1128 B-LYMPHOCYTE ALLOANTIGENS AND INSULIN-DEPENDENT DIABETES MELLITUS
SIR,-Viral infections and autoimmune processes, possibly on a genetic susceptibility, have been implicated in the
based
highly complex pathogenesis of insulin-dependent diabetes (I.D.D.).’ This disorder was positively correlated with HLA B8, Bwl5, Cw3, Dw3 and Dw4 and negatively correlated with B5 and B7.’’ Some genes of the major histocompatibility system (M.H.C.) influence anti-insulin antibody formation7-9 and antiIa -TYPE ALLOANTIGENS IN INSULIN-DEPENDENT DIABETES
MELLITUS
islet cell antibody persistencel0 and may be selecting factors for late diabetic manifestations. Certain genes within the M.HC. code for alloantigens (la-type antigens) found on B lymphocytes which are identical to, or closely-linked with, genes which code for immune-responsiveness to a variety of antigens. Tests for seven specificities of these la-type alloantigens (DRwl-DRw7) were carried out on cells from 50 I.D.D. patients and 107 controls using a lymphocytotoxicity techni-
que.6 A significantly increased frequency of
DRw3 and DRw4 was observed in I.D.D. patients compared with the controls (see table). Individuals positive for DRw3 carry a 4.5-fold increased risk (calculated according to Woolf") and those positive for DRw4 a 2. 5-fold increased risk of developing I.D.D. The la-type alloantigen DRw3 is more closely associated with I.D.D. than all previously-investigated M.H.c.-associated antigens and we are now examining the influence of these Iatype alloantigens on the ability of I.D.D. patients to react to islet cell, viral, and insulin antigens. Department of Internal Medicine II, University of Vienna, Vienna, Austria
G. SCHERNTHANER H. LUDWIG
Institute of Blood Group Serology, University of Vienna
W. R. MAYR
PATIENTS AT RISK OF HYPOTHYROIDISM
SIR,-We read with interest the report by
Dr Barber and his
967) on the detection of hypothyroidism after radioiodine or surgical treatment of thyrotoxicosis, but note that thyroid-stimulating hormone (T.S.H.) levels were not determined. The statement, attributed to US,12 that thyroxine
colleagues (Nov. 5,
p.
1.
Andersen, O. O., Deckert, T., Nerup, J. Acta endocr. 1976, Suppl. no. 205, p. 52. 2. Nerup, J. and others Lancet, 1974, ii, 864. 3. Schernthaner, G., Mayr, W. R., Pacher, M., Ludwig, H., Erd. W., Eibl, M. Horm. Metab. Res. 1975, 7, 521. 4. Thomsen, M., Platz, P., Andersen, O. O., Christy, M., Lyngsoe, J., Nerup, J., Rasmussen, K., Ryder, L. P., Staub Nielsen, L., Svejgaard, A. Transpl. Rev. 1975, 22, 125. 5. Ludwig, H., Schernthaner, G., Mayr, W. R. New Engl. J. Med. 1976, 294, 1066.
Mayr, W. R., Ludwig, H., Schernthaner, G., Bartova, A., Menzel, G. R., Richter, K. V., Ceppellini, R. Histocompatibility Testing, 1977 (in the press). 7. Schernthaner, G., Ludwig, H., Mayr, W. R., Willvonseder, R. New Engl. Med. 1976, 295, 622. 8. Bertrams, J., Jansen, F. K., Grüneklee, D., Reis, H. E., Drost, H., Beyer, J., Gries, F. A., Kuwert, E. Tissue Antigens, 1976, 8, 13. 9. Ludvigsson, J., Säfwenberg, J., Heding, L. G. Diabetologia, 1977, 13, 13. 10. Irvine, W. J., McCallum, C. J., Gray, R. S., Campell, C. J., Duncan, L. J. P., Farquhar, J. W., Vaughan, H., Morris, P. I. Diabetes, 1977, 26,
useful index than T.S.H." has been early weeks after treatment of thyrotoxicosis there is suppression of the pituitary thyrotroph, previously exposed to high circulating levels of thyroid hormones, which persists for 4-12 weeks.’2-14 It is only at this stage that serum-total-T4 is a more sensitive indicator of impending clinical hypothyroidism than serum-T.s.H. In our experience of the longer-term follow-up of radioiodine-treated patients, serum-T.s.H. is the most valuable test of thyroid function in determining those patients at increased risk of thyroid failure." Accordingly, euthyroid patients with raised serumT.S.H. levels at one year after therapy in whom the risk of hypothyroidism is some 5% per year, should be reviewed annually, whereas review of patients with a normal ’serumT.S.H. level need be carried out at most every three years. The ,Birmingham group’s computerised follow-up could be made even more efficient if serum-T.s.H. were incorporated. An additional reason for measuring serum-T.s.H. in such patients is the increased security of diagnosis of hypothyroidism if it is supported by both low serum-thyroid-hormone and raised T.S.H. levels, and not by a measurement of serumtotal-T4 or free T4 index alone. This is especially important if circulating thyroid-hormone levels are just below the lower limit of normal, when the clinical features of thyroid failure may be difficult to detect. Barber et al. infer that hypothyroidism may be transient after radioiodine treatment of thyrotoxicosis, although the supporting reference contains only a general statement" Although temporary hypothyroidism has been described after surgical treatment,17 we have not encountered this problem after iodine-131 and are unaware of any reference which describes it both in clinical terms and on the basis of serum-thyroid-hormone and T.s.H. concentrations.
(T4) "is held taken out of
Royal Infirmary, Edinburgh EH3 9YW
a more
In the
A. D. TOFT W. J. IRVINE
BROMOCRIPTINE AND THYROID-STIMULATING-HORMONE SECRETION
SIR,-In seeking evidence of dopaminergic mechanisms in the control of thyrotrophin secretion in man, Dr Scanlon and colleagues (Aug. 27, p. 421) found that metoclopramide, which blocks dopamine receptors, stimulated the release of thyroidstimulating hormone (T.S.H.) in hypothyroid patients but not in normal subjects. Neuroendocrinological studies in parkinsonism indicate that a reduction in striatal dopamine concentrations may be associated with defective dopaminergic activity in the hypothalamus and pituitary .1.2 Although basal thyroid function is normal in patients with untreated Parkinson’s disease3 chronic levodopa treatment inhibits T.s.H. release after stimulation with thyrotrophin-releasing hormone (T.R.H.).’ The T.S.H. depression during dopamine infusion found by Dr Delitala (Oct. 8, p. 760) is evidence of a dopaminergic inhibition of T. s. H. secretion. These mechanisms can be usefully studied using specific dopamine-receptor-stimulating drugs. Apomorphine does not alter 13. Sanchez-Franco, F., Garcia, M. D., Cacidedo, L., Martin-Zurro, A., Escobar del Ray, F., Morreale de Escobar, G. J. clin. Endocr. 1974, 38, 1098. 14. Toft, A. D., Irvine, W. J., Hunter, W. M., Ratcliffe, J. G., Seth, J. ibid. 1974,
39, 607. 15. Toft, A. D., Irvine, W. J., Seth, J., Hunter, W. M., Cameron, E. H. D. Lancet, 1975, ii, 576. 16. Einhorn, J., Wicklund, H. J. Clin. Endocr. 1966, 26, 33. 17. Toft, A. D., Irvine, W. J., McIntosh, D., Seth, J., Cameron, E. H. D., Lidgard, G. P. Lancet, 1976, ii, 817. 1. Mena, I., Cotzias, G. C., Brown, F. C., Papavasiliou, P. S., Miller, S. T. 2. 3.
138.
Woolf, B. Ann. hum. Genet, 1955, 19, 25. 12. Toft, A. D., Seth, J., Hunter, W. M , Irvine, W. J. Lancet, 1974, i, 704.
be
context.
Endocrine Unit
6.
11.
to
4.
New Eng. J. Med. 1973, 288, 320. Horrobm, D. F. ibid. 1976, 294, 1347. Boyd, A. E., Lebovitz, H. E., Feldman, J. M. J. clin. Endocr. Metab. 1971, 33, 829. Spaulding, S. W., Burrow, G. N., Donabedian, R., Van Woert, M. ibid. 1972, 35, 182.
1129 the T.S.H. response to T.R.H.,’ whereas bromocriptine lowers the raised T.S.H. found in hypothyroid patients6 but does not influence T.S.H. in normal people.’ We have examined the T.S.H. response to T.R.H. stimulation in nine severe postencephalitic Parkinson’s disease patients before and after three months of bromocriptine therapy (mean dosage 45 mg daily). The pretreatment T.S.H. was normal. Although the T.S.H. response to T.R.H. after bromocriptine treatment suggested a partial suppression, this was not statistically significant. The normal thyroid function in parkinsonism and the negligible effect of bromocriptine on T.S.H. secretion suggest that direct dopaminergic mechanisms within the hypothalamus and pituitary do not greatly influence the regulation of T.S.H. release and that the effects of levodopa and dopamine probably involve in-
termediate mechanisms.3 Departments of Endocrinology and Neurology,
University College Hospital, London WC1E 6AU
K. M. SHAW
A. J. LEES G. M. STERN
HYPERTHYRODDISM SiR,—The case described by Dr Turner and his colleagues (Aug. 20, p. 410) shows that hyperthyroidism can recur after l2SI-induced hypothyroidism. A confirmed primary hypothyroidism,is usually permanent, but progression to thyrotoxicosis Case1 had bilateral proptosis in March, 1975. Serum-thyroxine (T4) was 2-9 g/dl (normal 4-5-10), resin-T3 test 0.72 (normal 0-80-1-25), serum thyroid-stimulating horand long-acting thyroid mone (T.S.H.). 49 U/ml (normal
SIR,-Viral infections and autoimmune processes, possibly on a genetic susceptibility, have been implicated in the
based
highly complex pathogenesis of insulin-dependent diabetes (I.D.D.).’ This disorder was positively correlated with HLA B8, Bwl5, Cw3, Dw3 and Dw4 and negatively correlated with B5 and B7.’’ Some genes of the major histocompatibility system (M.H.C.) influence anti-insulin antibody formation7-9 and antiIa -TYPE ALLOANTIGENS IN INSULIN-DEPENDENT DIABETES
MELLITUS
islet cell antibody persistencel0 and may be selecting factors for late diabetic manifestations. Certain genes within the M.HC. code for alloantigens (la-type antigens) found on B lymphocytes which are identical to, or closely-linked with, genes which code for immune-responsiveness to a variety of antigens. Tests for seven specificities of these la-type alloantigens (DRwl-DRw7) were carried out on cells from 50 I.D.D. patients and 107 controls using a lymphocytotoxicity techni-
que.6 A significantly increased frequency of
DRw3 and DRw4 was observed in I.D.D. patients compared with the controls (see table). Individuals positive for DRw3 carry a 4.5-fold increased risk (calculated according to Woolf") and those positive for DRw4 a 2. 5-fold increased risk of developing I.D.D. The la-type alloantigen DRw3 is more closely associated with I.D.D. than all previously-investigated M.H.c.-associated antigens and we are now examining the influence of these Iatype alloantigens on the ability of I.D.D. patients to react to islet cell, viral, and insulin antigens. Department of Internal Medicine II, University of Vienna, Vienna, Austria
G. SCHERNTHANER H. LUDWIG
Institute of Blood Group Serology, University of Vienna
W. R. MAYR
PATIENTS AT RISK OF HYPOTHYROIDISM
SIR,-We read with interest the report by
Dr Barber and his
967) on the detection of hypothyroidism after radioiodine or surgical treatment of thyrotoxicosis, but note that thyroid-stimulating hormone (T.S.H.) levels were not determined. The statement, attributed to US,12 that thyroxine
colleagues (Nov. 5,
p.
1.
Andersen, O. O., Deckert, T., Nerup, J. Acta endocr. 1976, Suppl. no. 205, p. 52. 2. Nerup, J. and others Lancet, 1974, ii, 864. 3. Schernthaner, G., Mayr, W. R., Pacher, M., Ludwig, H., Erd. W., Eibl, M. Horm. Metab. Res. 1975, 7, 521. 4. Thomsen, M., Platz, P., Andersen, O. O., Christy, M., Lyngsoe, J., Nerup, J., Rasmussen, K., Ryder, L. P., Staub Nielsen, L., Svejgaard, A. Transpl. Rev. 1975, 22, 125. 5. Ludwig, H., Schernthaner, G., Mayr, W. R. New Engl. J. Med. 1976, 294, 1066.
Mayr, W. R., Ludwig, H., Schernthaner, G., Bartova, A., Menzel, G. R., Richter, K. V., Ceppellini, R. Histocompatibility Testing, 1977 (in the press). 7. Schernthaner, G., Ludwig, H., Mayr, W. R., Willvonseder, R. New Engl. Med. 1976, 295, 622. 8. Bertrams, J., Jansen, F. K., Grüneklee, D., Reis, H. E., Drost, H., Beyer, J., Gries, F. A., Kuwert, E. Tissue Antigens, 1976, 8, 13. 9. Ludvigsson, J., Säfwenberg, J., Heding, L. G. Diabetologia, 1977, 13, 13. 10. Irvine, W. J., McCallum, C. J., Gray, R. S., Campell, C. J., Duncan, L. J. P., Farquhar, J. W., Vaughan, H., Morris, P. I. Diabetes, 1977, 26,
useful index than T.S.H." has been early weeks after treatment of thyrotoxicosis there is suppression of the pituitary thyrotroph, previously exposed to high circulating levels of thyroid hormones, which persists for 4-12 weeks.’2-14 It is only at this stage that serum-total-T4 is a more sensitive indicator of impending clinical hypothyroidism than serum-T.s.H. In our experience of the longer-term follow-up of radioiodine-treated patients, serum-T.s.H. is the most valuable test of thyroid function in determining those patients at increased risk of thyroid failure." Accordingly, euthyroid patients with raised serumT.S.H. levels at one year after therapy in whom the risk of hypothyroidism is some 5% per year, should be reviewed annually, whereas review of patients with a normal ’serumT.S.H. level need be carried out at most every three years. The ,Birmingham group’s computerised follow-up could be made even more efficient if serum-T.s.H. were incorporated. An additional reason for measuring serum-T.s.H. in such patients is the increased security of diagnosis of hypothyroidism if it is supported by both low serum-thyroid-hormone and raised T.S.H. levels, and not by a measurement of serumtotal-T4 or free T4 index alone. This is especially important if circulating thyroid-hormone levels are just below the lower limit of normal, when the clinical features of thyroid failure may be difficult to detect. Barber et al. infer that hypothyroidism may be transient after radioiodine treatment of thyrotoxicosis, although the supporting reference contains only a general statement" Although temporary hypothyroidism has been described after surgical treatment,17 we have not encountered this problem after iodine-131 and are unaware of any reference which describes it both in clinical terms and on the basis of serum-thyroid-hormone and T.s.H. concentrations.
(T4) "is held taken out of
Royal Infirmary, Edinburgh EH3 9YW
a more
In the
A. D. TOFT W. J. IRVINE
BROMOCRIPTINE AND THYROID-STIMULATING-HORMONE SECRETION
SIR,-In seeking evidence of dopaminergic mechanisms in the control of thyrotrophin secretion in man, Dr Scanlon and colleagues (Aug. 27, p. 421) found that metoclopramide, which blocks dopamine receptors, stimulated the release of thyroidstimulating hormone (T.S.H.) in hypothyroid patients but not in normal subjects. Neuroendocrinological studies in parkinsonism indicate that a reduction in striatal dopamine concentrations may be associated with defective dopaminergic activity in the hypothalamus and pituitary .1.2 Although basal thyroid function is normal in patients with untreated Parkinson’s disease3 chronic levodopa treatment inhibits T.s.H. release after stimulation with thyrotrophin-releasing hormone (T.R.H.).’ The T.S.H. depression during dopamine infusion found by Dr Delitala (Oct. 8, p. 760) is evidence of a dopaminergic inhibition of T. s. H. secretion. These mechanisms can be usefully studied using specific dopamine-receptor-stimulating drugs. Apomorphine does not alter 13. Sanchez-Franco, F., Garcia, M. D., Cacidedo, L., Martin-Zurro, A., Escobar del Ray, F., Morreale de Escobar, G. J. clin. Endocr. 1974, 38, 1098. 14. Toft, A. D., Irvine, W. J., Hunter, W. M., Ratcliffe, J. G., Seth, J. ibid. 1974,
39, 607. 15. Toft, A. D., Irvine, W. J., Seth, J., Hunter, W. M., Cameron, E. H. D. Lancet, 1975, ii, 576. 16. Einhorn, J., Wicklund, H. J. Clin. Endocr. 1966, 26, 33. 17. Toft, A. D., Irvine, W. J., McIntosh, D., Seth, J., Cameron, E. H. D., Lidgard, G. P. Lancet, 1976, ii, 817. 1. Mena, I., Cotzias, G. C., Brown, F. C., Papavasiliou, P. S., Miller, S. T. 2. 3.
138.
Woolf, B. Ann. hum. Genet, 1955, 19, 25. 12. Toft, A. D., Seth, J., Hunter, W. M , Irvine, W. J. Lancet, 1974, i, 704.
be
context.
Endocrine Unit
6.
11.
to
4.
New Eng. J. Med. 1973, 288, 320. Horrobm, D. F. ibid. 1976, 294, 1347. Boyd, A. E., Lebovitz, H. E., Feldman, J. M. J. clin. Endocr. Metab. 1971, 33, 829. Spaulding, S. W., Burrow, G. N., Donabedian, R., Van Woert, M. ibid. 1972, 35, 182.
1129 the T.S.H. response to T.R.H.,’ whereas bromocriptine lowers the raised T.S.H. found in hypothyroid patients6 but does not influence T.S.H. in normal people.’ We have examined the T.S.H. response to T.R.H. stimulation in nine severe postencephalitic Parkinson’s disease patients before and after three months of bromocriptine therapy (mean dosage 45 mg daily). The pretreatment T.S.H. was normal. Although the T.S.H. response to T.R.H. after bromocriptine treatment suggested a partial suppression, this was not statistically significant. The normal thyroid function in parkinsonism and the negligible effect of bromocriptine on T.S.H. secretion suggest that direct dopaminergic mechanisms within the hypothalamus and pituitary do not greatly influence the regulation of T.S.H. release and that the effects of levodopa and dopamine probably involve in-
termediate mechanisms.3 Departments of Endocrinology and Neurology,
University College Hospital, London WC1E 6AU
K. M. SHAW
A. J. LEES G. M. STERN
HYPERTHYRODDISM SiR,—The case described by Dr Turner and his colleagues (Aug. 20, p. 410) shows that hyperthyroidism can recur after l2SI-induced hypothyroidism. A confirmed primary hypothyroidism,is usually permanent, but progression to thyrotoxicosis Case1 had bilateral proptosis in March, 1975. Serum-thyroxine (T4) was 2-9 g/dl (normal 4-5-10), resin-T3 test 0.72 (normal 0-80-1-25), serum thyroid-stimulating horand long-acting thyroid mone (T.S.H.). 49 U/ml (normal
