GRAVES DISEASE is the commonest form of hyperthyroidism,

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1 X/00/$03.00/0 Vol. 85, No. 3 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright 2000 by The Endocrine Society Age and Gender Predict the Outcome of Treatment for Graves Hyperthyroidism* AMIT ALLAHABADIA, JACQUIE DAYKIN, ROGER L. HOLDER, MICHAEL C. SHEPPARD, STEPHEN C. L. GOUGH, AND JAYNE A. FRANKLYN Division of Medical Sciences and Department of Mathematics and Statistics (R.L.H.), University of Birmingham, Edgbaston, Birmingham, United Kingdom B15 2TH ABSTRACT The response to treatment in Graves hyperthyroidism is unpredictable, and factors postulated to predict outcome have not generally proved clinically useful or been widely adopted in clinical practice. We audited outcome in 536 patients with Graves hyperthyroidism presenting consecutively to determine whether simple clinical features predict disease presentation and response to treatment. At presentation males had slightly more severe biochemical hyperthyroidism [free T 4 : males, pmol/l (mean SE); females, (P 0.45); free T 3 : males, pmol/l; females, , (P 0.04)]. Patients less than 40 yr at diagnosis had more severe hyperthyroidism than patients more than 40 yr old [free T 4 : 40 yr, ; 40 yr, (P 0.02); free T 3 : 40 yr, ; 40 yr, (P 0.003)]. Males had a lower remission rate than females after a course of antithyroid medication [19.6% vs. 40%; odds ratio, 0.37; 95% confidence (CI), ; P 0.01]. Similarly, Received August 19, Revision received November 2, Accepted November 19, Address all correspondence and requests for reprints to: Dr. A. Allahabadia, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom B15 2TH. j.a.franklyn@bham.ac.uk. * This work was supported by the West Midlands National Health Service Executive Research and Development Directorate and the Endowment Fund of the Former United Birmingham Hospitals. Smith and Nephew Foundation Research Fellow. patients aged less than 40 yr had a lower remission rate than older patients (32.6% vs. 47.8%; odds ratio, 0.53; 95% CI, ; P 0.01). One dose of radioiodine cured hyperthyroidism in fewer males than females (47% vs. 74%; P ). Logistic regression analysis demonstrated male sex (odds ratio, 2.80; 95% CI, ; P 0.008), serum free T 4 concentration at diagnosis (odds ratio, 1.02; 95% CI, ; P 0.01), and dose of radioiodine administered (odds ratio, 0.99; 95% CI, ; P 0.001) were contributing factors associated with failure to respond to a single dose of radioiodine. As males and younger patients are more likely to fail to respond to medical treatment, and male patients are likewise less likely to respond to a single dose of radioiodine, we suggest that those groups with low remission rates should be offered definitive treatment with radioiodine or surgery soon after presentation and that the value of higher initial doses of radioiodine in males be evaluated (J Clin Endocrinol Metab 85: , 2000) GRAVES DISEASE is the commonest form of hyperthyroidism, affecting women 5 10 times more frequently than men (1). The treatments available are antithyroid drugs, radioiodine, and surgery (2). Opinions vary as to the optimal form of therapy, as no single treatment regularly results in permanent euthyroidism (3, 4). Antithyroid drugs are effective in controlling hyperthyroidism, but long term remission rates are low, varying between 30 50% (5, 6), with geographical differences in iodine intake accounting for some of the variation in remission rates. Although radioiodine is a more effective means of curing Graves disease and is used increasingly as both first line treatment and in those with relapsed disease after medical therapy, it has proved impossible to titrate doses for individual patients accurately in order to guarantee a euthyroid state (2). Several studies have attempted to determine factors that may predict outcome after drug treatment and the response to radioiodine. Various studies have examined human leukocyte antigen types, the results of the TRH test, and TSH receptor antibody status in predicting response to medical treatment, but none has proved reliable for individual patients (6 9). Likewise, measures of thyroid size, isotope uptake, and turnover have been used to predict response to radioiodine (7, 10), but, again, none has been adopted widely, so that a proportion of patients given radioiodine require more than one dose, whereas many become hypothyroid (11). In the present study we have examined the hypothesis that simple clinical features, such as gender, age, and smoking history, may affect both disease presentation and predict response to treatment in subjects with Graves hyperthyroidism. To explore this hypothesis we have used our large thyroid database in which we have recorded clinical, biochemical, and immunological findings at diagnosis as well as details of treatment and response to treatment in a large cohort of subjects with Graves disease. Patients Subjects and Methods We performed a retrospective audit of 536 new patients presenting consecutively with Graves disease to the Thyroid Clinic at the Queen Elizabeth Hospital, Birmingham between 1975 and Data were retrieved from our thyroid clinic database, which has been used in other studies (11 13), and case notes were also reviewed. Graves disease was defined as the presence of biochemical hyperthyroidism (raised serum free T 4 concentration and undetectable TSH) together with two of the following: diffuse goiter, significant titer of thyroid peroxidase and/or thyroglobulin autoantibodies (a titer of 1:100 was considered significant), and presence of dysthyroid eye disease. Thyroid function and thyroid autoantibodies were measured as described previously (14). The size of goiter at diagnosis was categorized on the basis of physical examination by M.C.S. or J.A.F.: none, small, medium, or large. Eye disease was defined according to the presence of eye signs in categories 1038

2 OUTCOME OF TREATMENT FOR GRAVES HYPERTHYROIDISM, AGE, AND GENDER of the NOSPECS classification (15). The following factors were defined at diagnosis (before initiation of treatment) and recorded in the database: gender, age at diagnosis, smoking history, family history of thyroid disease, presence of eye disease, presence and size of diffuse goiter, autoantibody status and titer, and serum concentrations of free T 4 and free T 3. Information regarding dose and duration of antithyroid drugs, dose and timing of radioiodine treatment, and outcome was also recorded. Patients were divided into those electively treated with antithyroid drugs and those electively treated with radioiodine. Our policy over the period of the study was to offer a course of an antithyroid drug (carbimazole or propylthiouracil for 18 months) in the hope of achieving remission in those with a first episode of Graves disease, with the vast majority (95%) having been treated with carbimazole and drug doses being titrated according to free T 4 concentrations. For patients with relapse after antithyroid drug therapy or a preference for radioiodine, antithyroid drugs were given for a short time ( 4 months) before definitive treatment with a fixed empirical dose of radioiodine [ megabecquerels (MBq)], as described previously (2, 11). Outcome after a course of antithyroid drugs was defined as 1) successful (euthyroid for at least 6 months after withdrawal of thionamide treatment), or 2) failed (persistent or relapsed disease after a full course of thionamide treatment and progression to radioiodine or surgery). Outcome after radioiodine was defined as the number of doses of radioiodine required to result in cure of hyperthyroidism (euthyroid off all treatment for 6 months or T 4 replacement for biochemical hypothyroidism). analysis The 2 test was used to test for association between two categorical factors, and the unpaired t test was used to assess the relationship between continuous and dichotomous categorical factors. The results of t tests were confirmed using the Mann-Whitney test for continuous data that were not normally distributed. These analyses were performed using StatView version 4.5 (Abacus Concepts, Berkeley, CA). Binary logistic regression was used to determine which factors contributed to the prediction of outcome of treatment using MINITAB 12. Results The demographic, clinical, and laboratory characteristics at presentation of the cohort of 536 patients are summarized in Table 1. Outcome after treatment was determined in a total of 423 patients, with an additional 78 patients remaining under follow-up (presenting later in the consecutive series, outcome not yet determined) and 35 lost to follow-up. Of those in whom outcome was determined, the number of patients who received elective medical treatment was 314, of whom 116 had successful medical treatment and 198 failed medical treatment and proceeded to radioiodine or surgery. In the outcome group, 109 patients were electively treated with radioiodine, and an additional 179 were treated with radioiodine after failed medical therapy, so that outcome of radioiodine therapy was evaluated in a total group of 288 subjects. The number of subjects cured with 1 dose of radioiodine was 196, with 92 requiring more than 1 dose. Similar findings (see below) were evident when patients treated electively with radioiodine, and those treated with radioiodine after failure of medical treatment were analyzed separately (data not shown). Relationships of gender, age of onset, and other clinical and laboratory factors with presentation and outcome of treatments are discussed below. Gender Characteristics of males and females at presentation with Graves disease were similar (Table 2), apart from the presence of significantly higher concentrations of free T 3 and TABLE 1. Clinical and laboratory characteristics of cohort of patients with Graves disease Parameter No. (%) Total no. of patients 536 (100) Age of onset (yr) Mean SEM Range 8 77 Patients 40 yr 349 (65.1) Patients 40 yr 187 (34.9) Gender Females 444 (82.8) Males 92 (17.2) Current smoker Yes 200 (37.3) No 260 (48.5) Unknown 76 (14.2) Family history Yes 224 (41.8) No 286 (53.3) Unknown 26 (4.9) Diffuse goiter None/small 380 (70.9) Medium/large 156 (29.1) Ophthalmopathy Yes 216 (40.3) No 320 (59.7) Antibody status Positive 394 (73.5) Negative 64 (11.9) Unknown 78 (14.6) Free T 4 at diagnosis (pmol/l) Mean SEM Range Free T 3 at diagnosis (pmol/l) Mean SEM Range nonsignificantly higher mean free T 4 values. Male gender was, however, significantly associated with failure of medical treatment ( 2 7.0; P 0.01; 1 df; Table 3), and this association was shown to be in addition to any association with age using logistic regression. Males were more likely than females [estimated odds ratio, 2.6; 95% confidence (CI), ; P 0.02] to fail to enter long term remission after medical treatment. Males were also more likely than females to require treatment with more than one dose of radioiodine to cure hyperthyroidism ( ; P ; 1 df) despite administration of a similar dose of radioiodine. The association between sex and the requirement for more than one dose of radioiodine was in addition to the association with a number of other variables (see below) determined using logistic regression analysis (estimated odds ratio, 2.8; 95% CI, ; P 0.008). Age of onset For analysis, patients were divided into those less than 40 yr at presentation and those greater than 40 yr. Younger patients were more likely to have a family history of thyroid disease than older patients ( 2 8.1; P 0.01) and more frequently had medium sized or large goiters at presentation ( ; P ; Table 2). Age less than 40 yr was a significant predictor for the presence of larger goiters at diagnosis, a finding still evident after allowing for variation between patients in smoking habits (estimated odds ratio,

3 1040 ALLAHABADIA ET AL. JCE&M 2000 Vol 85 No 3 TABLE 2. The relationship of gender and age with features at presentation of Graves disease Males Females (P) of difference between males and females 4.31; 95% CI, ; P ). In contrast, eye disease was found more frequently at presentation in the older age group ( ; P 0.001), and this association remained significant after allowing for variation between patients in smoking habits (estimated odds ratio, 2.45; 95% CI, ; P 0.001). Patients in the younger age group were more frequently autoantibody positive ( 2 7.1; P 0.01) and had significantly higher mean free T 4 ( vs pmol/l; mean sem; t 2.3; P 0.02) and mean free T 3 concentrations ( vs pmol/l; t 3.0; P 0.01; Table 2). It should be noted that when age was analyzed as a continuous variable, the conclusions drawn were identical to those above (data not shown). Patients in the younger age group were more likely to fail to respond to medical treatment ( 2 6.4; P 0.01; Table 3). Age of onset was a significant further predictor for failure of medical treatment after allowing for any association with sex Odds ratio and 95% confidence Age 40 yr Age 40 yr (P) of difference between age groups Odds ratio and 95% confidence Mean age of onset (yr) No. of patients Sex Female (%) Male (%) Smoking Yes (%) No (%) Family history Yes (%) ( ) ( ) No (%) ( ) ( ) Diffuse goiter None/small (%) ( ) ( ) Medium/large (%) ( ) ( ) Ophthalmopathy Yes (%) ( ) ( ) No (%) ( ) Antibody status Positive (%) ( ) ( ) Negative (%) ( ) ( ) Free T 4 at diagnosis (pmol/l; mean SE) Free T 3 at diagnosis (pmol/l; mean SE) TABLE 3. The relationship of gender and age with outcome of Graves disease Males Females (P) of difference between males and females Odds ratio and 95% confidence Age 40 yr Age 40 yr (P) of difference between age groups (by 2 /t test) Odds ratio and 95% confidence Successful medical treatment ( ) ( ) (%) Failed medical treatment (%) ( ) ( ) Mean first dose of radioiodine (MBq) Cure with 1 dose of ( ) ( ) radioiodine (%) Cure with 1 dose of radioiodine (%) ( ) ( ) of the patient using logistic regression, and patients less than 40 yr of age were more likely than patients 40 yr or older (estimated odds ratio, 1.79; 95% CI, ; P 0.02) to fail to enter long term remission after medical treatment. In contrast to response to medical therapy, there was no association between age of onset and the response to a single dose of radioiodine (Table 4). Other clinical and laboratory factors Goiter size at presentation was strongly correlated with mean free T 4 (t 6.4; P ) and free T 3 concentrations at diagnosis (t 6.6; P ) and was associated with positive autoantibody status ( 2 5.4; P 0.02). Current history of cigarette smoking was associated with larger goiters ( 2 7.8; P 0.01; 1 df), and this association remained significant after adjusting for age (estimated odds ratio, 1.67;

4 OUTCOME OF TREATMENT FOR GRAVES HYPERTHYROIDISM, AGE, AND GENDER 1041 TABLE 4. Factors predictive of successful response to one dose of radioiodine using logistic regression analysis Adjusted odds ratio of successful response 95% Confidence (P) Male sex Free T 4 conc. at presentation Radioiodine dose % CI, ; P 0.01). Current cigarette smoking was also strongly associated with the presence of thyroid eye disease ( ; P ) and remained a predictor for the presence of eye disease at diagnosis after allowing for variation between patients in age at diagnosis (estimated odds ratio, 2.0; 95% CI, ; P 0.001; Table 2). There were few factors other than male sex or young age (described above) that were significantly associated with failure of medical treatment. Patients who failed to respond to medical treatment had nonsignificantly higher serum mean free T 4 concentrations than patients entering remission after medical treatment ( vs pmol/l; P 0.06), with a smaller and nonsignificant difference for free T 3. The presence of larger goiters (medium/large on clinical examination) was significantly associated with failure of medical treatment ( 2 5.0; P 0.03; 1 df). This association of goiter was nonsignificant after allowing for variation in patient age and sex. The presence of a medium or large goiter was associated with failure to respond to a single dose of radioiodine ( 2 6.1; P 0.01; 1 df). Patients who required more than one dose of radioiodine also had higher serum mean free T 4 ( vs pmol/l; P 0.001) and higher mean free T 3 concentrations ( vs pmol/l; P 0.001) and had received a significantly lower mean first dose of radioiodine than patients who were cured with one dose (267 vs. 315 MBq; P 0.001). The use of antithyroid drugs before or after radioiodine administration was associated with failure to respond to one dose of radioiodine ( 2 9.1; P 0.01; 1 df). Using logistic regression analysis (Table 4), the contributions of antithyroid drugs and goiter size became statistically nonsignificant. In the case of goiter, this was likely to be as a result of the strong correlation between goiter size and free T 4 concentration. Discussion As the response to treatment for Graves disease is unpredictable, it would be useful to identify factors that predict outcome before starting treatment and, therefore, to initiate the most appropriate form of therapy in individual patients. Several studies have been performed in an attempt to identify such factors. These have largely focussed upon investigations not widely undertaken in routine practice, such as the TRH test, measurement of TSH receptor antibodies at the end of medical treatment, determination of human leukocyte antigen status, or isotope or ultrasound imaging of the thyroid. None of these tests has proved clinically useful or been adopted widely in clinical practice for this purpose. Several other factors have been postulated to indicate a poor prognosis in terms of remission rates after medical treatment; these include large goiter size (5, 6, 8, 10) and severity of biochemical hyperthyroidism (7, 8, 16, 17), although studies have produced conflicting results (18, 19). In contrast to many of these putative indicators of outcome, gender and age of onset are factors readily defined at presentation, not subject to inconsistencies of clinical examination, and do not require laboratory or imaging procedures. Graves disease occurs with greater frequency in females, which may relate to the influence of estrogens on the immune system, particularly the B cell repertoire (20, 21). Although it has been suggested previously that males suffer worse biochemical hyperthyroidism with less severe symptoms (22), little evidence exists to suggest any difference in treatment outcome. Although a recent study of Italian subjects reported a small excess in the long term relapse rate after medical therapy in male patients, the difference between the sexes was not tested for independent association (5). Age-related differences in clinical presentation of Graves hyperthyroidism have also been reported (23), with severity of hyperthyroidism and prevalence of antibodies shown to decrease with advancing age (24, 25). The severity of eye disease may, conversely, increase with age (26). Several studies have reported younger patients to have higher relapse rates after medical treatment (5, 27), but it is unknown whether agerelated differences exist for response to radioiodine. Our data showed no difference between the sexes for clinical findings at diagnosis, particularly in goiter size, although males had slightly higher mean free T 3 concentrations, but no significant difference in mean free T 4 concentrations. Males, however, had a markedly worse outcome after medical treatment, with a remission rate of only 19.6% compared with 40% for females. Furthermore, successful outcome was defined after a minimum period off treatment of only 6 months (mean duration of follow-up, 9 months), so eventual remission rates are likely to be lower (28). Similarly, males responded poorly to a single dose of radioiodine, with only 47% cured by one dose compared with 74% of females. The effect of male sex on the response to radioiodine was independent of other factors, particularly radioiodine dosage and the use of antithyroid drugs before or after treatment; thionamides have been shown by ourselves and others to be associated with relative resistance to radioiodine treatment (11, 29). Analysis of the influence of age confirmed previously reported associations with features at diagnosis of Graves disease (23, 24), with younger patients having more severe biochemical hyperthyroidism, larger goiters, and a higher prevalence of thyroid antibodies. We also found that younger patients were more likely to have a family history of thyroid disease (of all types). In contrast, older patients had eye disease more frequently at diagnosis, in agreement with a previous study (26). Our results for the influence of age on the response to medical treatment are consistent with previous work (5, 8, 27). Despite the limitations of assessment of goiter size by clinical examination, our results for goiter size showed a significant association of the presence of larger goiters with failure of medical treatment. These findings contrast with some studies (19, 30) but agree with most others, which have also demonstrated significant associations (5, 6, 8, 10). Although the association between goiter size and failure to

5 1042 ALLAHABADIA ET AL. JCE&M 2000 Vol 85 No 3 respond to one dose of radioiodine was significant, this was not independent of other factors after logistic regression analysis. Free T 4 concentrations at presentation, although not significantly associated with response to medical treatment, were independently associated with failure to respond to a single dose of radioiodine, in accord with our previous findings (11). The striking findings in the present study of a large cohort of subjects with Graves hyperthyroidism in terms of influence of gender and age at presentation determine that these two easily defined characteristics should be taken into account when planning disease management. Although these data have been obtained from an area of adequate iodine intake (United Kingdom), determining that they should be interpreted with caution in other parts of the world with differing iodine intake, the poor response of males to medical treatment in terms of remission rates despite only slightly more severe disease than that in females highlights the need to discuss other treatment options with male patients and to offer radioiodine soon after presentation. The poor response of males in our cohort to a single dose of radioiodine also suggests that the size of the initial dose of radioiodine should be increased, as a cure rate of 47% is unacceptably low (2, 31), although this would need to be addressed in a prospective study. The present study has also highlighted the presence of more severe disease in those presenting with Graves hyperthyroidism at less than 40 yr of age, as indicated by biochemical findings. The lower remission rate with medical treatment in this age group suggests that definitive treatment with radioiodine or surgery should again be considered soon after disease presentation. Radioiodine probably represents the treatment of choice in such patients, although slight concerns about thyroid cancer determine that surgery may be more appropriate in those subjects less than 20 yr of age (32). The present findings also highlight the value of clinical databases in allowing investigation of factors associated with adverse outcomes of treatment and recognition of clinical factors that have not previously been regarded as important determinants of outcome. References 1. Tunbridge WMG, Evered DC, Hall R, et al The spectrum of thyroid disease in a community: the Whickam survey. Clin Endocrinol (Oxf). 7: Franklyn JA The management of hyperthyroidism. 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