 401 Postgrad Med J: first published as 10.1136/pgmj.44.511.398 on 1 May 1968. Downloaded from ease processes anomalies in synthesis are com- in a community whose thyroids have enlarged monly found. For example in Hashimoto's auto- sufficiently to be visible and palpable but who do immune thyroiditis a minor defect in organifica- not have large goitres do not appear to be iodine tion is found in about half the cases and an ab- deficient (Greig et al., 1967). This finding and normal iodoprotein in the majority (Murray & other bits of evidence including the observation McGirr, 1960). An abnormal iodoprotein may that sporadic goitres are more common in females be found in thyroid cancer and occasionally in and that hormone synthesis may be deranged in non-toxic goitre (Pitt-Rivers & Tata, 1960). them (Pitt-Rivers, Hubble & Hoather, 1957) as well as in cases of familial goitre (McGirr, 1960) Iodine deficiency indicate that factors other than iodine deficiency Iodine deficiency produces characteristic are involved in the development of sporadic changes in iodine metabolism (Wayne, Kontras goitre. & Alexander, 1964) with a low value for plasma Deficient production of TSH inorganic iodine (PII), and increased thyroid If the supply of TSH is inadequate the whole avidity for tracer doses of radioiodine. The mechanism of trapping iodine and synthesizing pattern of hormonogenesis is altered with an in- the thyroid hormones becomes defective. The creased amount of MIT relative to DIT and of thyroid becomes less avid for iodine and it has iodotyrosines relative to iodothyronines. difficulty in producing iodotyrosines, particularly Endemic goitre is the classical example of the diiodotyrosine, and iodothyronines. The mode result of severe iodine deficiency, but there are of action of TSH on the thyroid is poorly under- good reasons to believe that other factors are stood. Deficiency of TSH in the adult is likely often if not usually also involved. Genetic pre- to be accompanied by evidence of deficiency of disposition seems to be especially important in other anterior pituitary factors, particularly Protected by copyright. endemic cretinism, but there is also an individual ACTH and the gonadotrophins. Occasionally in factor as far as the goitre itself is concerned. In childhood there is an isolated of TSH endemic areas non-goitrous individuals can be deficiency shown by present-day techniques to be as iodine leading to secondary hypothyroidism. deficient as those who are goitrous (Malamos Defects in the transport of T3 and T4 et al., 1966). Furthermore up to the age of pub- The thyroid hormones travel in the peripheral erty goitre is equally common in males and blood bound to plasma proteins. The one with females but after puberty goitre is more common the highest specificity for T4 is an interalpha in females. globulin called thyroxine binding globulin (TBG) Anomalies in iodine metabolism may some- The other binding proteins are albumin, which times occur in endemic goitres but whether they has a large binding capacity but low specificity are a consequence or a cause of the cellular and thyroid binding pre-albumin (TBPA) a bind- hyperplasia is unknown. The goitre may allow ing protein running in front of albumin on paper as much inorganic iodine to leak from it as it electrophoresis. This latter protein is subject to http://pmj.bmj.com/ uses in hormone production (Ermans, Dumont alteration in acute non-thyroidal illness (Oppen- & Bastenie, 1963). Iodotyrosines are sometimes heimer et al., 1963). T3 is rather less firmly detected in the circulation, and so are butanol- bound to TBG than T4 and is not bound at all insoluble iodoproteins (Soto et al., 1967). Re- to TBPA. This is thought to account, at least cently in the sera of a group of patients studied in part, for the more rapid clinical effect of T3 in an endemic goitre region in the Argentine, as compared to T4. Soto et al. found a incidence Patients have been described with lowered TBG

(1967) very high on September 27, 2021 by guest. of positive tests for antithyroglobulin antibodies. levels in association with thyrotoxicosis (Lemar- They explained the development of goitre in chand-Beraud, Assayah & Vanotti, 1964; Cava- some individuals and not in others on the basis lieri, 1961) or without thyroid abnormality of a preestablished genetically determined, dim- (Tanaka & Starr, 1959); with increased TBG inished immunological tolerance. Whether such levels in association with hypothyroidism (Lem- findings in endemic areas are the exception or archand-Beraud et al., 1964) or without clinical the rule is obviously as yet unknown. thyroid abnormality (Florsheim et al., 1962). The In many but not all hospital patients seen in TBG level is also elevated in pregnancy and this country with sporadic goitre iodine meta- following the administration of oestrogens (in- bolism assumes an iodine deficiency pattern cluding oral contraceptives) and is lowered by (Wayne et al., 1964), which suggests that iodine drugs of the hydantoin series and by androgens. deficiency may be a significant cause of sporadic Alterations in the TBG levels do not seem to goitre. By contrast, otherwise healthy individuals be causally related to clinically abnormal thy- 402 E. M. McGirr andJohn A. Thomson Postgrad Med J: first published as 10.1136/pgmj.44.511.398 on 1 May 1968. Downloaded from roid states but are usually diagnosed by the A contrasting abnormality has been suggested finding of a PBI level in the serum which is out by Luft et al. (1962) who described a patient of keeping with the clinical status of the patient, with hypermetabolism but with a normal PB127I. thus leading to more exact estimations of the They postulated that there was a defect at the TBG capacity being performed. It must be pre- mitochondrial level which resulted in a loss of sumed that an equilibrium is reached in these capacity for respiratory control at a subcellular patients between the binding proteins of the level. plasma, the circulating free thyroxine and the Though the case material appears fragmentary cellular binding proteins which allows a normal and the investigations, by virtue of a lack of level of free thyroxine to be offered to the appropriate techniques, are limited we consider cells. that some reference to clinical problems in rela- Both diminished levels of TBG and elevated tion to hormone transport and peripheral utili- levels of TBG have been reported in several zation is desirable if for no other reason than members of a family. The pedigrees of the af- to direct attention to them and the need for fected families are consistent with each of these their more intensive study. traits being transmitted by X- linked dominant inheritance (Nikolai & Seal, 1967; Conclusions Jones & Seal, 1967). The assertion that dyshormonogenesis plays a fundamental aetiological role in the evolution of Peripheral defects thyroid dysfunction is certainly true for inherited Theoretically there could be at least three types intrathyroidal defects of hormone synthesis. Pre- of peripheral defect: sumably in these cases difficulty in hormone (1) defective binding proteins in the peripheral production leads to overactivity of the anterior tissues to accept thyroxine from the pituitary, increased production of TSH with con-Protected by copyright. plasma sequent thyroid hyperplasia and enlargement which (2) failure of the mechanism for transporting in greater or lesser degree compensates for its the hormones across the cell membrane to fundamental inefficiency. We find as a result the the site of action clinical conditions of familial goitre or sporadic (3) failure of the peripheral tissues to respond (non-endemic) goitrous cretinism and hypothyroi- There are no techniques at present available dism. by which such mechanisms may be studied and Where the dyshormonogenesis is a result of defects detected and elucidated. Our shortcom- or is associated with other conditions such as ings are unfortunate as there certainly seem to be Hashimoto's autoimmune thyroiditis or iodine patients, as some of the following examples deficiency the aetiological contribution of the show, who have some peripheral defect which dyshormonogenesis to the clinical and metabolic cannot at present be clearly delineated. A peri- status of the affected individual is uncertain. It pheral defect was suggested by us (Hutchison, is, however, important to an understanding of http://pmj.bmj.com/ Arneil & McGirr, 1957) to be present in a cretin the pathogenesis of such conditions that we who failed to respond to dry thyroid, which we should be aware that there may be an accom- had good reason to believe was potent, but re- panying derangement in thyroid function and sponded to triiodothyronine. Unfortunately the that in appropriate circumstances we should be response to thyroxine was not tested. prepared to study it with a view to assessing its Recently we described patients with dyshor- significance and relationship to the primary con- of the deiodi- monogenetic goitres iodotyrosine dition. on September 27, 2021 by guest. nase (dehalogenase) type, who showed abnormal Theoretical considerations suggest that more handling of intravenously administered s3lI-T4 thought and investigational effort should be de- without there being any significant change in voted to the study of hormone transport and TBG levels (Thomson & Wallace, 1966). peripheral utilization. Past investigations, parti- An apparent lack of response to the circulat- cularly in the latter field, have been hampered ing thyroid hormones has been noted as a fami- by inadequate techniques. Undoubtedly defects lial disorder in several members of a family who of transport occur and there is evidence that had high PB127I and BE127I levels, who were some of them are hereditary. So far, however, euthyroid, and who had normal TBG levels they have not been shown to be responsible for (Refetoff, De Wind & De Groot, 1967). These goitre production or hypothyroidism. Most if findings were associated with stippled epiphyses, not all of the reports which suggest defects in which could not be related to a previous episode utilization have so far been more speculative than of hypothyroidism, and with deaf-mutism. factual. Hypothyroidism due to enzyme defects 403 Postgrad Med J: first published as 10.1136/pgmj.44.511.398 on 1 May 1968. Downloaded from References MURRAY, I.P.C., THOMSON, J.A., MCGIRR, E.M., WALLACE, CAVALIERI, R.R. (1961) Hyperthyroidism and decreased T.J., MACDONALD, E.M. & MACCABE, H.J. (1956b) Absent thyroxine binding by serum proteins. J. clin. 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