1201 NOMENCLATURE OF THYROIDSTIMULATING ANTIBODIES
SIR In the interest of wider appreciation of the nature activities of the long-acting thyroid stimulator (LATS) 1-6 and LATS protector (LATS-P),7-10 we feel that a change in terminology is desirable. LATS.-P is a thyroid autoantibody found in at least 90% of cases of diffuse toxic goitre. There is now strong evidence that it is the direct cause of the thyroid hyperactivity in this condition. The levels in patients’ bloodsamples show a close correlation with the patients’ thyroidgland 131I uptakes,8 and infusions of plasma with high LATS-protector content stimulate the thyroid glands of volunteers.9 LATS-P does not stimulate the mouse thyroid gland. In contrast, the related human thyroid autoantibody, LATS, is a powerful mouse thyroid stimulator,2 but recent evidence suggests that it does not actually stimulate the human thyroid, although there is a binding and
reaction. Both LATS and LATS-P have been shown to compete with thyrotrophic hormone for reaction with its receptor site on the thyroid cell.11-14 This reaction explains the thyroid-stimulating properties of LATS and LATS-P. We propose in future to use the term thyroid-stimulating antibodies (TSAb) for both LATS and LATS-P; the term human thyroid stimulator (HTS) for LATS-P; and the term mouse stimulator (MTS) for LATS. D. D. ADAMS* H. K. IBBERTSON S. DIRMIKIS W. J. IRVINE DEBORAH DONIACH P. KENDALL-TAYLOR D. J. EL KABIR S. W. MANLEY R. HALL S. Q. MEHDI D. S. MUNRO Clinical Research Centre, H. D. PURVES Division of Cell Pathology, B. R. SMITH Watford Road, R. D. H. STEWART. Harrow, Middlesex HA1 3UJ.
thyroid
defects (A.S.B.). As far as I can see, the only data supporting the original hypothesis (and its generalisation) are those suggesting that in Wales women in high A.s.B. areas report lower spontaneous-abortion rates than women in low A.S.B. areas. 16 It seems, however, that a reporting deficit may have caused this result. 17 It is worth recalling that a similar hypothesis was advanced in regard to the action of thalidomide 18: it was urged that, instead of causing malformations, it supported the already malformed fetuses. The weakness of this hypothesis seems to lie in the absence of limb deformities in fetuses spontaneously aborted in the absence of thalidomide ingestion.19 Roberts and Lowe’s hypothesis can be similarly tested. In regard to A.S.B., for example, samples of spontaneously aborted fetuses should be taken from areas with high A.S.B. rates and low A.S.B. rates: if Roberts and Lowe are correct, there should be a higher proportion of A.s.B. fetuses in the low-risk area. Galton Laboratory, University College London, Wolfson House, 4 Stephenson Way,
WILLIAM H. JAMES.
London NW1 2HE.
D-PENICILLAMINE-INDUCED MEMBRANOUS GLOMERULONEPHRITIS
SIR,—Although renal complications of D-penicillamine therapy are rarely reported, we have seen something of an epidemic in the past 18 months. However, D-penicillamine has been used more extensively in West Germany than in England. An average of 2000 renal biopsies per year are examined here and the table below shows the annual frequencies of D-penicillamine and gold induced cases of membranous (perimembranous) glomerulonephritis (M.G.). ,
CONGENITAL-MALFORMATION RATES AND SPONTANEOUS-ABORTION RATES
SIR,-No-one would doubt that Nature operates
a
quality-control process, a high proportion of substandard specimens being spontaneously aborted. Roberts and Lowe 15 hypothesise that variations in malformation-rates at
birth
are
conception,
not to variations in but to environmentally
due,
malformation-rates at caused differences in
the efficiency of this quality-control process. This is a generalisation to all malformations from a hypothesis originally proposed 16 in respect of neural-tube * Division of Cell Pathology, Clinical Research Centre, Watford Road, Harrow. Middlesex HA1 3UJ. 1. Adams, D. D., Purves, H. D. Proc. Univ. Otago med. Sch. 1956,
34, 11. McKenzie, J. M. Endocrinology, 1958, 62, 865. Adams, D. D. Br. med. J. 1965, i, 1015. Kriss, J. P., Pleshakov, V., Chien, J. R. J. clin. Endocr. Metab. 1964, 24, 1005. 5. McKenzie, J. M. Physiol. Revs, 1968, 48, 252. 6. Smith, B. R., Dorrington, K. J., Munro, D. S. Biochim. biophys.
2. 3. 4.
7. 8. 9.
10. 11.
12. 13. 14. 15. 16.
Acta, 1969, 192, 277. Adams, D. D., Kennedy, T. H. J. clin. Endocr. Metab. 1967, 27, 173. Adams, D. D., Kennedy, T. H., Stewart, R. D. H. Br. med. J. 1974, ii, 199. Adams, D. D., Fastier, F. N., Howie, J. B., Kennedy, T. H., Kilpatrick, J. A., Stewart, R. D. H. J. clin. Endocr. Metab. 1974, 39, 826. Dirmikis, S. J. Endocr., Copenh. 1974, 63, 427. Manley, S. W., Bourke, J. R., Hawker, R. W. ibid. 1974, 61, 437. Mehdi, S. Q., Nussey, S. S., Gibbons, C. P., El Kabir, D. J. Biochem. Soc. Trans. 1973, 1, 89. Mehdi, S. Q., Nussey, S. S. Biochem. J. 1975, 145, 105. Smith, B. R., Hall, R. Lancet, 1974, ii, 427. Roberts, C. J., Lowe, C. R. ibid, March 1, 1975, p. 498. Roberts, C. J., Lloyd, S. Br. med. J. 1973, iv, 20.
Total
M.G.
includes all
years and includes
registered as M.G. in these associated with systemic lupus, well as D-penicillamine, gold, and cases
cases
diabetes, tumours, as drugs (troxidone, chlormethiazole, mercury). However, without knowledge of the drug history, 14 patients would have been classified on periodic-acid/Schiff stained sections alone as having minimal-change glomerulonephritis (minimal proliferative intercapillary glomerulonephritis) and 3 as having mesangioproliferative glomerulonephritis. In all these cases, subepithelial electron-dense deposits typical for M.G. w,:re seen on electron microscopy, although in some cases the diagnosis had already been established by immunofluorescence. All patients receiving gold and 28 out of 31 receiving D-penicillamine were being treated for rheumatoid arthritis. In the 3 other cases D-penicillamine was used in the treatAfter proteinuria ment of chronic aggressive hepatitis. was first seen, nephrotic syndrome developed in 8 of the 31 cases, despite immediate discontinuation of the drug, and 11 were treated for- a further period (one to seven months) before nephrotic syndrome developed. In 12 further cases nephrotic syndrome never developed, but, despite treatment being stopped, these patients had proteinuria (1-5 g. per day) for varying times. In 4 of the patients, proteinuria was first noticed between other
17. 18. 19.
James, W. H. ibid. p. 425. Hellmann, K., Duke, D. I., Tucker, James, W. H. ibid. p. 1064.
D. F. ibid. 1965,
ii, 687.
SIR In the interest of wider appreciation of the nature activities of the long-acting thyroid stimulator (LATS) 1-6 and LATS protector (LATS-P),7-10 we feel that a change in terminology is desirable. LATS.-P is a thyroid autoantibody found in at least 90% of cases of diffuse toxic goitre. There is now strong evidence that it is the direct cause of the thyroid hyperactivity in this condition. The levels in patients’ bloodsamples show a close correlation with the patients’ thyroidgland 131I uptakes,8 and infusions of plasma with high LATS-protector content stimulate the thyroid glands of volunteers.9 LATS-P does not stimulate the mouse thyroid gland. In contrast, the related human thyroid autoantibody, LATS, is a powerful mouse thyroid stimulator,2 but recent evidence suggests that it does not actually stimulate the human thyroid, although there is a binding and
reaction. Both LATS and LATS-P have been shown to compete with thyrotrophic hormone for reaction with its receptor site on the thyroid cell.11-14 This reaction explains the thyroid-stimulating properties of LATS and LATS-P. We propose in future to use the term thyroid-stimulating antibodies (TSAb) for both LATS and LATS-P; the term human thyroid stimulator (HTS) for LATS-P; and the term mouse stimulator (MTS) for LATS. D. D. ADAMS* H. K. IBBERTSON S. DIRMIKIS W. J. IRVINE DEBORAH DONIACH P. KENDALL-TAYLOR D. J. EL KABIR S. W. MANLEY R. HALL S. Q. MEHDI D. S. MUNRO Clinical Research Centre, H. D. PURVES Division of Cell Pathology, B. R. SMITH Watford Road, R. D. H. STEWART. Harrow, Middlesex HA1 3UJ.
thyroid
defects (A.S.B.). As far as I can see, the only data supporting the original hypothesis (and its generalisation) are those suggesting that in Wales women in high A.s.B. areas report lower spontaneous-abortion rates than women in low A.S.B. areas. 16 It seems, however, that a reporting deficit may have caused this result. 17 It is worth recalling that a similar hypothesis was advanced in regard to the action of thalidomide 18: it was urged that, instead of causing malformations, it supported the already malformed fetuses. The weakness of this hypothesis seems to lie in the absence of limb deformities in fetuses spontaneously aborted in the absence of thalidomide ingestion.19 Roberts and Lowe’s hypothesis can be similarly tested. In regard to A.S.B., for example, samples of spontaneously aborted fetuses should be taken from areas with high A.S.B. rates and low A.S.B. rates: if Roberts and Lowe are correct, there should be a higher proportion of A.s.B. fetuses in the low-risk area. Galton Laboratory, University College London, Wolfson House, 4 Stephenson Way,
WILLIAM H. JAMES.
London NW1 2HE.
D-PENICILLAMINE-INDUCED MEMBRANOUS GLOMERULONEPHRITIS
SIR,—Although renal complications of D-penicillamine therapy are rarely reported, we have seen something of an epidemic in the past 18 months. However, D-penicillamine has been used more extensively in West Germany than in England. An average of 2000 renal biopsies per year are examined here and the table below shows the annual frequencies of D-penicillamine and gold induced cases of membranous (perimembranous) glomerulonephritis (M.G.). ,
CONGENITAL-MALFORMATION RATES AND SPONTANEOUS-ABORTION RATES
SIR,-No-one would doubt that Nature operates
a
quality-control process, a high proportion of substandard specimens being spontaneously aborted. Roberts and Lowe 15 hypothesise that variations in malformation-rates at
birth
are
conception,
not to variations in but to environmentally
due,
malformation-rates at caused differences in
the efficiency of this quality-control process. This is a generalisation to all malformations from a hypothesis originally proposed 16 in respect of neural-tube * Division of Cell Pathology, Clinical Research Centre, Watford Road, Harrow. Middlesex HA1 3UJ. 1. Adams, D. D., Purves, H. D. Proc. Univ. Otago med. Sch. 1956,
34, 11. McKenzie, J. M. Endocrinology, 1958, 62, 865. Adams, D. D. Br. med. J. 1965, i, 1015. Kriss, J. P., Pleshakov, V., Chien, J. R. J. clin. Endocr. Metab. 1964, 24, 1005. 5. McKenzie, J. M. Physiol. Revs, 1968, 48, 252. 6. Smith, B. R., Dorrington, K. J., Munro, D. S. Biochim. biophys.
2. 3. 4.
7. 8. 9.
10. 11.
12. 13. 14. 15. 16.
Acta, 1969, 192, 277. Adams, D. D., Kennedy, T. H. J. clin. Endocr. Metab. 1967, 27, 173. Adams, D. D., Kennedy, T. H., Stewart, R. D. H. Br. med. J. 1974, ii, 199. Adams, D. D., Fastier, F. N., Howie, J. B., Kennedy, T. H., Kilpatrick, J. A., Stewart, R. D. H. J. clin. Endocr. Metab. 1974, 39, 826. Dirmikis, S. J. Endocr., Copenh. 1974, 63, 427. Manley, S. W., Bourke, J. R., Hawker, R. W. ibid. 1974, 61, 437. Mehdi, S. Q., Nussey, S. S., Gibbons, C. P., El Kabir, D. J. Biochem. Soc. Trans. 1973, 1, 89. Mehdi, S. Q., Nussey, S. S. Biochem. J. 1975, 145, 105. Smith, B. R., Hall, R. Lancet, 1974, ii, 427. Roberts, C. J., Lowe, C. R. ibid, March 1, 1975, p. 498. Roberts, C. J., Lloyd, S. Br. med. J. 1973, iv, 20.
Total
M.G.
includes all
years and includes
registered as M.G. in these associated with systemic lupus, well as D-penicillamine, gold, and cases
cases
diabetes, tumours, as drugs (troxidone, chlormethiazole, mercury). However, without knowledge of the drug history, 14 patients would have been classified on periodic-acid/Schiff stained sections alone as having minimal-change glomerulonephritis (minimal proliferative intercapillary glomerulonephritis) and 3 as having mesangioproliferative glomerulonephritis. In all these cases, subepithelial electron-dense deposits typical for M.G. w,:re seen on electron microscopy, although in some cases the diagnosis had already been established by immunofluorescence. All patients receiving gold and 28 out of 31 receiving D-penicillamine were being treated for rheumatoid arthritis. In the 3 other cases D-penicillamine was used in the treatAfter proteinuria ment of chronic aggressive hepatitis. was first seen, nephrotic syndrome developed in 8 of the 31 cases, despite immediate discontinuation of the drug, and 11 were treated for- a further period (one to seven months) before nephrotic syndrome developed. In 12 further cases nephrotic syndrome never developed, but, despite treatment being stopped, these patients had proteinuria (1-5 g. per day) for varying times. In 4 of the patients, proteinuria was first noticed between other
17. 18. 19.
James, W. H. ibid. p. 425. Hellmann, K., Duke, D. I., Tucker, James, W. H. ibid. p. 1064.
D. F. ibid. 1965,
ii, 687.
