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Original Studies |
Division of Medical Sciences and Department of Mathematics and Statistics (R.L.H.), University of Birmingham, Edgbaston, Birmingham, United Kingdom B15 2TH
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. E-mail: j.a.franklyn{at}bham.ac.uk
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Abstract |
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Introduction |
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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, 7, 8, 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.
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Subjects and Methods |
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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 1998. Data were retrieved from our thyroid clinic database, which has been used in other studies (11, 12, 13), and case notes were also reviewed. Graves’ disease was defined as the presence of biochemical hyperthyroidism (raised serum free T4 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 2–6 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 T4 and free T3. 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 T4 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 [185–390 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 T4 replacement for biochemical hypothyroidism).
Statistical 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.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. 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.
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Characteristics of males and females at presentation with Graves’
disease were similar (Table 2), apart
from the presence of significantly higher concentrations of free
T3 and nonsignificantly higher mean free
T4 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 interval
(CI), 1.18–5.54; 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 (2 = 17.5;
P < 0.0001; 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,
1.31–5.98; P = 0.008).
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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
(2 = 40.3; P < 0.0001; 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,
4.31; 95% CI, 2.66–7.0; P < 0.0001). In contrast,
eye disease was found more frequently at presentation in the older age
group (2 = 24.1; P < 0.001),
and this association remained significant after allowing for variation
between patients in smoking habits (estimated odds ratio, 2.45; 95%
CI, 1.69–3.45; 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 T4 (64.3 ±
2.0 vs. 56.7 ± 2.3 pmol/L; mean ±
SEM; t = 2.3; P =
0.02) and mean free T3 concentrations (22.8
± 0.8 vs. 19.0 ± 0.9 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 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, 1.09–2.96; 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).
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Goiter size at presentation was strongly correlated with mean free
T4 (t = 6.4; P <
0.0001) and free T3 concentrations at diagnosis
(t = 6.6; P < 0.0001) 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; 95% CI, 1.12–2.48; P =
0.01). Current cigarette smoking was also strongly associated with the
presence of thyroid eye disease (2 = 15.7;
P < 0.0001) 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,
1.39–2.88; 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 T4
concentrations than patients entering remission after medical treatment
(57.9 ± 3.0 vs. 65.2 ± 2.4 pmol/L;
P = 0.06), with a smaller and nonsignificant difference
for free T3. 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
T4 (55.8 ± 1.9 vs. 71.0 ±
4.6 pmol/L; P < 0.001) and higher mean free
T3 concentrations (19.3 ± 0.9
vs. 24.9 ± 1.5 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 T4 concentration.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 age-related 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 T3 concentrations, but no significant difference in mean free T4 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 respond to one dose of radioiodine was significant, this was not independent of other factors after logistic regression analysis. Free T4 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.
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Footnotes |
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2 Smith and Nephew Foundation Research Fellow.
Received August 19, 1999.
Revised November 2, 1999.
Accepted November 19, 1999.
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