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Thyroid Autoimmune Disease: a Broad Spectrum
874
against fatal arrhythmias is challenging and important. It will be a pity if these suggestive results cannot be put firmer basis. Those who conducted this trial are to be congratulated on an excellent study with a splendid result. They have shown beyond reasonable doubt that, in these patients, timolol achieved a major reduction in deaths, and possibly in the rate of reinfarction. The full implications are clearly far-reaching, but it would be a mistake to predict them at this stage. Experience with earlier large trials has taught us the danger of hasty judgments. There now begins for the timolol trial an important process of questioning and debate, aided (one hopes) by a further and more detailed report. Until this process has taken place, conclusions must at best be on a
incomplete. The findings are based on a broad cross-section of Norwegian hospital cases of confirmed myocardial infarction, which are likely to be generally similar to those in other countries. The trial cases, however, amounted to no more than 17% of all patients admitted with suspected infarction. The beneficial findings of this trial do not necessarily apply to unconfirmed cases of infarction, including those treated at home without full investigation. Earlier trials have shown that home care of suspected infarction can often be a reasonable option;9,10 the timolol results imply an added need to establish the diagnosis, for beta-blockers can have potentially dangerous effects on blood pressure, sinoatrial and atrioventricular conduction, and cardiac failure. They are not drugs to be given without good cause.
Has timolol now been shown to be superior to other beta-blockers for myocardial infarction survivors? Certainly the results show that intrinsic sympathomimetic activity (which timolol lacks) is not essential to the benefit, but we cannot yet answer questions on the importance in this situation of other differences between beta-blockers, in pharmacokinetics, pharmacodynamics, and dosage. The various trials are not comparable in terms of the age and severity of cases, the interval between onset (or hospital admission) and start of treatment, dosages, or duration; nor anyway is there a statistically significant difference between their outcomes. One can, however, say that so far only timolol and alprenolol are of demonstrated value for myocardial infarction survivors. Questions of dosage and duration of treatment remain unresolved. The results of this post-infarction trial should not be extrapolated to the very different situation of hypertension treatment. Timolol is a useful antihypertensive; but there is no evidence that this or any other beta-blocker reduces the coronary risk in hypertension. If the conclusions of the timolol trial survive the 9. Mather
HG, Morgan DC, Pearson NG, Read KLQ, Shaw DB, Steed GAR, Thorne MG, Lawrence CJ, Riley IS. Myocardial infarction: a comparison between home and hospital care for patients. Br Med 1976; i: 925-29. J 10. Hill JD, Hampton JR, Mitchell JRA. A randomised trial of home-versus-hospital management for patients with suspected myocardial infarction. Lancer 1978; i: 837-41.
process of intensive scrutiny which they will now face, a beta-blocker (timolol or alternative) will become a part of the normal care given to many myocardial infarction survivors, in the absence of a reason to the contrary. That being so, then in trials of other forms of treatment-such as platelet-acting drugs-timolol or some other appropriate beta-blocker would either have to replace placebos or would have to be available to all
trial
participants.
Thyroid Autoimmune Disease: a Broad Spectrum hyperthyroidism of Graves’ disease is almost certainly due to thyroid stimulating immunoglobulins.’ When TSI are detected by assays that measure stimulation of the adenyl cyclase systemprobably the pathway by which pituitary thyrotropin (TSH) and TSI act on the rate of T3/T4 synthesis-the results correlate well with clinical signs of thyroTHE
toxicosis and with recurrence rates after treatment,2,3 Blocking antibodies directed against TSH receptors were first identified by ORGIAZZI et a1.,4 who found that some immunoglobulins from thyrotoxic patients inhibited the rise in cyclic AMP normally evoked by addition of TSH to thyroid membranes. These blocking antibodies also inhibited the cyclic AMP produced in response to "human thyroid adenyl cyclase stimulators" (HTACS). (Since no-one now believes that the effects are confined to man,5 these TSH-Rantibodies are best included under the term TSI, the
corresponding blocking antibodies being designated TSI-block.) TSI-block was identified clinically by ENDO and co-workers6 in a patient with primary myxoedema, and the same team’ later showed that TSI-block could be transmitted via the placenta from a myxoedematous mother to her offspring, causing a temporary neonatal hypothyroidism in the same way that TSI cause neonatal thyrotoxicosis.8 This was presumably the mechanism in the family studied by GOLDSMITH et al.,9 in which a woman with 1.
2.
3. 4.
5.
6.
7.
8.
9.
Zacharija M, McKenzie JM. The thyroid stimulating antibody of Graves’ disease its assay, some physicochemical characteristics and clinical significance. In: Pinchera et al, eds. Autoimmune aspects of endocrine disorders. London: Academic Press. 1980: 83-89. McGregor AM, Smith RB, Hall R, Peterson MM, Miller M, Dewar PJ. Prediction of relapse in hyperthyroid Graves’ disease. Lancet 1980; i:1101-03. Zacharija M, McKenzie MJ, Banovac K. Clinical significance of thyroid stimulating antibody in Graves’ disease. Ann Intern Med 1980; 93: 28-32. Orgiazzi J, Williams DE, Chopra IJ, Solomon DH. Human thoroid adenyl-cyclase stimulating activity in immunoglobulin G of patients with Graves’ disease J Clin Endocr Metab 1976; 42: 341-48. McKenzie JM, Zacharija M. A reconstruction of a thyroid stimulating immunoglobulin as the cause of hyperthyroidism in Graves’ disease. J Clin Endor Metab 1976; 42: 778-81. Endo K, Kasagi K, Konishi J. Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves’ disease and Hashimoto’s thyroiditis J Clin Endocr Metab 1978; 46: 734-39. Matsuura N, Yamada Y, Nohara Y, Konishi J, Kasagi K, Endo K, Kojima H, Watava K Familial neonatal transient hypothyroidism due to maternal TSH-binding inhibitor immunoglobulins. N Engl J Med 1980; 303: 738-41. Munro DS, Dirmikis SM, Humphries H, Smith T, Boradhead GD The role of thyroid stimulating immunoglobulins of Graves’ disease in neonatal thyrotoxicosis Br J Obstet Gynaecol 1978; 85: 837-43. Goldsmith RE, McAdams AG, Larsen PR, McKenzie M, Hess EV. Familial autoimmune thyroiditis: maternal-fetal relationship and the role of generalized autoimmunity. J Clin Endocr Metab 1973; 37: 265-75.
875
myxoedema had six babies of whom four were shown to have transient hypothyroidism (the other two died a few days after birth). In Graves’ disease there is a striking discrepancy between the degree of hyperthyroidism and goitre size; 10% of patients, some of them very thyrotoxic, have no goitre at all, suggesting that function and growth of the gland are probably controlled by different stimulators. Furthermore, in some goitrous patients with a family history of thyroid autoimmunity the goitre is diffuse or nodular and non-toxic, and the response to the TSH releasing hormone (TRH) test is blunted or absent. This observation led to the hypothesis that some forms of thyroid hyperplasia are due to separate growthpromoting antibodies 10-thyroid growth immunoglobulins (TGI)-and such antibodies have now been detected in a bioassay employing guineapig thyroid in the of segments cultured presence immunoglobulin." The growth stimulating effect was demonstrated by two cytochemical methods.12,13The immunoglobins perhaps act through an intracellular pathway which stimulates division in thyroid cells without affecting hormone synthesis. The two parallel functions of pituitary TSH itself can now likewise be
dissociated experimentally. 14 In view of the evidence for separate antigenic sites for TSI and TGI and the data on TSI-block, DREXHAGE and co-workers devised a means of looking for TGIblock in primary myxoedema. Immunoglobulins from myxoedema patients with atrophic thyroiditis had no effect on DNA synthesis by themselves; however, when both TSH and the immunoglobulins were incubated with thyroid segments there was blocking of the growth effect usually seen with TSH alone.15If in the cases of ENDO and co-workers6,7 it was TSI-block that prevented the thyroid responding to increased output of pituitary TSH, then it is equally likely that TGIblock will cause the gland to become atrophic. Obviously some patients with myxoedema will have both growth-blocking and cyclic-AMP-blocking immunoglobulins, but TGI-block seems to be more common than TSI-block in this disease. Nor does the complexity end here, since some sera block growth and yet stimulate the production and release of thyroid hormones in vitro.16 10. Doniach D. Clinical observations and hypotheses related to TSH-receptors. In: Muhlen A, Schleusener H, eds. Biochemical basis of thyroid stimulation and thyroid hormone action. Stuttgart: George Thieme, 1976: 24-34. 1 . Drexhage HA, Bottazzo GF, Domach D, Bitensky L, Chayen J. Evidence for thyroidgrowth-stimulating immunoglobulins in some goitrous thyroid diseases. Lancet 1980; ii: 287-92. 12. Sandritter WA.A review of nucleic acid cytophotometryingeneralpathology.In:Pattison JR, Bitensky L, Chayen J, eds. Quantitative cytochemistry. London: Academic Press, 1979: 1 13. Drexhage HA, Hammond LJ, Bitensky L, Chayen J, Bottazzo GF, Doniach D. The involvement of the pentose shunt in thyroid metabolism after stimulation with TSH or with immunoglobulins from patients with thyroid disease. I. The generation of NADPH in relation to stimulation of thyroid growth. Clin Endocrinol (in press). 4. Dumont JE, Lamy F The regulation of thyroid cell metabolism function, growth and differentiation In: De Visscher M. ed. The thyroid gland. New York: Raven Press, 1980 153-67.
15. Drexhage HA, Bottazzo GF, Bitensky L, Chayen J, Doniach D.Thyroid growth-blocking antibodies
in
primary
myxoedema. Nature 1981; 289:
594-96.
16. Drexhage HA, Hammond LJ, Bitensky L, Chayen J, Bottazzo GF, Doniach D. The involvement ofthe pentose shunt in thyroid metabolism after stimulation with TSH or with immunoglobulins from patients with thyroid disease.II. The reoxidation of NADPH and stimulation of hormone synthesis. Clin Endocrinol (in press).
This
information on TSH-receptor antibodies has thrown light on the strange behaviour of thyroid function indices in autoimmunity. Syndromes such as "hashitoxicosis" result from a mixture of different antibodies. Patients who are toxic and have no goitre possess mostly TSI and no TGI, while some who have euthyroid goitres have mainly TGI and occasionally TSI.17 In Hashimoto’s goitre the main stimulus to thyroid growth is probably TSH itself, in addition to the sheer volume of the immunocytes which infiltrate the gland. However, lymphadenoid goitres that recur after operation or which are resistant to T4 replacement have TGI in addition to the usual microsomal and thyroglobulin antibodies.11,18 In primary myxoedema the tissue distruction is brought about by cytotoxic antibodies and cell-mediated immunity, as in Hashimoto’s goitre; but, owing to blocking antibodies, the gland is unable to regenerate in response to the raised output of TSH. We should now be able to distinguish between the pathogenesis of goitrous (Hashimoto) thyroiditis and that of atrophic autoimmune thyroiditis, since Hashimoto patients have no blocking antibodies.15HLA typing suggests that these two forms of autoimmune thyroiditis differ in their genetic background, since primary myxoedema is associated with an excess of DR3 whereas in goitrous thyroiditis DR5 seems to be predominant.19 Perhaps the most important message is that the autoimmune response is polyclonal and each patient may produce a great variety ofautoantibodies of different specificities, sometimes with opposing effects on thyroid function. Variations in this complex immune response probably account for the fluctuations in clinical activity so familiar in this group of disorders. new
Cimetidine Now THE histamine H2-receptor blocking agent cimetidine has been generally available in Britain for four years. The manufacturers have had a runaway commercial success with the drug, though this partly reflects initial enthusiastic but inappropriate usage by doctors: the practice of hospital gastroenterology was quite distorted for a time by the referral of numerous patients whose dyspepsia had been treated with cimetidine without initial investigation. Evaluation of such individuals is difficult and their diagnosis and correct management is usually delayed by this approach. Last month many of the leading workers in cimetidine research gathered at the Royal College of Physicians of London to make a fresh appraisal of the drug. There is now a clearer picture as to where the usefulness of cimetidine is definite, where it is doubtful, and where it is disproved. RS, Jackson IMD, Ponl SL, Reichlin S. Do thyroid stimulating immunoglobulins cause non-toxic and toxic multinodular goitre? Lancet 1978; i. 904-06 18. Doniach D, Cudworth AG, Khoury EL, Bottazzo GF Autoimmunity and the HLAsystem in endocrine diseases. In: O’Riordan JLH, ed. Recent advances in endocrinology and metabolism. Edinburgh. Churchill Livingstone (in press). 19. Weissel M, Hoffer R, Zasmeta H, Mayr WR. HLA-DR and Hashimoto’s thyroiditis. Tissue Antigens 1980; 16: 256-57. 17. Brown
against fatal arrhythmias is challenging and important. It will be a pity if these suggestive results cannot be put firmer basis. Those who conducted this trial are to be congratulated on an excellent study with a splendid result. They have shown beyond reasonable doubt that, in these patients, timolol achieved a major reduction in deaths, and possibly in the rate of reinfarction. The full implications are clearly far-reaching, but it would be a mistake to predict them at this stage. Experience with earlier large trials has taught us the danger of hasty judgments. There now begins for the timolol trial an important process of questioning and debate, aided (one hopes) by a further and more detailed report. Until this process has taken place, conclusions must at best be on a
incomplete. The findings are based on a broad cross-section of Norwegian hospital cases of confirmed myocardial infarction, which are likely to be generally similar to those in other countries. The trial cases, however, amounted to no more than 17% of all patients admitted with suspected infarction. The beneficial findings of this trial do not necessarily apply to unconfirmed cases of infarction, including those treated at home without full investigation. Earlier trials have shown that home care of suspected infarction can often be a reasonable option;9,10 the timolol results imply an added need to establish the diagnosis, for beta-blockers can have potentially dangerous effects on blood pressure, sinoatrial and atrioventricular conduction, and cardiac failure. They are not drugs to be given without good cause.
Has timolol now been shown to be superior to other beta-blockers for myocardial infarction survivors? Certainly the results show that intrinsic sympathomimetic activity (which timolol lacks) is not essential to the benefit, but we cannot yet answer questions on the importance in this situation of other differences between beta-blockers, in pharmacokinetics, pharmacodynamics, and dosage. The various trials are not comparable in terms of the age and severity of cases, the interval between onset (or hospital admission) and start of treatment, dosages, or duration; nor anyway is there a statistically significant difference between their outcomes. One can, however, say that so far only timolol and alprenolol are of demonstrated value for myocardial infarction survivors. Questions of dosage and duration of treatment remain unresolved. The results of this post-infarction trial should not be extrapolated to the very different situation of hypertension treatment. Timolol is a useful antihypertensive; but there is no evidence that this or any other beta-blocker reduces the coronary risk in hypertension. If the conclusions of the timolol trial survive the 9. Mather
HG, Morgan DC, Pearson NG, Read KLQ, Shaw DB, Steed GAR, Thorne MG, Lawrence CJ, Riley IS. Myocardial infarction: a comparison between home and hospital care for patients. Br Med 1976; i: 925-29. J 10. Hill JD, Hampton JR, Mitchell JRA. A randomised trial of home-versus-hospital management for patients with suspected myocardial infarction. Lancer 1978; i: 837-41.
process of intensive scrutiny which they will now face, a beta-blocker (timolol or alternative) will become a part of the normal care given to many myocardial infarction survivors, in the absence of a reason to the contrary. That being so, then in trials of other forms of treatment-such as platelet-acting drugs-timolol or some other appropriate beta-blocker would either have to replace placebos or would have to be available to all
trial
participants.
Thyroid Autoimmune Disease: a Broad Spectrum hyperthyroidism of Graves’ disease is almost certainly due to thyroid stimulating immunoglobulins.’ When TSI are detected by assays that measure stimulation of the adenyl cyclase systemprobably the pathway by which pituitary thyrotropin (TSH) and TSI act on the rate of T3/T4 synthesis-the results correlate well with clinical signs of thyroTHE
toxicosis and with recurrence rates after treatment,2,3 Blocking antibodies directed against TSH receptors were first identified by ORGIAZZI et a1.,4 who found that some immunoglobulins from thyrotoxic patients inhibited the rise in cyclic AMP normally evoked by addition of TSH to thyroid membranes. These blocking antibodies also inhibited the cyclic AMP produced in response to "human thyroid adenyl cyclase stimulators" (HTACS). (Since no-one now believes that the effects are confined to man,5 these TSH-Rantibodies are best included under the term TSI, the
corresponding blocking antibodies being designated TSI-block.) TSI-block was identified clinically by ENDO and co-workers6 in a patient with primary myxoedema, and the same team’ later showed that TSI-block could be transmitted via the placenta from a myxoedematous mother to her offspring, causing a temporary neonatal hypothyroidism in the same way that TSI cause neonatal thyrotoxicosis.8 This was presumably the mechanism in the family studied by GOLDSMITH et al.,9 in which a woman with 1.
2.
3. 4.
5.
6.
7.
8.
9.
Zacharija M, McKenzie JM. The thyroid stimulating antibody of Graves’ disease its assay, some physicochemical characteristics and clinical significance. In: Pinchera et al, eds. Autoimmune aspects of endocrine disorders. London: Academic Press. 1980: 83-89. McGregor AM, Smith RB, Hall R, Peterson MM, Miller M, Dewar PJ. Prediction of relapse in hyperthyroid Graves’ disease. Lancet 1980; i:1101-03. Zacharija M, McKenzie MJ, Banovac K. Clinical significance of thyroid stimulating antibody in Graves’ disease. Ann Intern Med 1980; 93: 28-32. Orgiazzi J, Williams DE, Chopra IJ, Solomon DH. Human thoroid adenyl-cyclase stimulating activity in immunoglobulin G of patients with Graves’ disease J Clin Endocr Metab 1976; 42: 341-48. McKenzie JM, Zacharija M. A reconstruction of a thyroid stimulating immunoglobulin as the cause of hyperthyroidism in Graves’ disease. J Clin Endor Metab 1976; 42: 778-81. Endo K, Kasagi K, Konishi J. Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves’ disease and Hashimoto’s thyroiditis J Clin Endocr Metab 1978; 46: 734-39. Matsuura N, Yamada Y, Nohara Y, Konishi J, Kasagi K, Endo K, Kojima H, Watava K Familial neonatal transient hypothyroidism due to maternal TSH-binding inhibitor immunoglobulins. N Engl J Med 1980; 303: 738-41. Munro DS, Dirmikis SM, Humphries H, Smith T, Boradhead GD The role of thyroid stimulating immunoglobulins of Graves’ disease in neonatal thyrotoxicosis Br J Obstet Gynaecol 1978; 85: 837-43. Goldsmith RE, McAdams AG, Larsen PR, McKenzie M, Hess EV. Familial autoimmune thyroiditis: maternal-fetal relationship and the role of generalized autoimmunity. J Clin Endocr Metab 1973; 37: 265-75.
875
myxoedema had six babies of whom four were shown to have transient hypothyroidism (the other two died a few days after birth). In Graves’ disease there is a striking discrepancy between the degree of hyperthyroidism and goitre size; 10% of patients, some of them very thyrotoxic, have no goitre at all, suggesting that function and growth of the gland are probably controlled by different stimulators. Furthermore, in some goitrous patients with a family history of thyroid autoimmunity the goitre is diffuse or nodular and non-toxic, and the response to the TSH releasing hormone (TRH) test is blunted or absent. This observation led to the hypothesis that some forms of thyroid hyperplasia are due to separate growthpromoting antibodies 10-thyroid growth immunoglobulins (TGI)-and such antibodies have now been detected in a bioassay employing guineapig thyroid in the of segments cultured presence immunoglobulin." The growth stimulating effect was demonstrated by two cytochemical methods.12,13The immunoglobins perhaps act through an intracellular pathway which stimulates division in thyroid cells without affecting hormone synthesis. The two parallel functions of pituitary TSH itself can now likewise be
dissociated experimentally. 14 In view of the evidence for separate antigenic sites for TSI and TGI and the data on TSI-block, DREXHAGE and co-workers devised a means of looking for TGIblock in primary myxoedema. Immunoglobulins from myxoedema patients with atrophic thyroiditis had no effect on DNA synthesis by themselves; however, when both TSH and the immunoglobulins were incubated with thyroid segments there was blocking of the growth effect usually seen with TSH alone.15If in the cases of ENDO and co-workers6,7 it was TSI-block that prevented the thyroid responding to increased output of pituitary TSH, then it is equally likely that TGIblock will cause the gland to become atrophic. Obviously some patients with myxoedema will have both growth-blocking and cyclic-AMP-blocking immunoglobulins, but TGI-block seems to be more common than TSI-block in this disease. Nor does the complexity end here, since some sera block growth and yet stimulate the production and release of thyroid hormones in vitro.16 10. Doniach D. Clinical observations and hypotheses related to TSH-receptors. In: Muhlen A, Schleusener H, eds. Biochemical basis of thyroid stimulation and thyroid hormone action. Stuttgart: George Thieme, 1976: 24-34. 1 . Drexhage HA, Bottazzo GF, Domach D, Bitensky L, Chayen J. Evidence for thyroidgrowth-stimulating immunoglobulins in some goitrous thyroid diseases. Lancet 1980; ii: 287-92. 12. Sandritter WA.A review of nucleic acid cytophotometryingeneralpathology.In:Pattison JR, Bitensky L, Chayen J, eds. Quantitative cytochemistry. London: Academic Press, 1979: 1 13. Drexhage HA, Hammond LJ, Bitensky L, Chayen J, Bottazzo GF, Doniach D. The involvement of the pentose shunt in thyroid metabolism after stimulation with TSH or with immunoglobulins from patients with thyroid disease. I. The generation of NADPH in relation to stimulation of thyroid growth. Clin Endocrinol (in press). 4. Dumont JE, Lamy F The regulation of thyroid cell metabolism function, growth and differentiation In: De Visscher M. ed. The thyroid gland. New York: Raven Press, 1980 153-67.
15. Drexhage HA, Bottazzo GF, Bitensky L, Chayen J, Doniach D.Thyroid growth-blocking antibodies
in
primary
myxoedema. Nature 1981; 289:
594-96.
16. Drexhage HA, Hammond LJ, Bitensky L, Chayen J, Bottazzo GF, Doniach D. The involvement ofthe pentose shunt in thyroid metabolism after stimulation with TSH or with immunoglobulins from patients with thyroid disease.II. The reoxidation of NADPH and stimulation of hormone synthesis. Clin Endocrinol (in press).
This
information on TSH-receptor antibodies has thrown light on the strange behaviour of thyroid function indices in autoimmunity. Syndromes such as "hashitoxicosis" result from a mixture of different antibodies. Patients who are toxic and have no goitre possess mostly TSI and no TGI, while some who have euthyroid goitres have mainly TGI and occasionally TSI.17 In Hashimoto’s goitre the main stimulus to thyroid growth is probably TSH itself, in addition to the sheer volume of the immunocytes which infiltrate the gland. However, lymphadenoid goitres that recur after operation or which are resistant to T4 replacement have TGI in addition to the usual microsomal and thyroglobulin antibodies.11,18 In primary myxoedema the tissue distruction is brought about by cytotoxic antibodies and cell-mediated immunity, as in Hashimoto’s goitre; but, owing to blocking antibodies, the gland is unable to regenerate in response to the raised output of TSH. We should now be able to distinguish between the pathogenesis of goitrous (Hashimoto) thyroiditis and that of atrophic autoimmune thyroiditis, since Hashimoto patients have no blocking antibodies.15HLA typing suggests that these two forms of autoimmune thyroiditis differ in their genetic background, since primary myxoedema is associated with an excess of DR3 whereas in goitrous thyroiditis DR5 seems to be predominant.19 Perhaps the most important message is that the autoimmune response is polyclonal and each patient may produce a great variety ofautoantibodies of different specificities, sometimes with opposing effects on thyroid function. Variations in this complex immune response probably account for the fluctuations in clinical activity so familiar in this group of disorders. new
Cimetidine Now THE histamine H2-receptor blocking agent cimetidine has been generally available in Britain for four years. The manufacturers have had a runaway commercial success with the drug, though this partly reflects initial enthusiastic but inappropriate usage by doctors: the practice of hospital gastroenterology was quite distorted for a time by the referral of numerous patients whose dyspepsia had been treated with cimetidine without initial investigation. Evaluation of such individuals is difficult and their diagnosis and correct management is usually delayed by this approach. Last month many of the leading workers in cimetidine research gathered at the Royal College of Physicians of London to make a fresh appraisal of the drug. There is now a clearer picture as to where the usefulness of cimetidine is definite, where it is doubtful, and where it is disproved. RS, Jackson IMD, Ponl SL, Reichlin S. Do thyroid stimulating immunoglobulins cause non-toxic and toxic multinodular goitre? Lancet 1978; i. 904-06 18. Doniach D, Cudworth AG, Khoury EL, Bottazzo GF Autoimmunity and the HLAsystem in endocrine diseases. In: O’Riordan JLH, ed. Recent advances in endocrinology and metabolism. Edinburgh. Churchill Livingstone (in press). 19. Weissel M, Hoffer R, Zasmeta H, Mayr WR. HLA-DR and Hashimoto’s thyroiditis. Tissue Antigens 1980; 16: 256-57. 17. Brown