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TEMPORARY HYPOTHYROIDISM AFTER SURGICAL TREATMENT OF THYROTOXICOSIS
Saturday TEMPORARY HYPOTHYROIDISM AFTER SURGICAL TREATMENT OF THYROTOXICOSIS A. D. TOFT D. MCINTOSH E. H. D. CAMERON
W.
J. IRVINE J. SETH
G. P. LIDGARD
Departments of Endocrinology and Surgery, Royal Infirmary, and University Departments of Therapeutics and Clinical
Chemistry, Edinburgh Mild clinical hypothyroidism associated with low levels of serum total thyroxine T4) and tri-iodothyronine (T3) and raised levels of serum thyroid-stimulating hormone (T.S.H.) has been observed in 14 of 40 patients (35%) in the early months after a subtotal thyroidectomy for thyrotoxicosis under cover of propranolol. In 10 of the patients, however, the hypothyroidism was temporary and at 6 months after operation the thyroid hormone levels were normal and the serum T.S.H. levels had fallen. In 4 of the patients in whom clinical and biochemical evidence of hypothyroidism persisted 6 months postoperatively, longterm T4 replacement therapy was instituted. It is concluded that the diagnosis of permanent hypothyroidism should not be made with confidence before 6 months have elapsed after operation and that the incidence of hypothyroidism following the surgical treatment of thyrotoxicosis may have been overestimated in the past.
Summary
16 October
1976
of thyrotoxicosis was made on clinical grounds and on the basis of a raised serum total T4, T3, effective thyroxine ratio (E.T.R.),12 and a lack of response of serum-T.S.H. level to T.S.H.releasing hormone 200 ILg intravenously. Following operation the patients were reviewed by one observer (A.D.T.) at 1, 2, 3, 4, and 6 months and, in addition to clinical examination, blood was withdrawn for the estimation of serum total T4, T3, and T.S.H. Serum total T4 and T3 were measured by specific radioimmunoassays,13 the inter-assay precision using anonymous control sera averaging 11.7% for T4 and 7-9% for T3 expressed as coefficient of variation. Serum-T.S.H. was measured by a double antibody radioimmunoassay14 in which the upper limit of normal is 5.77 mU/l, and in which the betweenassay coefficient of variation is 11-2%.
Results Mild clinical hypothyroidism associated with low levels of serum total T3 and T4 and raised levels of serum-T.s.H. occurred at 2-3 months after operation in
Introduction
hypothyroidism after subtotal for thyroidectomy thyrotoxicosis depends upon many factors among which are the size of the thyroid remnant," the degree of lymphocytic infiltration of the gland,34 the presence of complement-fixing thyroid antibody in the serum,-7 the length of follow-up,s and the progression of thyrotoxicosis10 to spontaneous hypohvroidism in some patients.9 It became apparent dur.ng the follow-up of patients treated surgically for thyrotoxicosis under cover of propranolol that clinical and biochemical evidence of hypothyroidism was not uncommon in the early months after operation, but in most paagents this was a temporary phenomenon. This paper :ports the sequential levels of serum total thyroxine 14, tri-iodothyronine (T3), and thyroid-stimulating THE incidence of
".ormone
(T.S.H.) in such patients. Patients and Methods
0
patients (37 females, 3 males), aged 20-63 years, ’:rred to the endocrine clinic, Royal Infirmary, Edinburgh, - ::erurent subtotal thyroidectomy for thyrotoxicosis under of propranolol as previously described." The diagnosis
Months after operation
Mean+S.E. total
serum T4, T3, and T.S.H. levels in 10 patients who developed temporary hypothyroidism following sub-total thyroidectomy for thyrotoxicosis under cover of propranolol. The normal ranges are indicated by the shaded areas.
818 14 of the 40 patients studied (35%). In 10 of these patients the hypothyroidism proved to be temporary and by 6 months after surgery the euthyroid state, both clinically and biochemically, had been regained and the levels of serum total T3 and T4 lay within the normal range. The serum-T.s.H. levels which were maximal at 3 months postoperatively in 9 of the 10 patients and ranged from 27 to 282 mU/1, had fallen in each case at the 6-month review. In no patient, however, was the serum-T.s.H. level within the normal range at this stage. The sequential mean ± s.E. levels of serum total T4 and T3 and serum-T.S.H. in the 10 patients with temporary hypothyroidism are shown in the accompanying figure. It is of interest that the thyroid hormone levels were lower at 2 months than at one month after operation and that the eventual rise in serum total T3 levels preceeded the rise in the serum total T4 levels. In the remaining 4 patients in whom the features of mild clinical hypothyroidism were present in the early months after surgery, there was no recovery of thyroid function at 6 months after operation and long-term replacement therapy with thyroxine was instituted. It was not possible to predict at 2-3 months after operation which patients would remain hypothyroid. Of the 26 patients, who remained clinically euthyroid throughout the period of observation, the serum total T3 levels were normal at each review but the serum total T4 level was transiently reduced in 4 patients.
Discussion It is apparent from the present study that a condition of mild hypothyroidism associated with low levels of serum total T4 and T3 may occur in some patients in the early months after operation. However, thyroid hormone levels may return to the normal range as a result of a raised serum-T.S.H. level and permanent hypothyroidism should not be diagnosed with confidence before 6 months have elapsed. In some seriess 15 it is reported that over 50% of patients ultimately developing thyroid failure after thyroidectomy do so within 6 months of operation. However, in view of the above findings, it is probable that such high figures include patients with temporary hypothyroidism. Although there have been many retrospective studies of the incidence of hypothyroidism following the surgical treatment of thyrotoxicosis16-21 with figures of between 6% at ten years and 43% at five years of follow-up, there is little information available about the stage at which the diagnosis of permanent hypothyroidism was made postoperatively. It is possible, therefore, that some of the variation from centre to centre in the incidence of hypothyroidism may be accounted for by the review policy of the clinic. The hypothyroidism developing in the early weeks after surgery is presumably related not only to the size of the thyroid remnant but also to a reduced titre of stimulating T.S.H. receptor antibodies consequent upon the removal of antigen at operation,22 and to the suppression of the pituitary thyrotrophs previously exposed to high circulating levels of thyroid hormones.23-2s Indeed, the finding of lower concentrations of serum total T4 and T3 at 2 months than at one month after operation may reflect falling levels of stimulating T.s.H. receptor antibodies which are IgG immunoglobulins with a halflife of some 3 weeks,29 in addition to the 4-6 weeks required for the recovery of the suppressed brain-thyroid
following surgical treatment of thyrotoxicosis.11 =The T.s.H.-dependent growth of the thyroid remnar,: appears to be a relatively slow process and 3-4 month: are required before these patients with temporar. hypothyroidism become euthyroid. It is conceivable tha. longer periods may be required for maximal growth o; axis
Ii :
the remnant under the influence of T.S.H. but to withhold T4 replacement therapy beyond 6 months after operation would not seem to be justified. Requests for reprints should be addressed to W.].I., DepartmentJi Therapeutics, Royal Infirmary, Edinburgh EH3 9YW. REFERENCES
1. Crile, G., McCullagh, E. P. Ann. Surg. 1951, 134, 18. 2. Michie, W., Pegg, C. A. S., Bewsher, P. D. Br. med. J. 1972, i, 13 3. Whitesell, F. B., Black, B. M. J. clin. Endocr. Metab. 1949, 9, 1202 4. Greene, R. J. Endocr. 1950, 7, 1. 5. Irvine, W. J., MacGregor, A. G., Stuart, A. E. Lancet, 1962, ii, 843 6. Buchanan, W. W., Koutras, D. A., Crooks, J., Alexander, W. D., Brass, W., Anderson, J. R., Goudie, R. B., Gray, K. G. J. Endocr. 1962, 24, 115 7. Irvine, W. J., Stewart, A. G. in Thyrotoxicosis (edited by W. J Irvine, Edin-
burgh, 1967. 8.
Nofal,
M.
M., Beierwaltes, W. H., Patno, M. E. J. Am.
med. Ass
1966, 197,
605. 9. Baldwin, W. W. Lancet, 1895, i, 145. 10. Gowan, B. C. ibid. p. 478. 11. Toft, A. D., Irvine, W. J., McIntosh, D., Macleod, D. A. D, Seth, J. Cameron, E. H. D., Lidgard, G. P. J. clin. Endocr. Metab. (in the press 12. Toft, A. D., Seth, J., Kirkham, K. E., Marshall, A., Irvine, W. J. Clin. Endocr. 1973, 2, 127. 13. Seth, J., Toft, A. D., Irvine, W. J. Clinca chim. Acta, 1976, 68, 291 14. Irvine, W. J., Toft, A. D., Hunter, W. M. Kirkham, K. E. Clin. Endocr 1973, 2, 135. 15. Bartels, E. C. J. clin. Endocr. Metab. 1953, 13, 95. 16. Green, M., Wilson, G. M. Br. med. J. 1964, i, 1005. 17. Roy, A. D., Allan, J., Harden, R. McG. Lancet, 1967, ii, 684. 18. Beahrs, O. H., Sakulsky, S. B. Archs Surg. Chicago, 1968, 96, 512. 19. McNeill, A. D., Thomson, J. A. Br. med. J. 1968, 3, 643. 20. Olsen, W. R., Nishiyama, R. H., Graber, L. W. Archs Surg. Chicago. 1970.
101, 175. Evered, D., Young, E. T., Tunbridge, W. M. G., Ormston, B. J., Green. E., Petersen, V. B., Dickinson, P. H. Br. med. J. 1975, i, 25. 22. Mukhtar, E. D., Smith, B. R., Pyle, G. A., Hall, R., Vice, P. Lancet, 1975, i, 713. 23. Sanchez-Franco, F., Garcia, M. D., Cacicedo, L., Martin-Zurro, A., Escobar del Ray, F., Morreale de Escobar, G. J. clin. Endocr. Metab 1974, 38, 21.
24. 25. 26. 27.
28.
1098. A.
Toft,
D., Irvine, W. J., Hunter, W. M., Ratchffe, J. G., Seth, J. ibid. 1974, 39, 607. Krugman, L. G., Hershman, J. M., Chopra, I. J., Levine, G. A., Pekary, A. E., Geffner, D. L., Chua Teco, G. N. ibid. 1975, 41, 70. Mühlen, A., Hesch, R. D., Kobberling, J. Clin. Endocr. 1975, 4, 165. Vagenakis, A. G., Braverman, L. E., Azizi, F., Portnay, G. I., Ingbar, S. H New Engl. J. Med. 1975, 293, 681. Demeester-Mirkine, N., Brauman, H., Corvilain, J. Clin. Endocr 1976, 5, 9.
29.
Spiegelberg, H. L. Adv. Immun. 1974, 19, 259. 30. Toft, A. D. M.D. thesis, University of Edinburgh, 1976.
AMINE METABOLISM AND THE SMALL BOWEL IN URÆMIA MICHAEL L. SIMENHOFF JUSSI J. SAUKKONEN LAURENCE G. WESSON JAMES F. BURKE RUSSELL W. SCHAEDLER
Departments of Medicine and Microbiology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Intestinal intubation was carried out in 21 subjects: 9 with end-stage renal fail2 with ure, early renal insufficiency, 7 untreated patients with blind-loop syndrome, and 3 normal volunteers. All 9 patients with uræmia had significantly raised duodenal dimethylamine (D.M.A.) concentrations compared with the other groups tested. Alteration of the intestinal bac-
Summary
W.
J. IRVINE J. SETH
G. P. LIDGARD
Departments of Endocrinology and Surgery, Royal Infirmary, and University Departments of Therapeutics and Clinical
Chemistry, Edinburgh Mild clinical hypothyroidism associated with low levels of serum total thyroxine T4) and tri-iodothyronine (T3) and raised levels of serum thyroid-stimulating hormone (T.S.H.) has been observed in 14 of 40 patients (35%) in the early months after a subtotal thyroidectomy for thyrotoxicosis under cover of propranolol. In 10 of the patients, however, the hypothyroidism was temporary and at 6 months after operation the thyroid hormone levels were normal and the serum T.S.H. levels had fallen. In 4 of the patients in whom clinical and biochemical evidence of hypothyroidism persisted 6 months postoperatively, longterm T4 replacement therapy was instituted. It is concluded that the diagnosis of permanent hypothyroidism should not be made with confidence before 6 months have elapsed after operation and that the incidence of hypothyroidism following the surgical treatment of thyrotoxicosis may have been overestimated in the past.
Summary
16 October
1976
of thyrotoxicosis was made on clinical grounds and on the basis of a raised serum total T4, T3, effective thyroxine ratio (E.T.R.),12 and a lack of response of serum-T.S.H. level to T.S.H.releasing hormone 200 ILg intravenously. Following operation the patients were reviewed by one observer (A.D.T.) at 1, 2, 3, 4, and 6 months and, in addition to clinical examination, blood was withdrawn for the estimation of serum total T4, T3, and T.S.H. Serum total T4 and T3 were measured by specific radioimmunoassays,13 the inter-assay precision using anonymous control sera averaging 11.7% for T4 and 7-9% for T3 expressed as coefficient of variation. Serum-T.S.H. was measured by a double antibody radioimmunoassay14 in which the upper limit of normal is 5.77 mU/l, and in which the betweenassay coefficient of variation is 11-2%.
Results Mild clinical hypothyroidism associated with low levels of serum total T3 and T4 and raised levels of serum-T.s.H. occurred at 2-3 months after operation in
Introduction
hypothyroidism after subtotal for thyroidectomy thyrotoxicosis depends upon many factors among which are the size of the thyroid remnant," the degree of lymphocytic infiltration of the gland,34 the presence of complement-fixing thyroid antibody in the serum,-7 the length of follow-up,s and the progression of thyrotoxicosis10 to spontaneous hypohvroidism in some patients.9 It became apparent dur.ng the follow-up of patients treated surgically for thyrotoxicosis under cover of propranolol that clinical and biochemical evidence of hypothyroidism was not uncommon in the early months after operation, but in most paagents this was a temporary phenomenon. This paper :ports the sequential levels of serum total thyroxine 14, tri-iodothyronine (T3), and thyroid-stimulating THE incidence of
".ormone
(T.S.H.) in such patients. Patients and Methods
0
patients (37 females, 3 males), aged 20-63 years, ’:rred to the endocrine clinic, Royal Infirmary, Edinburgh, - ::erurent subtotal thyroidectomy for thyrotoxicosis under of propranolol as previously described." The diagnosis
Months after operation
Mean+S.E. total
serum T4, T3, and T.S.H. levels in 10 patients who developed temporary hypothyroidism following sub-total thyroidectomy for thyrotoxicosis under cover of propranolol. The normal ranges are indicated by the shaded areas.
818 14 of the 40 patients studied (35%). In 10 of these patients the hypothyroidism proved to be temporary and by 6 months after surgery the euthyroid state, both clinically and biochemically, had been regained and the levels of serum total T3 and T4 lay within the normal range. The serum-T.s.H. levels which were maximal at 3 months postoperatively in 9 of the 10 patients and ranged from 27 to 282 mU/1, had fallen in each case at the 6-month review. In no patient, however, was the serum-T.s.H. level within the normal range at this stage. The sequential mean ± s.E. levels of serum total T4 and T3 and serum-T.S.H. in the 10 patients with temporary hypothyroidism are shown in the accompanying figure. It is of interest that the thyroid hormone levels were lower at 2 months than at one month after operation and that the eventual rise in serum total T3 levels preceeded the rise in the serum total T4 levels. In the remaining 4 patients in whom the features of mild clinical hypothyroidism were present in the early months after surgery, there was no recovery of thyroid function at 6 months after operation and long-term replacement therapy with thyroxine was instituted. It was not possible to predict at 2-3 months after operation which patients would remain hypothyroid. Of the 26 patients, who remained clinically euthyroid throughout the period of observation, the serum total T3 levels were normal at each review but the serum total T4 level was transiently reduced in 4 patients.
Discussion It is apparent from the present study that a condition of mild hypothyroidism associated with low levels of serum total T4 and T3 may occur in some patients in the early months after operation. However, thyroid hormone levels may return to the normal range as a result of a raised serum-T.S.H. level and permanent hypothyroidism should not be diagnosed with confidence before 6 months have elapsed. In some seriess 15 it is reported that over 50% of patients ultimately developing thyroid failure after thyroidectomy do so within 6 months of operation. However, in view of the above findings, it is probable that such high figures include patients with temporary hypothyroidism. Although there have been many retrospective studies of the incidence of hypothyroidism following the surgical treatment of thyrotoxicosis16-21 with figures of between 6% at ten years and 43% at five years of follow-up, there is little information available about the stage at which the diagnosis of permanent hypothyroidism was made postoperatively. It is possible, therefore, that some of the variation from centre to centre in the incidence of hypothyroidism may be accounted for by the review policy of the clinic. The hypothyroidism developing in the early weeks after surgery is presumably related not only to the size of the thyroid remnant but also to a reduced titre of stimulating T.S.H. receptor antibodies consequent upon the removal of antigen at operation,22 and to the suppression of the pituitary thyrotrophs previously exposed to high circulating levels of thyroid hormones.23-2s Indeed, the finding of lower concentrations of serum total T4 and T3 at 2 months than at one month after operation may reflect falling levels of stimulating T.s.H. receptor antibodies which are IgG immunoglobulins with a halflife of some 3 weeks,29 in addition to the 4-6 weeks required for the recovery of the suppressed brain-thyroid
following surgical treatment of thyrotoxicosis.11 =The T.s.H.-dependent growth of the thyroid remnar,: appears to be a relatively slow process and 3-4 month: are required before these patients with temporar. hypothyroidism become euthyroid. It is conceivable tha. longer periods may be required for maximal growth o; axis
Ii :
the remnant under the influence of T.S.H. but to withhold T4 replacement therapy beyond 6 months after operation would not seem to be justified. Requests for reprints should be addressed to W.].I., DepartmentJi Therapeutics, Royal Infirmary, Edinburgh EH3 9YW. REFERENCES
1. Crile, G., McCullagh, E. P. Ann. Surg. 1951, 134, 18. 2. Michie, W., Pegg, C. A. S., Bewsher, P. D. Br. med. J. 1972, i, 13 3. Whitesell, F. B., Black, B. M. J. clin. Endocr. Metab. 1949, 9, 1202 4. Greene, R. J. Endocr. 1950, 7, 1. 5. Irvine, W. J., MacGregor, A. G., Stuart, A. E. Lancet, 1962, ii, 843 6. Buchanan, W. W., Koutras, D. A., Crooks, J., Alexander, W. D., Brass, W., Anderson, J. R., Goudie, R. B., Gray, K. G. J. Endocr. 1962, 24, 115 7. Irvine, W. J., Stewart, A. G. in Thyrotoxicosis (edited by W. J Irvine, Edin-
burgh, 1967. 8.
Nofal,
M.
M., Beierwaltes, W. H., Patno, M. E. J. Am.
med. Ass
1966, 197,
605. 9. Baldwin, W. W. Lancet, 1895, i, 145. 10. Gowan, B. C. ibid. p. 478. 11. Toft, A. D., Irvine, W. J., McIntosh, D., Macleod, D. A. D, Seth, J. Cameron, E. H. D., Lidgard, G. P. J. clin. Endocr. Metab. (in the press 12. Toft, A. D., Seth, J., Kirkham, K. E., Marshall, A., Irvine, W. J. Clin. Endocr. 1973, 2, 127. 13. Seth, J., Toft, A. D., Irvine, W. J. Clinca chim. Acta, 1976, 68, 291 14. Irvine, W. J., Toft, A. D., Hunter, W. M. Kirkham, K. E. Clin. Endocr 1973, 2, 135. 15. Bartels, E. C. J. clin. Endocr. Metab. 1953, 13, 95. 16. Green, M., Wilson, G. M. Br. med. J. 1964, i, 1005. 17. Roy, A. D., Allan, J., Harden, R. McG. Lancet, 1967, ii, 684. 18. Beahrs, O. H., Sakulsky, S. B. Archs Surg. Chicago, 1968, 96, 512. 19. McNeill, A. D., Thomson, J. A. Br. med. J. 1968, 3, 643. 20. Olsen, W. R., Nishiyama, R. H., Graber, L. W. Archs Surg. Chicago. 1970.
101, 175. Evered, D., Young, E. T., Tunbridge, W. M. G., Ormston, B. J., Green. E., Petersen, V. B., Dickinson, P. H. Br. med. J. 1975, i, 25. 22. Mukhtar, E. D., Smith, B. R., Pyle, G. A., Hall, R., Vice, P. Lancet, 1975, i, 713. 23. Sanchez-Franco, F., Garcia, M. D., Cacicedo, L., Martin-Zurro, A., Escobar del Ray, F., Morreale de Escobar, G. J. clin. Endocr. Metab 1974, 38, 21.
24. 25. 26. 27.
28.
1098. A.
Toft,
D., Irvine, W. J., Hunter, W. M., Ratchffe, J. G., Seth, J. ibid. 1974, 39, 607. Krugman, L. G., Hershman, J. M., Chopra, I. J., Levine, G. A., Pekary, A. E., Geffner, D. L., Chua Teco, G. N. ibid. 1975, 41, 70. Mühlen, A., Hesch, R. D., Kobberling, J. Clin. Endocr. 1975, 4, 165. Vagenakis, A. G., Braverman, L. E., Azizi, F., Portnay, G. I., Ingbar, S. H New Engl. J. Med. 1975, 293, 681. Demeester-Mirkine, N., Brauman, H., Corvilain, J. Clin. Endocr 1976, 5, 9.
29.
Spiegelberg, H. L. Adv. Immun. 1974, 19, 259. 30. Toft, A. D. M.D. thesis, University of Edinburgh, 1976.
AMINE METABOLISM AND THE SMALL BOWEL IN URÆMIA MICHAEL L. SIMENHOFF JUSSI J. SAUKKONEN LAURENCE G. WESSON JAMES F. BURKE RUSSELL W. SCHAEDLER
Departments of Medicine and Microbiology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Intestinal intubation was carried out in 21 subjects: 9 with end-stage renal fail2 with ure, early renal insufficiency, 7 untreated patients with blind-loop syndrome, and 3 normal volunteers. All 9 patients with uræmia had significantly raised duodenal dimethylamine (D.M.A.) concentrations compared with the other groups tested. Alteration of the intestinal bac-
Summary