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HORMONAL PATTERN OF RELAPSE IN HYPERTHYROIDISM
944
HORMONAL PATTERN OF RELAPSE IN HYPERTHYROIDISM P. MARSDEN S. CHALKLEY B. LEATHERDALE
P.
J. N. HOWORTH
M. ACOSTA C. G. MCKERRON
Departments of Medicine and Chemical Pathology, King’s College Hospital Medical School, London SE5; and Clinical Research Centre, Watford Road, Harrow, Middlesex
with Graves’ disease were up for up to a year after antithyroid drug therapy was discontinued. Clinical assessment and serum T3, T4, and thyroid-stimulatinghormone (T.S.H.) estimations were done serially and simultaneously. Serum T3 or T4 concentrations may be elevated briefly in the first few weeks after antithyroid drugs are stopped, as a rebound effect not necessarily indicative of subsequent relapse. Clinical relapse of hyperthyroidism with subsequent improvement on antithyroid drugs occurred in 13 patients. Of these 13, serum T3 concentrations became elevated before serum T4 concentrations in 5, thus predicting the subsequent development of clinical hyperthyroidism. In the remaining 8 patients who relapsed, serum T3 and T4 rose together in 7 and in 1 patient serum T4 was elevated a month before the serum T3. Hyperthyroidism was diagnosed clinically after elevated serum T3 concentrations in 11 patients and at the same time in 2 patients. The mean period of " biochemical hyperthyroidism" in these 11 patients was 12 weeks, with a range of 1 to 56 weeks. During this period 9 of the 11 had minor clinical changes attributable to hyperthyroidism. It is concluded that serial estimations of serum T3 provide the most reliable method of monitoring relapse in hyperthyroidism. 22
patients
Summary followed
Introduction
development of direct and simple radioimmunoassay techniques for serum T3 estimation has led to rapid progress in the knowledge of this hormone’s contribution to thyroid economy.-’ Hollander et al.4 showed that serum T3 concentrations may be elevated without elevated serum T concentrations in patients who subsequently develop hyperthyroidism. Jacobs et a1.5 reported a patient with T3 hyperthyroidism for a year before the development of a raised serum T4 concentration. The suggestion of THE
DR VESSEY AND OTHERS: REFERENCES 1. 2.
3. 4.
5. 6. 7. 8. 9. 10.
Vessey, M. P., Doll, R., Sutton, P. M. Br. med. J. 1972, iii, 719. Lowe, C. R., MacMahon, B. Lancet, 1970, i, 153. Valaoras, V. G., MacMahon, B., Trichopoulos, D., Polychronopoulou, A. Int. J. Cancer, 1969, 4, 350. MacMahon, B., Cole, P., Brown, J. J. natn. Cancer Inst. 1973, 50, 21. Davis, H. H., Simons, M., Davis, J. B. Cancer, 1964, 17, 957. Br. med. J. 1974, iii, 329. Sartwell, P. E., Arthes, F. G., Tonascia, J. A. New Engl. J. Med. 1973, 288, 551. Boston Collaborative Drug Surveillance Program, Lancet, 1973 i, 1399. Kelsey, J. L., Lindfors, K. K., White, C. Int. J. Epidem. 1974, 3, 333. Royal College of General Practitioners. Oral Contraceptives and Health.
London,
1974.
Alderson, M. R. in Reviews of United Kingdom Statistical Sources (edited by W. F. Maunder), vol. II. London, 1974. 12. Armstrong, B. Unpublished. 11.
Hollander et al.4 that many patients with hyperthyroidism may pass through a preliminary stage of T3 hyperthyroidism has been widely cited.6 However, the relative number of hyperthyroid patients who have " " premonitory rises of serum Tg has not been determined, nor has the relationship between serum concentrations of Tg and T and clinical thyroid status before and during the relapse of hyperthyroidism been evaluated. We describe here the hormonal patterns in a sequential study of patients with Graves’ disease who were being followed in case of relapse after a course of antithyroid drugs. The findings may have a practical bearing on the management of such patients. Methods
patients with Graves’ disease were studied by five physicians experienced in thyroid disease. All patients had just completed a course of antithyroid drugs for a previous episode of hyperthyroidism. In addition, 3 patients had previously received a therapeutic dose of radioactive iodine and 1 was studied after partial thyroidectomy. 18 of the patients were first assessed while still taking antithyroid drugs. The patients were evaluated at 1, 2, and 4 weeks off therapy and then at monthly intervals as far as possible. On each occasion thyroid status was evaluated clinically and blood was taken for estimation of Tg, T4, and thyroidstimulating hormone (T.S.H.), the serum being deep-frozen after centrifugation. Clinical evaluation was on a proforma, the physician being asked to note the symptoms and signs appropriate to Graves’ disease and then to evaluate thyroid status as hypothyroid, ,euthyroid, or hyperthyroid or as doubtful. The patients were followed for 7 to 13 months or until a relapse of hyperthyroidism occurred (in 13 cases). Hormone concentrations and clinical evaluations were then compared. At no time during the study were the results of hormone estimations available to the attending clinician. However, if clinical relapse was definite or strongly suspected, a separate serum T4 estimation was available to enable treatment to be given. In this way " clinical suspicion " was isolated from confirmation by laboratory tests. The level of clinical suspicion taken to be " diagnostic " was that point at which the clinician would feel justified in starting antithyroid drugs in a situation in which diagnostic tests were not available. Serum Tg concentration was measured by radioimmunoassay on unextracted serum,-; serum T4 concentration by a competitive protein-binding method 8.9; and serum T.s.H. by radioimmunoassay using M.R.C. rabbit antihuman T.s.H. preparation 68/58, human T.s.H. from N.I.H., Bethesda, U.S.A., as hormone for labelling by the chloramine-T method, and M.R.C. international reference preparation 68/38 for standards. Normal ranges were 0-2-2-0 ng. per ml. for serum T3; 40-110 ng. per ml. for serum T4; and <1-4.8 µu. per ml. for serum T.s.H. 22
Results
patients were initially assessed whilst on carbimazole (see accompanying table); all were considered clinically euthyroid. However, 2 had elevated serum Tg and T4 concentrations at the time and both relapsed clinically when carbimazole was stopped. 8 patients had normal serum Tg, T, and T.S.H. concentrations and 1 had normal serum Tg and T4 concentrations with a slightly elevated T.S.H. concentration of 8µu. per ml. 3 patients had normal serum Tg but low T4 concentra18
945 SERUM HORMONAL PATTERNS IN 16 CLINICALLY PATIENTS WHILST STILL TAKING CARBIMAZOLE, AND RELAPSE BEHAVIOUR
EUTHYROID
SUBSEQUENT
N== normal. = elevated. =low.
tions. In 2 of these the serum T .S.H. was elevated above 6 µu. per ml. and in 1 it was normal. 2 patients had low serum Tg but normal serum T4 concentrations. Serum T.s.H. was elevated in 1 and normal in the other. In 2 patients the data were incomplete. After stopping carbimazole, 5 patients remained clinically euthyroid for the whole period of observa-
tion and serum T3, T4, and T.S.H. concentrations remained within the normal range. 1 patient, who was clinically euthyroid throughout the study and is still so at present, had a serum T3 concentration of 2-1 ng. per ml. and a serum T4 concentration of 115 ng. per ml. on one occasion at 45 weeks off carbimazole. T3 and T, concentrations both before and after were entirely normal and serum T.S.H. concentrations were all <1 µu. per ml. 2 patients, 1 of whom subsequently relapsed at 8 months, had elevated serum T3 concentrations (2-6-2-2 ng. per ml.) in the first 2 weeks after stopping carbimazole therapy; the concentrations then became normal. A slower sequential rise of serum T4 concentrations above the normal range (110-125 ng. per ml.) was seen in 2 further patients up to 12 weeks. in Serum T3 concentrations rose significantly (P<0.05) parallel in both patients, becoming abnormal in 1. Serum T.S.H. concentrations were <1 gu. per ml. at the time of the raised serum T or T concentrations. Neither patient subsequently relapsed. A relapse of hyperthyroidism occurred clinically in 13 patients. The serum T3 was elevated before the serum T4 and before the clinical diagnosis was made in 5 patients. In 1 of these 5, elevation of serum T3 preceded elevation of serum T4 by only a week. In 3 patients there was a sustained rise of serum T3
Three hormonal patterns of relapse encountered: (a) premonitory T hyperthyroidism; (b) simultaneous rise of T, and T,,; (c) early relapse of hyperthyroidism with a " T, phase " of only 1 week. The time of clinical diagnosis of hyperthyroidism is indicated by the vertical arrows, and clinical doubt of hyperthyroidism
expressed by the clinician by a question mark. c.M.z. = carbimazole.
946
dissociated in some patients is not clear. Only 1 of the 4 patients with a prolonged premonitory T3 phase had received a previous therapeutic dose of radioiodine. The other 2 patients who had received radioiodine therapy both relapsed with simultaneous elevations of Tg and T,. However, as, in general, patients were seen monthly after the first month’s observation, a short premonitory Tg phase, actually observed in 1 patient, could not be excluded in more patients first observed with elevated T3 and T, concentrations. The clinical diagnosis of relapse was made simul. taneously with a rise of serum T3 and T4 in 2 cases and with a rise of serum T4 after a premonitory rise of serum T3 in a 3rd. Clinical diagnosis lagged behind elevations of serum T3 and T4 in all other cases. Of the patients with a premonitory rise of serum Tg the clinical diagnosis was made before a rise in serum T, in 2; and of the 4 patients with a prolonged premonitory phase, minor clinical changes attributable to hyperthyroidism were present during this phase in 3. The subsequent development of overt hyperthyroidism in these patients with persistent elevation of serum T leads us to suggest that they may be in " a state of subclinical hyperthyroidism ", as has been " previously suggested in patients with "hot nodules" of the thyroid and in patients with euthyroid ophthalmic Graves’ disease."’ Such a suggestion is supported by the findings of Evered et al.12 that such patients with " hot nodules " may have absent responses of serum T.S.H. to thyrotropin-releasing hormone (T.R.H.). These suggestions are also consonant with the hypothesis that T3 and not T, is the active thyroid hormone. However, in other circumstances such as iodine T4. Of the 11 patients in whom clinical diagnosis lagged deficiency 13 or in patients on antithyroid drugs or behind elevated serum-hormone concentrations, clinical following radioiodine therapy/’ an elevated serum Ta doubt on the basis of minor symptoms or signs was concentration may not indicate that the patient is in in the 9 when horperiod expressed intermittently hyperthyroid but in a state of " compensated euthymone concentrations were elevated. The mean period roidism ". Such patients may have a low serum T, of " biochemical hyperthyroidism " was 12 weeks with and a high serum T.S.H. concentration, and under such a range of 1 to 56 weeks. Serum T.S.H. concentrations circumstances measurements of T3, T4, and T.S.H. as observed during this period remained suppressed. well as full clinical assessment will be necessary to define thyroid status. In this study, of those patients Discussion assessed whilst taking carbimazole therapy, the only 2 with elevated serum T3 concentrations also had elevated Elevated serum Ts concentrations in the first 2 weeks serum T, concentrations and both subsequently reafter discontinuance of antithyroid drugs do not neceslapsed clinically when therapy was stopped. sarily indicate subsequent relapse of hyperthyroidism. It is generally recognised as sound clinical practice These changes and subsequent changes in serum T4 and T3 appear to occur while serum T.s.H. concentrato consider the results of laboratory investigations in the light of clinical evaluation. In certain conditions, tions are suppressed, and hence may be looked upon as autoregulatory thyroidal responses. however, such as primary hyperparathyroidism, Elevations of serum T3 occurred as the earliest maniclinical diagnosis is less precise than a biochemical festation of relapse in 5 cases. In 1 patient both parameter, such as the serum-calcium estimation.15-16 Patients with Graves’ disease who are euthyroid serum T3 and T4 were rising but serum Tg became abnormal a week before serum T4’ Serum T3 may clinically and have just completed a course of antitherefore reflect rapid changes in thyroid function more thyroid drugs are at a different stage of the natural does serum as has been in observed faithfully than T4) history of the disorder than a new or recurrent case other situations such as the control of hyperthyroidism presenting to the physician because of symptoms. This by large doses of stable iodine.10 In 4 other patients study suggests that clinical evaluation under the former serum T3 was elevated for a long time before serum circumstances is inferior as a prognostic index. It is not suggested that elevated serum Tg or T4 concentraT4, and in 1 of these the serum T did not become elevated before treatment was given. In over half the tions in such a clinically euthyroid patient should patients who relapsed, serum T3 and T4 were first necessarily be taken as indicative of hyperthyroidism observed to be elevated simultaneously. Why the necessitating treatment. However, if serum T3 conbehaviour of Ts and T4 should thus be qualitatively centrations had been available to the clinicians at the
for 4, 12, and 14 weeks. In the 5th patient the serum T4 did not become elevated before a confident clinical diagnosis of hyperthyroidism was made. The patient was then given treatment. This patient, but not the other 4, had previously received a therapeutic dose of radioactive iodine. In the period before serum T became elevated and before a relapse was diagnosed clinically, 3 of the patients with a prolonged premonitory rise of serum Ts exhibited minor or isolated clinical changes such as tachycardia or slight weight loss compatible with mild hyperthyroidism but, in the light of the whole clinical picture, not interpreted at the time as suggestive of relapse. In 7 patients who relapsed, serum T3 and T concentrations became elevated simultaneously. In 1 case the serum T was slightly elevated (115 ng. per ml.) when the patient was first observed 3 months after partial thyroidectomy. The serum T3 was normal (1.6 ng. per ml.) at this time and the patient was clinically euthyroid. A month later both serum T3 and T4 were elevated and subsequently remained so until the patient relapsed clinically. The accompanying figure shows three relapse patterns encountered. The clinical diagnosis of relapse was made subsequent to elevated serum Tg concentrations in 11 cases, synchronously in 2 cases, and never before the serum Ts became elevated. The clinical diagnosis was made subsequent to elevated serum T concentrations in 8 cases, synchronously in 3 cases, and prior to elevation of serum T4 (Ts-toxicosis) in 2 cases. In 2 patients in whom the clinical diagnosis was made synchronously there were simultaneous sudden rises of T3 and T., and in the 3rd T3 had been elevated before
947
time of assessment, more weight may have been on those clinical features that were present.
which had a complete remission after intensive radiotherapy followed by a relapse of disease, prior to receiving combination chemotherapy, had the highest risk with 18·5 times greater incidence of second tumour than expected. It is noteworthy that, of the 16 second tumours, 2 were acute myeloid leukæmia; in both cases a similar chromosomal abnormality (45 chromosomes, C-group deletion) was noted. The mechanism of oncogenesis may represent a combination of the immunosuppressive effects and cellular effects of those forms of treatment.
placed
In any event we submit that serial serum T3 estimations appear to offer the most reliable method of monitoring patients for the recurrence of hyperthyroidism after a course of antithyroid drugs. Repeated clinical evaluation under these circumstances is time-consuming and expensive. Such a screening programme could well be coordinated with automated
follow-up proceduresP We are grateful to the King’s College Hospital voluntary research fund and to Nicholas Laboratories Ltd. for financial help, and to Mr Paul Facer for technical assistance.
Introduction IT is well known that some forms of malignant disease are associated with an increased likelihood of other tumours developing. Acute leukxmia complicating the course of polycythaemia vera and an increased incidence of skin cancer in chronic lymphocytic leukaemia have been described.2 It is not clear whether the disease itself renders the host more prone to second tumours or whether the therapy in certain settings is capable of inducing cellular changes or suppressed immunity which can subsequently lead to tumour formation. The oncogenic potential of radiation and/or chemotherapy in second-tumour induction can be best studied in those patients with advanced malignant disease who survive for long periods after successful
Requests for reprints should be addressed to P. M., DepartMedicine, King’s College Hospital, London SE58RX.
ment of
REFERENCES
Brown, B. L., Ekins, R. P., Ellis, S. M., Williams, E. S. Proceedings of the fourth annual meeting of the European Thyroid Association, 1970, p. 1107. 2. Mitsuma, T., Colucci, J., Shenkman, L., Hollander, C. S. Biochem. biophys. Res. Commun. 1972, 46, 2107. 3. Larsen, P. R. Metabolism, 1972, 21, 1073. 4. Hollander, C. S., Mitsuma, T., Kastin, A. J., Shenkman, L., Blum, M., Anderson, D. G. Lancet, 1971, ii, 731. 5. Jacobs, H. S., Eastman, C. J., Ekins, R. P., Mackie, D. B., Ellis, S. M., McHardy-Young, S. ibid. 1973, ii, 236. 6. Hall, R., Anderson, J., Smart, G. A., Besser, M. Fundamentals of Clinical Endocrinology; p. 117. London, 1974. 7. Marsden, P., McKerron, C. G. Clin. Endocr. 1975, 4, 183. 8. Gyde, O. H. B., Hirst, A. D., Howorth, P. J. N. Clinica chim. Acta, 1973, 45, 443. 9. Howorth, P. J. N., McKerron, C. G. J. clin. Path. 1974, 27, 153. 10. Marsden, P., McKerron, C. G. Clin. Sci. mol. Med. 1974, 47, 4P (abstr.). 11. Ormston, B. J., Alexander, L., Evered, D. C., Clark, F., Bird, T., Appleton, D., Hall, R. Clin. Endocr. 1973, 2, 369. 12. Evered, D. C., Clark, F., Petersen, V. B. ibid. 1974, 3, 149. 13. Pharaoh, P. O. D., Lawton, N. F., Ellis, S. M., Williams, E. S., Ekins, R. P. ibid. 1973, 2, 193. 14. Patel, V. C., Burger, H. G. ibid. p. 339. 15. Marsden, P., Anderson, J., Doyle, D., Morris, B. A., Burns, D. A. Br. med. J. 1971, iii, 87. 16. Graber, A. L., Jacobs, K. J. Am. med. Ass. 1968, 204, 502. 17. Hedley, A. J., Scott, A. M., Deans Weir, R., Crooks, J. Br. med. J. 1970, i, 556. 1.
treatment.
In the past
National
Methods
VINCENT T. DEVITA
JACQUELINE WHANG-PENG RALPH E. C. JOHNSON Medicine, Radiation Branches, Cancer Institute, Bethesda, Maryland 20014, U.S.A.
The Summary
incidence
of
second
years, advances in the treatment of
advanced and localised disease has resulted in a population in which the potential oncogenic effect of these intensive modalities alone or in combination can be studied. We have analysed the risk of second tumours developing in patients with Hodgkin’s disease whose treatment and follow-up for the entire course of the disease were performed in one clinic.
SECOND MALIGNANCIES COMPLICATING HODGKIN’S DISEASE IN REMISSION GEORGE P. CANELLOS JAMES C. ARSENEAU
ten
Hodgkin’s disease have resulted from the intensive application of radiation or chemotherapy in high dosage and over long periods of time.’,’ The prolonged disease-free survival of patients with both
tumours
occurring in the course of Hodgkin’s disease has been investigated in a series of 452 patients treated with standard chemotherapy or radiotherapy, combination chemotherapy alone, intensive radiotherapy alone, or both intensive radiotherapy and combination chemotherapy administered in sequence. 16 tumours were noted. When analysed according mode of treatment, 6 cases occurred in a group of patients who received both modalities. When analysed for age, sex, and man-years of follow-up, this group appears to have 14·5 times the risk of developing a second tumour. However, that subgroup
to
62
’
452 cases of Hodgkin’s disease treated and followed at N.C.I. were divided into subgroups according to the type of treatment received and the incidence of new second malignancies recorded. Almost all cases were referred shortly after diagnosis and were previously untreated. Complete follow-up was available on all cases. The data are calculated on the basis of age, sex, and man-years of observation and the expected risk of second tumours derived from the Third National Cancer Survey of 1969. The data are expressed as ratios of the observed over the expected incidence. The category of intensive chemotherapy (r.c.) includes patients who received at least six monthly cycles of combination chemotherapy (M.o.p.p.): nitrogen mustard 6 mg. per sq. m. intravenously and vincristine 1’4 mg. per sq. m. intravenously are given on days 1 and 8 and procarbazine 100 mg. per sq. m. orally on days 1-14. Prednisone 40 mg. per sq. m. orally is given on days 1-14 of the lst and 4th cycles. No therapy is given on days 15-28.4.5 Intensive radiation (I.R.) therapy includes the application of at least 3000 r in a unified course of treatment to all axial lymph-node regions (total nodal irradiation); or
HORMONAL PATTERN OF RELAPSE IN HYPERTHYROIDISM P. MARSDEN S. CHALKLEY B. LEATHERDALE
P.
J. N. HOWORTH
M. ACOSTA C. G. MCKERRON
Departments of Medicine and Chemical Pathology, King’s College Hospital Medical School, London SE5; and Clinical Research Centre, Watford Road, Harrow, Middlesex
with Graves’ disease were up for up to a year after antithyroid drug therapy was discontinued. Clinical assessment and serum T3, T4, and thyroid-stimulatinghormone (T.S.H.) estimations were done serially and simultaneously. Serum T3 or T4 concentrations may be elevated briefly in the first few weeks after antithyroid drugs are stopped, as a rebound effect not necessarily indicative of subsequent relapse. Clinical relapse of hyperthyroidism with subsequent improvement on antithyroid drugs occurred in 13 patients. Of these 13, serum T3 concentrations became elevated before serum T4 concentrations in 5, thus predicting the subsequent development of clinical hyperthyroidism. In the remaining 8 patients who relapsed, serum T3 and T4 rose together in 7 and in 1 patient serum T4 was elevated a month before the serum T3. Hyperthyroidism was diagnosed clinically after elevated serum T3 concentrations in 11 patients and at the same time in 2 patients. The mean period of " biochemical hyperthyroidism" in these 11 patients was 12 weeks, with a range of 1 to 56 weeks. During this period 9 of the 11 had minor clinical changes attributable to hyperthyroidism. It is concluded that serial estimations of serum T3 provide the most reliable method of monitoring relapse in hyperthyroidism. 22
patients
Summary followed
Introduction
development of direct and simple radioimmunoassay techniques for serum T3 estimation has led to rapid progress in the knowledge of this hormone’s contribution to thyroid economy.-’ Hollander et al.4 showed that serum T3 concentrations may be elevated without elevated serum T concentrations in patients who subsequently develop hyperthyroidism. Jacobs et a1.5 reported a patient with T3 hyperthyroidism for a year before the development of a raised serum T4 concentration. The suggestion of THE
DR VESSEY AND OTHERS: REFERENCES 1. 2.
3. 4.
5. 6. 7. 8. 9. 10.
Vessey, M. P., Doll, R., Sutton, P. M. Br. med. J. 1972, iii, 719. Lowe, C. R., MacMahon, B. Lancet, 1970, i, 153. Valaoras, V. G., MacMahon, B., Trichopoulos, D., Polychronopoulou, A. Int. J. Cancer, 1969, 4, 350. MacMahon, B., Cole, P., Brown, J. J. natn. Cancer Inst. 1973, 50, 21. Davis, H. H., Simons, M., Davis, J. B. Cancer, 1964, 17, 957. Br. med. J. 1974, iii, 329. Sartwell, P. E., Arthes, F. G., Tonascia, J. A. New Engl. J. Med. 1973, 288, 551. Boston Collaborative Drug Surveillance Program, Lancet, 1973 i, 1399. Kelsey, J. L., Lindfors, K. K., White, C. Int. J. Epidem. 1974, 3, 333. Royal College of General Practitioners. Oral Contraceptives and Health.
London,
1974.
Alderson, M. R. in Reviews of United Kingdom Statistical Sources (edited by W. F. Maunder), vol. II. London, 1974. 12. Armstrong, B. Unpublished. 11.
Hollander et al.4 that many patients with hyperthyroidism may pass through a preliminary stage of T3 hyperthyroidism has been widely cited.6 However, the relative number of hyperthyroid patients who have " " premonitory rises of serum Tg has not been determined, nor has the relationship between serum concentrations of Tg and T and clinical thyroid status before and during the relapse of hyperthyroidism been evaluated. We describe here the hormonal patterns in a sequential study of patients with Graves’ disease who were being followed in case of relapse after a course of antithyroid drugs. The findings may have a practical bearing on the management of such patients. Methods
patients with Graves’ disease were studied by five physicians experienced in thyroid disease. All patients had just completed a course of antithyroid drugs for a previous episode of hyperthyroidism. In addition, 3 patients had previously received a therapeutic dose of radioactive iodine and 1 was studied after partial thyroidectomy. 18 of the patients were first assessed while still taking antithyroid drugs. The patients were evaluated at 1, 2, and 4 weeks off therapy and then at monthly intervals as far as possible. On each occasion thyroid status was evaluated clinically and blood was taken for estimation of Tg, T4, and thyroidstimulating hormone (T.S.H.), the serum being deep-frozen after centrifugation. Clinical evaluation was on a proforma, the physician being asked to note the symptoms and signs appropriate to Graves’ disease and then to evaluate thyroid status as hypothyroid, ,euthyroid, or hyperthyroid or as doubtful. The patients were followed for 7 to 13 months or until a relapse of hyperthyroidism occurred (in 13 cases). Hormone concentrations and clinical evaluations were then compared. At no time during the study were the results of hormone estimations available to the attending clinician. However, if clinical relapse was definite or strongly suspected, a separate serum T4 estimation was available to enable treatment to be given. In this way " clinical suspicion " was isolated from confirmation by laboratory tests. The level of clinical suspicion taken to be " diagnostic " was that point at which the clinician would feel justified in starting antithyroid drugs in a situation in which diagnostic tests were not available. Serum Tg concentration was measured by radioimmunoassay on unextracted serum,-; serum T4 concentration by a competitive protein-binding method 8.9; and serum T.s.H. by radioimmunoassay using M.R.C. rabbit antihuman T.s.H. preparation 68/58, human T.s.H. from N.I.H., Bethesda, U.S.A., as hormone for labelling by the chloramine-T method, and M.R.C. international reference preparation 68/38 for standards. Normal ranges were 0-2-2-0 ng. per ml. for serum T3; 40-110 ng. per ml. for serum T4; and <1-4.8 µu. per ml. for serum T.s.H. 22
Results
patients were initially assessed whilst on carbimazole (see accompanying table); all were considered clinically euthyroid. However, 2 had elevated serum Tg and T4 concentrations at the time and both relapsed clinically when carbimazole was stopped. 8 patients had normal serum Tg, T, and T.S.H. concentrations and 1 had normal serum Tg and T4 concentrations with a slightly elevated T.S.H. concentration of 8µu. per ml. 3 patients had normal serum Tg but low T4 concentra18
945 SERUM HORMONAL PATTERNS IN 16 CLINICALLY PATIENTS WHILST STILL TAKING CARBIMAZOLE, AND RELAPSE BEHAVIOUR
EUTHYROID
SUBSEQUENT
N== normal. = elevated. =low.
tions. In 2 of these the serum T .S.H. was elevated above 6 µu. per ml. and in 1 it was normal. 2 patients had low serum Tg but normal serum T4 concentrations. Serum T.s.H. was elevated in 1 and normal in the other. In 2 patients the data were incomplete. After stopping carbimazole, 5 patients remained clinically euthyroid for the whole period of observa-
tion and serum T3, T4, and T.S.H. concentrations remained within the normal range. 1 patient, who was clinically euthyroid throughout the study and is still so at present, had a serum T3 concentration of 2-1 ng. per ml. and a serum T4 concentration of 115 ng. per ml. on one occasion at 45 weeks off carbimazole. T3 and T, concentrations both before and after were entirely normal and serum T.S.H. concentrations were all <1 µu. per ml. 2 patients, 1 of whom subsequently relapsed at 8 months, had elevated serum T3 concentrations (2-6-2-2 ng. per ml.) in the first 2 weeks after stopping carbimazole therapy; the concentrations then became normal. A slower sequential rise of serum T4 concentrations above the normal range (110-125 ng. per ml.) was seen in 2 further patients up to 12 weeks. in Serum T3 concentrations rose significantly (P<0.05) parallel in both patients, becoming abnormal in 1. Serum T.S.H. concentrations were <1 gu. per ml. at the time of the raised serum T or T concentrations. Neither patient subsequently relapsed. A relapse of hyperthyroidism occurred clinically in 13 patients. The serum T3 was elevated before the serum T4 and before the clinical diagnosis was made in 5 patients. In 1 of these 5, elevation of serum T3 preceded elevation of serum T4 by only a week. In 3 patients there was a sustained rise of serum T3
Three hormonal patterns of relapse encountered: (a) premonitory T hyperthyroidism; (b) simultaneous rise of T, and T,,; (c) early relapse of hyperthyroidism with a " T, phase " of only 1 week. The time of clinical diagnosis of hyperthyroidism is indicated by the vertical arrows, and clinical doubt of hyperthyroidism
expressed by the clinician by a question mark. c.M.z. = carbimazole.
946
dissociated in some patients is not clear. Only 1 of the 4 patients with a prolonged premonitory T3 phase had received a previous therapeutic dose of radioiodine. The other 2 patients who had received radioiodine therapy both relapsed with simultaneous elevations of Tg and T,. However, as, in general, patients were seen monthly after the first month’s observation, a short premonitory Tg phase, actually observed in 1 patient, could not be excluded in more patients first observed with elevated T3 and T, concentrations. The clinical diagnosis of relapse was made simul. taneously with a rise of serum T3 and T4 in 2 cases and with a rise of serum T4 after a premonitory rise of serum T3 in a 3rd. Clinical diagnosis lagged behind elevations of serum T3 and T4 in all other cases. Of the patients with a premonitory rise of serum Tg the clinical diagnosis was made before a rise in serum T, in 2; and of the 4 patients with a prolonged premonitory phase, minor clinical changes attributable to hyperthyroidism were present during this phase in 3. The subsequent development of overt hyperthyroidism in these patients with persistent elevation of serum T leads us to suggest that they may be in " a state of subclinical hyperthyroidism ", as has been " previously suggested in patients with "hot nodules" of the thyroid and in patients with euthyroid ophthalmic Graves’ disease."’ Such a suggestion is supported by the findings of Evered et al.12 that such patients with " hot nodules " may have absent responses of serum T.S.H. to thyrotropin-releasing hormone (T.R.H.). These suggestions are also consonant with the hypothesis that T3 and not T, is the active thyroid hormone. However, in other circumstances such as iodine T4. Of the 11 patients in whom clinical diagnosis lagged deficiency 13 or in patients on antithyroid drugs or behind elevated serum-hormone concentrations, clinical following radioiodine therapy/’ an elevated serum Ta doubt on the basis of minor symptoms or signs was concentration may not indicate that the patient is in in the 9 when horperiod expressed intermittently hyperthyroid but in a state of " compensated euthymone concentrations were elevated. The mean period roidism ". Such patients may have a low serum T, of " biochemical hyperthyroidism " was 12 weeks with and a high serum T.S.H. concentration, and under such a range of 1 to 56 weeks. Serum T.S.H. concentrations circumstances measurements of T3, T4, and T.S.H. as observed during this period remained suppressed. well as full clinical assessment will be necessary to define thyroid status. In this study, of those patients Discussion assessed whilst taking carbimazole therapy, the only 2 with elevated serum T3 concentrations also had elevated Elevated serum Ts concentrations in the first 2 weeks serum T, concentrations and both subsequently reafter discontinuance of antithyroid drugs do not neceslapsed clinically when therapy was stopped. sarily indicate subsequent relapse of hyperthyroidism. It is generally recognised as sound clinical practice These changes and subsequent changes in serum T4 and T3 appear to occur while serum T.s.H. concentrato consider the results of laboratory investigations in the light of clinical evaluation. In certain conditions, tions are suppressed, and hence may be looked upon as autoregulatory thyroidal responses. however, such as primary hyperparathyroidism, Elevations of serum T3 occurred as the earliest maniclinical diagnosis is less precise than a biochemical festation of relapse in 5 cases. In 1 patient both parameter, such as the serum-calcium estimation.15-16 Patients with Graves’ disease who are euthyroid serum T3 and T4 were rising but serum Tg became abnormal a week before serum T4’ Serum T3 may clinically and have just completed a course of antitherefore reflect rapid changes in thyroid function more thyroid drugs are at a different stage of the natural does serum as has been in observed faithfully than T4) history of the disorder than a new or recurrent case other situations such as the control of hyperthyroidism presenting to the physician because of symptoms. This by large doses of stable iodine.10 In 4 other patients study suggests that clinical evaluation under the former serum T3 was elevated for a long time before serum circumstances is inferior as a prognostic index. It is not suggested that elevated serum Tg or T4 concentraT4, and in 1 of these the serum T did not become elevated before treatment was given. In over half the tions in such a clinically euthyroid patient should patients who relapsed, serum T3 and T4 were first necessarily be taken as indicative of hyperthyroidism observed to be elevated simultaneously. Why the necessitating treatment. However, if serum T3 conbehaviour of Ts and T4 should thus be qualitatively centrations had been available to the clinicians at the
for 4, 12, and 14 weeks. In the 5th patient the serum T4 did not become elevated before a confident clinical diagnosis of hyperthyroidism was made. The patient was then given treatment. This patient, but not the other 4, had previously received a therapeutic dose of radioactive iodine. In the period before serum T became elevated and before a relapse was diagnosed clinically, 3 of the patients with a prolonged premonitory rise of serum Ts exhibited minor or isolated clinical changes such as tachycardia or slight weight loss compatible with mild hyperthyroidism but, in the light of the whole clinical picture, not interpreted at the time as suggestive of relapse. In 7 patients who relapsed, serum T3 and T concentrations became elevated simultaneously. In 1 case the serum T was slightly elevated (115 ng. per ml.) when the patient was first observed 3 months after partial thyroidectomy. The serum T3 was normal (1.6 ng. per ml.) at this time and the patient was clinically euthyroid. A month later both serum T3 and T4 were elevated and subsequently remained so until the patient relapsed clinically. The accompanying figure shows three relapse patterns encountered. The clinical diagnosis of relapse was made subsequent to elevated serum Tg concentrations in 11 cases, synchronously in 2 cases, and never before the serum Ts became elevated. The clinical diagnosis was made subsequent to elevated serum T concentrations in 8 cases, synchronously in 3 cases, and prior to elevation of serum T4 (Ts-toxicosis) in 2 cases. In 2 patients in whom the clinical diagnosis was made synchronously there were simultaneous sudden rises of T3 and T., and in the 3rd T3 had been elevated before
947
time of assessment, more weight may have been on those clinical features that were present.
which had a complete remission after intensive radiotherapy followed by a relapse of disease, prior to receiving combination chemotherapy, had the highest risk with 18·5 times greater incidence of second tumour than expected. It is noteworthy that, of the 16 second tumours, 2 were acute myeloid leukæmia; in both cases a similar chromosomal abnormality (45 chromosomes, C-group deletion) was noted. The mechanism of oncogenesis may represent a combination of the immunosuppressive effects and cellular effects of those forms of treatment.
placed
In any event we submit that serial serum T3 estimations appear to offer the most reliable method of monitoring patients for the recurrence of hyperthyroidism after a course of antithyroid drugs. Repeated clinical evaluation under these circumstances is time-consuming and expensive. Such a screening programme could well be coordinated with automated
follow-up proceduresP We are grateful to the King’s College Hospital voluntary research fund and to Nicholas Laboratories Ltd. for financial help, and to Mr Paul Facer for technical assistance.
Introduction IT is well known that some forms of malignant disease are associated with an increased likelihood of other tumours developing. Acute leukxmia complicating the course of polycythaemia vera and an increased incidence of skin cancer in chronic lymphocytic leukaemia have been described.2 It is not clear whether the disease itself renders the host more prone to second tumours or whether the therapy in certain settings is capable of inducing cellular changes or suppressed immunity which can subsequently lead to tumour formation. The oncogenic potential of radiation and/or chemotherapy in second-tumour induction can be best studied in those patients with advanced malignant disease who survive for long periods after successful
Requests for reprints should be addressed to P. M., DepartMedicine, King’s College Hospital, London SE58RX.
ment of
REFERENCES
Brown, B. L., Ekins, R. P., Ellis, S. M., Williams, E. S. Proceedings of the fourth annual meeting of the European Thyroid Association, 1970, p. 1107. 2. Mitsuma, T., Colucci, J., Shenkman, L., Hollander, C. S. Biochem. biophys. Res. Commun. 1972, 46, 2107. 3. Larsen, P. R. Metabolism, 1972, 21, 1073. 4. Hollander, C. S., Mitsuma, T., Kastin, A. J., Shenkman, L., Blum, M., Anderson, D. G. Lancet, 1971, ii, 731. 5. Jacobs, H. S., Eastman, C. J., Ekins, R. P., Mackie, D. B., Ellis, S. M., McHardy-Young, S. ibid. 1973, ii, 236. 6. Hall, R., Anderson, J., Smart, G. A., Besser, M. Fundamentals of Clinical Endocrinology; p. 117. London, 1974. 7. Marsden, P., McKerron, C. G. Clin. Endocr. 1975, 4, 183. 8. Gyde, O. H. B., Hirst, A. D., Howorth, P. J. N. Clinica chim. Acta, 1973, 45, 443. 9. Howorth, P. J. N., McKerron, C. G. J. clin. Path. 1974, 27, 153. 10. Marsden, P., McKerron, C. G. Clin. Sci. mol. Med. 1974, 47, 4P (abstr.). 11. Ormston, B. J., Alexander, L., Evered, D. C., Clark, F., Bird, T., Appleton, D., Hall, R. Clin. Endocr. 1973, 2, 369. 12. Evered, D. C., Clark, F., Petersen, V. B. ibid. 1974, 3, 149. 13. Pharaoh, P. O. D., Lawton, N. F., Ellis, S. M., Williams, E. S., Ekins, R. P. ibid. 1973, 2, 193. 14. Patel, V. C., Burger, H. G. ibid. p. 339. 15. Marsden, P., Anderson, J., Doyle, D., Morris, B. A., Burns, D. A. Br. med. J. 1971, iii, 87. 16. Graber, A. L., Jacobs, K. J. Am. med. Ass. 1968, 204, 502. 17. Hedley, A. J., Scott, A. M., Deans Weir, R., Crooks, J. Br. med. J. 1970, i, 556. 1.
treatment.
In the past
National
Methods
VINCENT T. DEVITA
JACQUELINE WHANG-PENG RALPH E. C. JOHNSON Medicine, Radiation Branches, Cancer Institute, Bethesda, Maryland 20014, U.S.A.
The Summary
incidence
of
second
years, advances in the treatment of
advanced and localised disease has resulted in a population in which the potential oncogenic effect of these intensive modalities alone or in combination can be studied. We have analysed the risk of second tumours developing in patients with Hodgkin’s disease whose treatment and follow-up for the entire course of the disease were performed in one clinic.
SECOND MALIGNANCIES COMPLICATING HODGKIN’S DISEASE IN REMISSION GEORGE P. CANELLOS JAMES C. ARSENEAU
ten
Hodgkin’s disease have resulted from the intensive application of radiation or chemotherapy in high dosage and over long periods of time.’,’ The prolonged disease-free survival of patients with both
tumours
occurring in the course of Hodgkin’s disease has been investigated in a series of 452 patients treated with standard chemotherapy or radiotherapy, combination chemotherapy alone, intensive radiotherapy alone, or both intensive radiotherapy and combination chemotherapy administered in sequence. 16 tumours were noted. When analysed according mode of treatment, 6 cases occurred in a group of patients who received both modalities. When analysed for age, sex, and man-years of follow-up, this group appears to have 14·5 times the risk of developing a second tumour. However, that subgroup
to
62
’
452 cases of Hodgkin’s disease treated and followed at N.C.I. were divided into subgroups according to the type of treatment received and the incidence of new second malignancies recorded. Almost all cases were referred shortly after diagnosis and were previously untreated. Complete follow-up was available on all cases. The data are calculated on the basis of age, sex, and man-years of observation and the expected risk of second tumours derived from the Third National Cancer Survey of 1969. The data are expressed as ratios of the observed over the expected incidence. The category of intensive chemotherapy (r.c.) includes patients who received at least six monthly cycles of combination chemotherapy (M.o.p.p.): nitrogen mustard 6 mg. per sq. m. intravenously and vincristine 1’4 mg. per sq. m. intravenously are given on days 1 and 8 and procarbazine 100 mg. per sq. m. orally on days 1-14. Prednisone 40 mg. per sq. m. orally is given on days 1-14 of the lst and 4th cycles. No therapy is given on days 15-28.4.5 Intensive radiation (I.R.) therapy includes the application of at least 3000 r in a unified course of treatment to all axial lymph-node regions (total nodal irradiation); or