hyperthyroidism appreciated that subnormal TSH levels also occur

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1 Thyrotropin results in euthyroid patients with a past history of hyperthyroidism Bevan E. W. Brownlie and Helen M. Legge Department of Nuclear Medicine, Christchurch Hospital, Christchurch, New Zealand Abstract. Sensitive TSH levels were measured in 93 euthyroid patients with a past history of hyperthyroidism. Subnormal TSH values were found in 18 out of 75 (24%) patients previously treated with a course of antithyroid drugs, and in 3 out of 18 (17%) post-thyroidectomy patients. These subnormal TSH results are a limitation to the general applicationof the TSH-first strategy. Twelve months follow-up showed that subnormal TSH values are associated with increased risk of relapse in the antithyroid drug treated group (p<0.001). Longer follow-up varies in duration and some late relapses have occurred in drug treated patients with normal baseline TSH levels. To date relapses have occurred in 3 out of 56 normal TSH patients compared with in 6 out of 16 suppressed TSH patients; no thyroidectomy patients have relapsed. Prospective studies are needed to confirm the predictive value of sensitive TSH measurements. Sensitive thyrotropin assays using monoclonal an tibody technology are now generally available and have been a major advance in thyroid function test ing. These new immunometric TSH methods are 10 times more sensitive than the older radioimmunoassays and accurately discriminate between euthyroid and hyperthyroid patients. The finding of subnormal and often undetectable TSH levels (<0.1 mu/1) has become an important diagnostic criterion for hyperthyroidism, and in clinically marginal cases it is no longer necessary to perform TRH tests to confirm pituitary thyrotrope suppres sion (1). Clinicians, however, are currently experi encing problems interpreting subnormal TSH re sults in clinically euthyroid patients (2). It is now appreciated that subnormal TSH levels also occur in a variety of nonthyroidal conditions and these have been reviewed in editorials (3-5). TSH levels may remain suppressed for some weeks after medical control of hyperthyroidism due to delayed recovery of the thyrotropes, but recent reviews have made little comment on TSH results in patients with a past history of thyrotoxicosis. In this study we have assessed the frequency of subnormal TSH levels in euthyroid patients with a past history of hyperthyroidism. Patients and Methods Serum TSH levels were measured by a sensitive immu- (Maiaclone, noradiometric magnetic solid-phase assay Serono Diagnostics) which has a lower limit of sensitivity of <0.1 mu/1 (Serono data). The normal range of this laboratory is mu/1 (45 normal hospital workers, 23 female and 22 male, aged years) and the inter-assay and intra-assay coefficients of variation were 10% for a 0.4 mu/1 control sample. All samples were assayed in du plicate. Serum T4 was measured by radioimmunoassay (normal nmol/1), free T4 index (FT4I, normal ) was calculated from the product of T4 and T3 resin uptake ratio (normal ), and serum T3 was measured by radioimmunoassay (normal nmol/1) (6). Statistical comparisons between the outcome groups were made using either the Chi-square test or Student's i-test, as appropriate.

2 - - Patients Ninety-three patients with a past history of hyperthyroid ism were studied. Blood samples were taken when they attended for annual follow-up to detect possible relapse. The study population was confined to patients with normal FT4I, serum T3 and plasma TSH by radioimmu noassay (normal <5 mu/1). Group I. Patients previously treated with a 12-month course of antithyroid drugs; and euthyroid without med ication for at least 1 year. Seventy-five were patients stud ied, 66 females and 9 males, with a mean age of 47 years (range 9-73). This group included 66 patients with dif fuse hyperplasia, and 9 with toxic multinodular goitre as assessed by 99mTc pertechnetate thyroid scan. The mean time without medication was 5.1 years (range 1-14, with 14 patients off medication for less than 2 years). Group II. Post-thyroidectomy patients, with all patients at least 1 year post-surgery and patients on thyroxine ther apy excluded. This group of 18 patients (16 females, 2 males) had a mean age 35 years (range 16-60). Seventeen patients had diffuse hyperplasia and 1 patient toxic mul tinodular goitre. The mean time following surgery was 8.8 years (range , with 2 patients less than 2 years post-thyroidectomy). Further blood samples were available after 12 months for all patients except for 2 patients who were lost to follow-up one post-thyroidectomy patient and 1 patient from the antithyroid drug group; a further patient from the antithyroid drug group currently overseas remains clinically well with normal FT4I. Results The TSH results are shown in Fig. 1. The majority of patients previously treated with antithyroid drugs (Group I) had normal TSH results, but 24% (18 out of 75) had subnormal (undetectable in 11) results, and this subgroup of 18 patients included 3 of the 9 patients with multinodular goitre. In the post-thyroidectomy patients (Group II) 17% (3 out of 18 all with diffuse goitre) had undetectable TSH levels. Although all patients had normal thy roid hormone levels, patients with suppressed TSH levels had significantly higher serum T3 levels than patients with normal TSH levels (Group I, p<0.04; Group II, p<0.05) and serum T4 levels showed a similar but smaller and nonsignificant trend. Twelve month follow up data are available for 91 patients. Two patients from Group I (one with dif fuse and one with multinodular goitre) are ex cluded from further analysis as they required thyroidectomy for trachea! compression before n=75 n=18 Previous course Previous of Thyroidectomy Antithyroid Drugs Fig- I- TSH results for 93 euthyroid patients with a past history of hyperthyroidism. Horizontal lines indicate upper and lower limits of the normal range.

3 months follow-up; both patients had TSH levels <0.4 mu/1 in Fig. 1 and were euthyroid at the time of surgery. Analysis of one year data for the re maining 89 patients shows: Group I. All 56 patients with normal TSH remain well, but at follow-up 3 patients had subnormal TSH (2 patients <0.4 and 1 patient <0.1 mu/1), and 3 patients had marginally elevated TSH (4-7 mu/1). The 16 patients with suppressed TSH levels fared less well; 3 relapsed (after 3,6 and 9 months), and 13 remained well with 5 patients with persis tently subnormal TSH and 8 patients with normal TSH at 12 months. Group II. All 17 patients remain well. The 3 patients with undetectable TSH showed similar results at 12 months. Eleven of the 14 patients with normal TSH again had normal results, 2 patients had marginally elevated TSH (4-7 mu/1), and 1 patient had TSH <0.1 m U/l. Statistical analysis of 12 months follow-up data shows that in Group I a suppressed TSH level is associated with increased risk of relapse (Chi square x2 =H-0, p<0.001): 3 out of 16 relapsed, when compared with patients with normal TSH: none out of 56. When diffuse and nodular goitre patients in Group I are separated, 2 out of 14 dif fuse goitre patients with suppressed TSH relapsed compared with none out of 50 normal TSH pa tients = (x2, 7.4, p<0.01); the small nodular goitre group showed a similar trend: relapse in I out of 2 suppressed TSH patients compared with none out of 6 normal TSH patients. In Group II no patients have relapsed: none out of 3 with subnormal TSH and none out of 14 with normal TSH. Longer follow-up varies in duration. In some diffuse goitre patients from Group I the annual TSH levels have fluctuated from normal to sup pressed, with thyroid hormone levels remaining close to the middle of the normal range; e.g. in one such patient who had been without medication 18 months the annual TSH levels were 1.6, <0.1, and 1.4 mu/1 followed by relapse 31 months after entry to the study. To date, 6 further antithyroid drug treated patients with diffuse goitre have relapsed: 3 patients with suppressed TSH relapsed after 15, 19 and 30 months, and 3 patients with normal TSH relapsed after 18, 31 (noted above) and 36 months, respectively; no thyroidectomy patients have relapsed. Discussion In the present study of euthyroid patients who had received a course of antithyroid drugs or thyroi dectomy some years previously, almost a quarter of patients were found to have subnormal TSH levels. Our patient group was preselected to exclude pa tients with slightly elevated FT4I and T3 (subclinical hyperthyroidism) and it seems likely that we are underestimating the true frequency of subnormal TSH levels in patients with a past history of hy perthyroidism. The finding of undetectable TSH levels in euthyroid patients with a past history of thyrotoxicosis is not unexpected as suppression of the hypothalamic-pituitary-thyroid axis has been documented by TRH tests (no TSH response fol lowing TRH administration) to occur in a propor tion of patients after successful antithyroid drug treatment (7) and thyroidectomy (8). The finding of suppressed TSH levels also implies pituitary sup pression and this information is obtained from a single blood sample and without pharmacological manipulation of the patient. It has been suggested that the sensitive thyrotro pin assay could be the best first-line thyroid func tion test (9) (TSH-first strategy, (4) and this ap proach has been adopted in some centres. With the TSH-first strategy, an elevated TSH indicates sub normal thyroid function, a normal result euthyroidism, and a subnormal result hyperthyroidism. Many clinicians will not be aware that thyroid au after successful tonomy may persist many years treatment for hyperthyroidism and this may be the cause of 'anomalously low' TSH levels in clinically well patients. The present study documents this limitation of the TSH-first strategy. In patients with a past history of hyperthyroidism, subnormal TSH levels could indicate recurrent thyrotoxicosis or alternatively euthyroidism with thyroid auto nomy and suppression of pituitary thyrotropes. Pa tients with subnormal TSH levels should be re viewed clinically for evidence of relapse, and FT4I and T3 levels measured. The thyrotropin results in the present study have been available for some 12 months and we have to enable assessment of the clin delayed publishing ical significance of subnormal TSH values. It is well known that about 50% of antithyroid drug treated patients will relapse, with the highest risk of relapse being in the first 12 months after stopping medi cation. Most patients in Group I have been without antithyroid drugs for several years, and 12 months

4 follow-up has shown that subnormal TSH values are associated with a significantly increased risk of relapse. To date, 6 out of 16 Group I patients with subnormal TSH values have relapsed and 3 out of 56 with normal TSH have relapsed. These results suggest that thyrotropin results may be a useful index of relapse proneness following a course of antithyroid drugs and prospective trials are needed. The results of previous studies using HLA typing, TRH tests, and TSH receptor antibody assays to predict relapse have been largely disap pointing (10) and the tests are not generally avail able. All tests to predict relapse in Graves' disease have major limitations because of spontaneous fluctuations in the underlying autoimmune pro cesses. In the present study the alternate normal and subnormal TSH levels between baseline and 12 months are probably due to changes in thyroid stimulating (or blocking) antibody activity. This variability is most marked in Group I patients with subnormal TSH levels where half (8 out of 16) had normal TSH values after 12 months. Major fluc tuations in TSH levels were not observed in the but due to the small small nodular goitre subgroup, numbers no conclusion can be drawn. Seventeen per cent of the smaller post-thyroid ectomy group had subnormal TSH levels and to date no patients from Group II have relapsed. Re lapse occurs in some 10-15% of thyroidectomy pa tients and a larger series with long-term follow-up would be necessary to assess the value of sensitive thyrotropin assays in predicting relapse. The find ing of subnormal TSH levels following thyroidec tomy for hyperthyroidism has the same implica tions as the finding of persistent suppression of TRH responsiveness following thyroidectomy (8). Long-term follow-up of our patients with sup pressed TRH tests has shown an increased risk of relapse (data to be published). Radioiodine treated patients were excluded from the study population as relapse some years following successful 131I therapy is very uncommon (11). Suppressed TSH levels are to be expected in the months following radioiodine therapy (12), but in the years following treatment most patients will show elevated TSH levels with an increasing inci dence of clinical hypothyroidism. The present study documents that subnormal TSH levels are not uncommon in euthyroid pa tients some years following antithyroid drug ther apy or thyroidectomy. Although this could be con sidered a further limitation of the TSH-first strategy, follow-up of patients with suppressed TSH values shows an increased risk of relapse. Patients with subnormal TSH should be warned about pos sible relapse and they should be kept under closer review than patients with normal TSH levels. Sur veillance of patients in the present series beyond one year is variable and some relapses have subse quently occurred in Group I patients with normal baseline TSH. Prospective studies are needed to confirm the value of suppressed TSH values in the prediction of relapse. Acknowledgments The authors are most grateful to Dr J. E. Wells for the statistical analysis, Mrs S Moran for preparation of the manuscript, and the Department of Medical Illustration for the figure. References 1. Seth J, Kellett HA, Caldwell G, et al. A sensitive immunoradiometric assay for serum TSH a replace ment for the TRH test? Br Med J 1984;289: Ehrmann DA, Weinberg M, Same DH. Limitations to the use of a sensitive assay for thyrotropin in the assessment of thyroid status. Arch Intern Med 1989;149: Editorial. Sensitive thyrotropin measurements: util ity and futility. Lancet 1989;1: Utiger RD. Thyrotropin measurements: past, pre sent and future. Mayo Clin Proc 1988;63: Ehrmann DA, Same DH. Serum thyrotropin and the assessment of the thyroid status. Ann Intern Med 1989;110: Sadler WA, Brownlie BEW. Triiodothyronine rad ioimmunoassay in the assessment of thyroid func tion. NZ Med J 1975;81: Irvine WJ, Gray RS, Toft AD, et al. Spectrum of thy roid function in patients remaining in remission after antithyroid drug therapy for thyrotoxicosis. Lancet 1977;2: Brownlie BEW, Jensen CA, Turner JG, et al. The pituitary-thyroid axis following surgery for thyro toxicosis: thyrotropin-releasing hormone tests in dif fuse thyroid hyperplasia and toxic uninodular goitre. Clin Endocrinol (Oxf) 1977;7: Caldwell G, Kellett HA, Gow SM, et al. A new strategy for thyroid function testing. Lancet 1985;1: Schleusener H, Schwander J, Fisher C, et al. Prospec tive multicentre study on the prediction of relapse after antithyroid drug treatment in patients with Graves' disease. Acta Endocrinol (Copenh) 1989; 120:

5 11. Watson AB, Brownlie BEW, Frampton CM, et al. Outcome following standardized 185 MBg dose mi therapy for Graves' disease. Clin Endocrinol (Oxf) 1988;28: Davis JRE, Black FG, Sheppard MC. Evaluation of a sensitive chemiluminescent assay for TSH in the follow up of treated thyrotoxicosis. Clin Endocrinol (Oxf) 1987;27: Received December 14th, Accepted February 8th, Dr B. E. W. Brownlie, Department of Nuclear Medicine, Christchurch Hospital, Christchurch, New Zealand.