Endocrine DOI 10.1007/s12020-014-0289-8
ORIGINAL ARTICLE
Stress triggers the onset and the recurrences of hyperthyroidism in patients with Graves’ disease Roberto Vita • Daniela Lapa • Francesco Trimarchi Salvatore Benvenga
•
Received: 13 February 2014 / Accepted: 5 May 2014 Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to evaluate the relationship of stressful events (SE) with the onset and outcome of Graves’ disease (GD). Over a period of 21 years, we enrolled 58 consecutive patients in whom at least one SE had occurred B12 months before the onset of GD. Patients were treated with antithyroid drugs (ATD) for C12 months and followed up for C5 years after ATD withdrawal. We divided patients in three groups: REM (who reached remission; 25.9 %); EXA (who experienced C1 exacerbation during ATD; 10.3 %); and REL (who experienced C1 relapse after ATD withdrawal; 63.8 %). The average age at onset was similar in the three groups. All males aged B25 years at GD onset relapsed at least once; no patient aged C51 years at GD onset relapsed C2 times. All patients who exacerbated or relapsed had at least one SE preceding each exacerbation or relapse. The time lag between SE and onset of GD (19.3 ± 11.9 weeks) correlated with the age at onset (r = 0.292, P = 0.0002), particularly in the REL group (r = 0.346, P = 0.001). Overall, EXA and REL patients experienced more SE than REM patients
R. Vita (&) D. Lapa F. Trimarchi S. Benvenga Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy e-mail: [email protected] S. Benvenga Master Program on Childhood, Adolescence and Women’s Endocrine Health, University of Messina, Via Consolare Valeria, 98125 Messina, Italy S. Benvenga Interdepartmental Program of Molecular and Clinical Endocrinology and Women’s Endocrine Health, A.O.U. Policlinico G. Martino, Via Consolare Valeria, 98125 Messina, Italy
(P = 0.0002 and P = 0.003, respectively). In the REL group, the overall number of SE was correlated with the number of relapses (r = 0.486, P \ 0.0001). There exist GD patients who are prone to develop hyperthyroidism and its recurrences when exposed to SE. They are relatively young; the younger these patients are, the shorter is the time lag between SE and the onset of hyperthyroidism. Keywords Thyroid Autoimmunity Graves’ disease Stress Hyperthyroidism Recurrences Age at onset Outcome
Introduction Similar to other autoimmune diseases, autoimmune thyroid diseases (AITD), whose incidence is expected to increase over time [1], develop once one or more exogenous factors (also know as environmental or non-genetic factors) hit genetically predisposed individuals, rendering a factual potential disorder [2–4]. Among the non-genetic factors involved in Graves’ disease (GD), one is stress. The role of stress as a trigger of hyperthyroidism in GD patients remains controversial [5, 6]. Parry [6, 7] was the first to report in 1825 the occurrence of hyperthyroidism symptoms in a distressed patient because she had fallen out of a wheelchair. Many years later, authors reported an increased incidence of GD during every major war [8, 9] the so-called Kriegbasedow. Seven case–control studies focused on the role of stressful events (SE) preceding hyperthyroidism in patients with GD [10– 16], but they were criticized because of the recall bias and the difficulty to ascertain the cause–effect relationship between SE and GD [17]. In a recent paper, Topcu et al. [18] showed that the number of negative life events in GD
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patients is higher compared to healthy controls, but it is similar to the number of negative SE occurred in patients with toxic nodular goiter. Like age, stress is considered a major determinant of the severity of hyperthyroidism in GD patients [19]. However, stress exposure has not been linked with the presence of thyroid autoantibodies [20], strengthening the role of stress as trigger of GD hyperthyroidism only in genetic predisposed individuals [4, 21]. Stress also influences the outcome of hyperthyroidism, since the achievement of euthyroidism is delayed in GD patients who have experienced SE after the beginning of antithyroid drugs (ATD) treatment [22]. Similarly, in GD patients treated with radioiodine, hypothyroidism occurs earlier in those with the history of stress [23]. Therefore, stress management by rest or drugs (beta-blockers, benzodiazepines) is considered important in the GD treatment [24, 25]. The mechanism whereby stress triggers GD is still unknown. A recent review pointed out the imbalance of T-lymphocytes classes in patients with GD [26]. The imbalance of T cell classes [26–31] is, at least in part, related to activation of the hypothalamic–pituitary–adrenal axis induced by stress [27]. Thyroid hormones and proinflammatory cytokines contribute to this shift [17, 32]. Indeed, about 10 % of hyperthyroid patients are at risk of adrenal insufficiency [33]. In this study, we have evaluated the role of stress in triggering hyperthyroidism in GD patients. We reasoned that if stress was a major inducer of hyperthyroidism in GD patients, then negative life events would have preceded not only the onset, but also all or most of the subsequent episodes of hyperthyroidism (exacerbations and/or relapses). For this reason, we have elected not to perform a case– control study, but rather to follow-up GD patients who were already susceptible to stress, that is, whose GD onset had been preceded by negative life events. Accordingly, over a reasonably long period of follow-up, GD patients who remitted would have had fewer SE than patients who relapsed. In turn, among patients who relapsed, those who relapsed once would have had fewer SE than those who relapsed two or more times.
Materials and methods Patients and stressful events Between January 1986 and December 2007, we selected 58 consecutive Caucasian, non-immigrant patients (36 females, 62.1 %; 22 males, 37.9 %, F\M ratio = 1.6:1) with GD in whom one or more SE occurred within the 12 months before the onset of GD. Like done by other authors, the occurrence of SE was ascertained by an
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interview [23, 34] at our first observation and at each subsequent visit throughout the follow-up. Patients were visited monthly or every 2 months during ATD treatment, and at least once a year after ATD withdrawal. All patients were questioned whether one or more SE occurred before overt clinical symptoms, and then, they were asked to identify the SE(s). Patients were helped to remind specific stressful events that had occurred within the 12 months preceding the onset, or during the follow-up within the 12 months preceding the exacerbation(s)/the relapse(s). SE were divided into four types (categories): psychological, infectious, physical, and of other type [34]. We excluded patients with thyroid-associated ophthalmopathy (who could have been treated with corticosteroids), smokers, and patients who had been treated with radioiodine or thyroidectomy, in order to minimize factors that can alter the natural course of the disease and thus represent potential biases. Furthermore, we excluded patients with family history of hyperthyroidism and Hashimoto’s thyroiditis, in order to minimize the strength of genetic predisposition. During the follow-up, AITD appeared in eight consanguineous of seven patients (2/8 GD, 6/8 Hashimoto’s thyroiditis), while non-thyroid autoimmune diseases appeared in two consanguineous of two different patients (Addison’s disease and multiple sclerosis). Patients were treated with ATD (56/58 methimazole, 2/58 propylthiouracil) for at least 12 months. After ATD withdrawal, the 58 patients were followed up for at least 5 years (mean ± SD, 14.7 ± 9.1 years). Recurrences of hyperthyroidism (exacerbations or relapses) were defined by suppressed levels of TSH, coexisting with the increased levels of FT3 and/or FT4. Statistics Data are presented as mean ± SD. Differences between means of continuous variables were handled by ANOVA; if the distribution of the variable was non-Gaussian, we used the Mann–Whitney test. The Kruskal–Wallis test was applied to compare means of three or more groups. Differences in proportions between categorical variables were handled by the chi-square (v2) test or Fisher’s exact test, as appropriate. Correlations between variables were analyzed by linear regression. The level of statistical significance was set at P \ 0.05. P values between 0.05 and 0.10 were considered borderline significant.
Results Depending on the outcome of GD, we divided patients in three groups: REM (patients who reached remission and experienced neither exacerbations nor relapses; n = 15,
Endocrine Table 1 Duration of follow-up and age at onset of Graves’ disease in all patients and in different groups All patients
REM group
EXA group
REL group
Follow-up (years)
[13.0] 14.7 ± 9.1 (5–27)
[10.0] 10.0 ± 4.2 (5–10)
[6.0] 6.0 ± 7.1 (5–11)
[14.0] 17.2 ± 9.4 (6-27)
Age at onset (years)
[34.5] 35.4 ± 14.6 (12–81)
[30.0] 34.5 ± 12.6 (16–57)
[34.5] 35.2 ± 10.5 (17–46)
[35.0] 35.9 ± 16.2 (12–81)
All P values are not statistically significant (P [ 0.05). Data are presented as m ± SD, median in brackets, and range in parenthesis EXA group = patients who experienced one or more exacerbations, namely one or more recurrences of hyperthyroidism during antithyroid drug treatment; REL group = patients who experienced one ore more relapses, namely one or more recurrences of hyperthyroidism after antithyroid drug withdrawal; REM group = patients who reached remission
25.9 %); EXA (patients who experienced one or more exacerbations, namely recurrences of hyperthyroidism during ATD treatment; n = 6, 10.3 %); and REL (patients who experienced relapses, namely one ore more recurrences of hyperthyroidism after ATD withdrawal; n = 37, 63.8 %). In the last two groups, patients experienced either exacerbations or relapses, except for one woman who had two relapses and one exacerbation, and one man who had one relapse and two exacerbations. For the purposes of this paper, in which patients had to be classified in mutually exclusive categories, these two patients were included in the REL group. Of the 37 patients who relapsed, 23 (62.2 %; 14 F, 9 M) experienced one relapse, 10 (27.0 %; 5 F, 5 M) experienced two relapses, and 4 (10.8 %; 3 F, 1 M) experienced three relapses.
Table 2 Distribution of the 58 Graves’ disease patients among the specified classes of age at onset of hyperthyroidism, and relationship of these classes with the outcome of hyperthyroidism Group
Age at onset (years) B20
21–30
31–40
41–50
51–60
C61
Total
REM
1
8
1
2
3
0
15
EXA REL
1 6
0 6
3 15
2 5
0 2
0 3
6 37
df = 10, v2 = 19.08, P = 0.039 B30
31–50
C51
Total
1
9
9
5
23
C2
3
11
0
14
df = 2, v2 = 6.389, P = 0.041 Three to six different classes of age are considered
Gender and follow-up The two genders were represented with similar rates in the REM and in the REL groups (females = 9/15 [60.0 %] vs. 22/37 [59.5 %], P = 1.0; males = 6/15 [40.0 %] vs. 15/37 [40.5 %], P = 1.0), but not in the EXA group (females = 5/6 [83.3 %] vs. 9/15 [60.0 %] REM, P = 0.61 or vs. 22/37 [59.5 %] REL, P = 0.39; males 1/6 [16.7 %] vs. 6/15 [40.0 %] REM, P = 0.61 or vs. 15/37 [40.5 %] REL, P = 0.39). Not unexpectedly, the REL group patients had a longer (but not significantly) follow-up compared to REM and EXA groups (Table 1). Age at onset of hyperthyroidism This age was in the fourth decade of life (35.4 ± 14.6 years) (Table 1). The average age at onset was similar in the three groups (Table 1). In the REM group, women were 7.1 years younger than men, while in the REL group, women were 5.4 years older. In the REM group, most of the patients were B30-year old at onset (9/15, 60.0 %), while in the EXA and in the REL groups, most of the patients were C31-year old at onset (5/6 [83.3 %] and 25/37 [67.6 %], respectively; REM vs. EXA P = 0.041 and REM vs. REL, P = 0.033) (Table 2). Particularly, in the EXA and REL groups, most patients were 31–50-year old at onset (EXA group 5/6 [83.3 %]; REL group 20/37 [54 %]) as opposed to REM
group (3/15 [20 %]) (Table 2). When hyperthyroidism started at B20, at 31–40 or C61 years of age, patients were more likely to relapse (6/8 = 75.0 %, 15/19 = 78.9 %, or 3/3 = 100 %). Furthermore, none of the 14 patients who relapsed at least twice was C51-year old at the onset of GD. Thus, when the onset occurred C51 years of age, there were no chances (0/5) to have two or more relapses (Table 2). The relationship between gender and the age at onset of hyperthyroidism is presented illustratively in Fig. 1. Until age 25, 100 % of males (6/6) relapsed as opposed to approximately half of females (6/10, P = 0.23). Raising the threshold of the onset age at B30 years, the corresponding rates became 75.0 versus 42.9 % (P = 0.20). From C31 years of onset age, the situation reversed with women outnumbering men (Fig. 1). If relapses had been considered disregarding classes of ages, rates would have resulted similar in females versus males (22/36 or 61.1 vs. 15/22 = 68.2 %) (Fig. 1). Stressful events Interval between stressful events and episodes of hyperthyroidism The time lag between SE and onset of GD was always B12 months. This time lag could be chronologically
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Endocrine Fig. 1 Rate of relapse depending on the class of age at onset of Graves’ disease (GD). Hatched columns indicate all patients (females ? males), open columns indicate females, and filled columns indicate males. In males, note the inverse relationship of the relapse rate with age at onset of GD (from 100 % at ages B20 or B25–50 % at age C51)
narrowed down for 43/58 patients (74.1 %), in whom it was 19.3 ± 11.9 weeks (REM, n = 11, 19.7 ± 9.3 weeks; EXA, n = 4, 21.5 ± 8.5; REL, n = 28, 18.9 ± 13.3). This interval was B12 weeks (B3 months) in 20 of the 43 patients (46.5 %). Fifteen out of these 20 patients (75 %) belonged to the REL group, and they were relatively young (27.6 ± 10.3 years), while 5/20 (25 %) belonged to the REM group. This interval was [12 weeks ([3 months) in 23/43 patients (53.5 %). Thirteen out of the 23 patients belonged to the REL group (56.5 %) (13/23 vs. 15/20 REL patients with an interval B12 weeks, P = 0.34). These 13 patients were older if compared to the 15 patients in whom the interval was B12 weeks (45.3 ± 17.7 years vs. 27.6 ± 10.3, P = 0.006). The interval between SE and onset of GD was directly and significantly correlated with the age at onset (r = 0.292, CI 95 % 0.215–0.631, P = 0.0002), and in females more linearly than in males (r = 0.366, CI 95 % 0.199–0.629, P = 0.0005 vs. r = 0.144, CI 95 % -0.211 to 1.00, P = 0.18, respectively). Particularly, this relationship was weaker in the REM group (r = 0.119, CI 95 % -0.262 to 0.762, P = 0.30), intermediate in the EXA group (r = 0.196, CI 95 % -1.45 to 2.01, P = 0.56), and stronger in the REL group (r = 0.346, CI 95 % 0.211–0.735, P = 0.001). In the REL group, this relationship was somewhat steeper in females than in males (r = 0.456, CI 95 % 0.391–1.568, P = 0.0029 vs. r = 0.184, CI 95 % -0.208 to 0.917, P = 0.19). In the REL group, the average time lag between SE and the first relapse was 15.5 ± 8.4 weeks, and it was not significantly longer in females than in males (18.0 ± 7.4 vs. 12.4 ± 8.3 weeks, P = 0.17). This interval was similar
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to the time lag between stressful life events and the second or the third relapse (15.8 ± 14.7 vs. 15.5 ± 8.4 weeks, P = 0.68). In the EXA group, the average time lag between SE and the first exacerbation was 22.0 ± 8.7 weeks. Number of events All patients who exacerbated or relapsed had at least one SE preceding each exacerbation or each relapse. The number of SE per patient did not correlate with the followup period (r = 0.04, P = 0.15). In total, 138 SE occurred in the 58 patients from the 12 months preceding the onset of GD to the last observation at the follow-up (2.4 ± 1.8 per patient), with not significant intergender difference (2.6 ± 2.0 in females vs. 2.0 ± 1.3 in males, P = 0.17) (Table 3). In the REL group, the total number of SE was linearly and significantly correlated with the number of relapses per patient (r = 0.486, P \ 0.0001). This correlation was maintained also upon pooling REL and EXA groups (r = 0.402, P \ 0.0001). Furthermore, the total number of SE per patient did not correlate with the age at onset (r = 0.029, P = 0.20). The average number of SE was relatively low in the REM group (1.2 ± 0.6 per patient), and in females, it was 1.3-fold greater than in males. However, EXA and REL patients experienced more SE than REM patients (3.5 ± 3.2 and 2.7 ± 1.6 vs. 1.2 ± 0.6, P = 0.0002 and P = 0.003, respectively) (Table 3; Fig. 2). This difference was also evident considering only females (3.8 ± 3.5 and 2.9 ± 1.6 vs. 1.3 ± 0.7, P = 0.005 and P = 0.014, respectively). In the REL group, patients who had two or
Endocrine Table 3 Number of SE from the onset throughout the follow-up Group All (n = 58; 36 F, 22 M) REM (N = 15; 9 F, 6 M)
F?M
Females (F)
Males (M)
138
94
44
[2.0] 2.4 ± 1.8 (1–10)
[2.0] 2.6 ± 2.0 (1–10)
[1.5] 2.0 ± 1.3 (1–5)
18
12
6
[1.0] 1.2 ± 0.6 (1–3) EXA (N = 6; 5 F, 1 M) REL (N = 37; 22 F, 15 M) 1 relapse (N = 23; 14 F, 9 M)
a,c
b,d
[1.0] 1.3 ± 0.7 (1–3)
1.0 (1.0)
21
19
1
[2.0] 3.5 ± 3.2 (2–10)c
[2.0] 3.8 ± 3.5 (2–10)d
1.0 (1.0)
99
63
37
[2.0] 2.7 ± 1.6 (1–6)a
[2.0] 2.9 ± 1.6 (1–6)b
[2.0] 2.4 ± 1.4 (1–5)
44
29
15
[2.0] 1.9 ± 1.2 (1–6)
e,h
f,i
[2.0] 2.1 ± 1.3 (1–6)
[1.0] 1.7 ± 1.0 (1–4)g,j
C 2 relapses (N = 14; 8 F, 6 M)
55 [4.0] 3.9 ± 1.3 (2–6)e
34 [5.0] 4.3 ± 1.4 (2–6)f
21 [3.0] 3.5 ± 1.2 (2–5)g
2 relapses (N = 11; 6 F, 5 M)
39
23
16
[3.0] 3.5 ± 1.2 (2–5)h,k
[4.0] 3.8 ± 1.3 (2–5)i
[3.0] 3.2 ± 1.1 (2–5)j
16
11
5
[5.0] 5.3 ± 0.6 (5–6)k
(5–6)
5
3 relapses (N = 3; 2 F, 1 M)
Data are reported as total number and, in italics, number per patient Number per patient is described as median in brackets, m ± SD and range in parenthesis For abbreviations, see Table 1 (footnotes) a
REL versus REM, P = 0.00021
b
REL (females) versus REM (females), P = 0.0053
c
EXA versus REM, P = 0.0029
d
EXA (females) versus REM (females), P = 0.0141 REL—two or more relapses versus REL—one relapse, P \ 0.0001
e f
REL—two or more relapses (females) versus REL—one relapse (females), P = 0.0029
g
REL—two or more relapses (males) versus REL—one relapse (males), P = 0.011
h
REL—two relapses versus REL—one relapse, P \ 0.0001
i
REL—two relapses (females) versus REL—one relapse (females), P = 0.0105
j
REL—two relapses (males) versus REL—one relapse (males), P = 0.0254
k
REL—three relapses versus REL—two relapses, P = 0.046
more relapses experienced more SE than patients who relapsed once (3.9 ± 1.3 vs. 1.9 ± 1.2, P \ 0.0001). This difference was maintained even if females and males were taken separately (females 4.3 ± 1.4 vs. 2.1 ± 1.3, P = 0.0029; males 3.5 ± 1.2 vs. 1.7 ± 1.0, P = 0.011) (Table 3; Fig. 2). Similarly, patients who had two relapses experienced more SE than patients who relapsed once (3.5 ± 1.2 vs. 1.9 ± 1.2, P \ 0.0001; females 3.8 ± 1.3 vs. 2.1 ± 1.3, P = 0.010; males 3.2 ± 1.1 vs. 1.7 ± 1.0, P = 0.025). In turn, patients who relapsed three times had more SE than patients who relapsed twice (5.3 ± 0.6 vs. 3.5 ± 1.2, P = 0.0460) (Table 3; Fig. 2). In the REL group, 26 patients (70.3 %) had at least one SE within the 12 months before the first relapse (16/22 [72.3 %] in females; 10/15 [66.7 %] in males, P = 0.728). The total number of SE prior to the first relapse was 1.38 ± 0.7 per patient (1.6 ± 0.8 in women and 1.1 ± 0.3
in men, P = 0.133). As said for the SE that preceded the onset, patients who experienced two or more relapses had more events than those who relapsed once (1.5 ± 0.7 per patient vs. 1.3 ± 0.7 per patient, P = 0.05). Of the 14 patients who relapsed C2 times, 11 (78.6 %; seven females and four males) had at least one stressful event before the second relapse. Eight out of 11 patients (72.7 %) did not experience a third relapse. Type of events Figure 3 shows the types of stressful events and their frequencies. Psychological stress was by far the leading type of SE, accounting for 104 of the 138 SE (75.4 %). Psychological SE occurred in 49/58 patients (84.5 %) (Fig. 3), more frequently in women than in males (33/36 [91.7 %] vs. 16/22 [72.7 %], P = 0.07). As said for the total events
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(see section Number of events), REL patients experienced more psychological SE than REM patients (2.1 ± 1.6 vs. 0.9 ± 0.8, P = 0.004). In the REL group, patients who
Fig. 2 Mean number of SE per patient in each of the three groups of Graves’ disease patients (REM, EXA, REL) and, within the REL group, in subgroups defined on the basis of the number of relapses. Data are taken from Table 3. Hatched circles indicate all patients (females ? males), open circles indicate females, and filled circles indicate males
Fig. 3 Type of stressful events (SE) and their frequency in our series of 58 Graves’ disease patients. Of the 58 patients, 36 (62.1 %) experienced more than one stressful event throughout the course of the disease. Other type of stressful events is defined as events other than those covered by psychological, physical, and infectious categories
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relapsed at least twice had more psychological events than patients who relapsed once (3.5 ± 1.3 vs. 1.3 ± 1.0, P \ 0.0001). In turn, patients who relapsed three times experienced more psychological SE than those who relapsed twice (5.3 ± 0.6 vs. 3.0 ± 0.9, P = 0.02). The number of psychological SE correlated with the number of relapses per patient (r = 0.42, P \ 0.0001). Psychological events were the most frequent type of SE occurred within the 12 months before the onset of GD (54/ 67 events [80.6 %]). In the REL group, patients who relapsed at least twice had more psychological SE than patients who relapsed once (14/14 [100 %] vs. 15/22 [68.2 %], P = 0.029). Of the above 26 REL patients who had at least one SE within the 12 months before the first relapse (see section Number of events), 21 (80.8 %) had at least one psychological event. This type of event was more frequent in patients who experienced two or more relapses than those who experienced only one relapse (12/14 [85.7 %] vs. 9/23 [39.1 %], P = 0.007). In REL patients who relapsed at least twice, psychological stress was also the leading type of event preceding the second relapse, as it occurred in 9/11 patients (81.8 %), with an average of 1.4 ± 0.7 psychological events per patient. Two (one female, one male) out of three patients who relapsed three times had one psychological stressful event each before the third relapse. All the six patients in the EXA group experienced at least one stressful event before the first exacerbation (average of 2.0 ± 2.0 per patient). Five of these six patients (83.3 %) had psychological stressful events, while two (33.3 %) had infectious events.
Endocrine Table 4 Comparison of our series of stress-associated Graves’ disease patients with other two illustrative European series of consecutive patients with Graves’ disease
No. of patients (F:M ratio) Age (years)
Present study (Italy)
Vitti (ref. [35]) (Italy)
Allahabadia (ref. [36]) (UK)
58 (36 F, 22 M; F:M = 1.6:1)
306 (246 F, 60 M; F:M = 4.1:1)
536 patients (444 F, 92 M; F:M = 4.8:1)
35.4 ± 14.6 (range 12–81)
32.3 ± 12
36.1 ± 0.1 (SEM)
B20 years: 15.7 % 21–39 years: 52.9 % (\40: 68.6 %)
B20 years: 16.7 % 21–39 years: 56.2 % (\40: 72.9 %)
\ 40 years: 65.1 % 40 years: 34.9 %
40 years: 31.4 %
40 years: 15.4 %
Smokers
Excluded
Not specified
37.3 %
Ophtalmopathic
Excluded
37.2 %
40.3 %
Exclusion criteria
Smoking, ophtalmopathy, radioiodine, thyroidectomy
Patients with ophtalmopathy and voluminous goiter
Data not given
Stressful events
Evaluated
Not evaluated
Not evaluated
Onset (years)
Average age F: 36.1 ± 15.2
Data not given
Average age F: 34.8
M: 34.4 ± 14.0
M: 36.3
Therapy
Antithyroid drugs (12–30 months)
Antithyroid drugs (12–24 months in 81 % patients; \12 months in 4 %)
Antithyroid drugs (18 months) in 314/423 patients (74.2 %)
Definition of remission
Euthyroidism achieved after 12 months or more after antithyroid drug withdrawal 5–27 years (14.7 ± 9.1 years)
Euthyroidism achieved after 6 months or more after antithyroid drug withdrawal 28 ± 16 months
Euthyroidism achieved after 6 months or more after antithyroid drug withdrawal 9 months (mean)
Duration of follow-up after antithyroid drugs withdrawal Relapse rate
37/58 patients (63.8 %)
194/306 patients (63.4 %)
198/314 patients (63.1 %)
Relapse rate depending on gender and age
B20 years: 75 % (F: 50 %
B20 years: 76.4 %
\40 years: 67.4 %
21–39 years: 63.6 % (F: 63.6 %
21–39 years: 67.4 %
40 years: 52.2 % (P = 0.0.1)
\40 years: 65.8 % (F: 61.5 %
\40 years: 72.9 %
No data regarding gender
40 years: 58.8 % (F: 60 %
40 years: 47 % (P = 0.002) No data regarding gender
Discussion Even if the triggering role of stress in the pathogenesis of hyperthyroidism due to GD was proposed long time ago, it is still considered controversial (see section Introduction). The present study stems from the hypothesis that every switch from euthyroidism to hyperthyroidism (onset, exacerbations, and relapses) could be triggered by any given precipitating stressful event. Even though the relation between stress and recurrences of GD was evaluated in a prospective fashion, the relation between stress and onset of GD was evaluated retrospectively. Thus, a major limitation of our study and of other similar studies in the literature [17] is the recall bias, which is present in most of studies on this topic [17]. Another limitation, again shared with the literature, is that we have considered only negative SE, disregarding positive SE, which can also have some impact on the course of GD [16]. The number of SE is function of exposure time, so that one can argue that patients followed up for longer time had
more SE. However, this was not the case because the number of SE per patient did not correlate with the duration of the follow-up period (see section Number of events). In Tables 4 and 5, our data are comparable with those from the literature. For instance, the average ages at onset of GD were in the 30’s, and the relapse rates were *64 %; relapse rates were comparable also in age-stratified groups (Table 4). Interestingly, furthermore, in another Italian series [11], in a Portuguese series [16], and in a Chinese series [12], the average number of SE was one to two per patient (Table 5). In a Dutch study [19], in which patients were stratified into four age groups (B29, 30–39, 40–49, and C50 years), the number of negative events (as evaluated with hyperthyroid symptom scale score) decreased as age advanced (interquartile ranges of 3–10, 3–11, 2–7, and 2–7). Using the same stratification, and with negative SE evaluated differently, we observed a similar gradient (ranges of 1–4.5, 1.5–3, 1–3, and 1–2). Most of the studies on the role of stress as a precipitating event of hyperthyroidism have focused on the first episode
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Italy
Italy
Portugal
The Netherlands
The Netherlands
Sweden
Argentina
Hong Kong
Japan
Japan
Present study
Sonino (ref. [11])
Matos-Santos (ref. [16])
Vos (ref. [19])
Effraimidis (ref. [21])
Winsa (ref. [10])
Forteza (ref. [34])
Kung (ref. [12])
Yoshiuchi K (ref. [14])
Fukao (ref. [37])
69 (16.2:1)
228 (4.0:1)
95 (5.3: 1)
105 (&8:1)
208 (4.6:1)
11 GD (11:0)
263 (2.8:1)
31 (2.4:1)
70 (4.8:1)
58 (1.6:1)
Number and F:M ratio
&40
M = 42.3 ± 13.2
F = 37.4 ± 12.8
(m ± SEM)
33.1 ± 1.2
19–79
M = 47.9 ± 14.5
F = 45.6 ± 14.1
Selected from a group of women aged 8–65 years
43 (median)
38.4 ± 10.9
39.2 ± 13
35.4 ± 14.6
Age (years)
–
–
0.94 ± 1.54
a
–
NSI for major events, HDSLI for daily events
HRS scale
LES—self-evaluation
Anamnesis
SLESL, SSQ
DQ
DQ, DEPC, PANAS
7, 5, 4, 4b (median) 4 (median)
LES—self-evaluation
PIRLE (semi-structured interview)
Interview [Stewart [23], Forteza [34]
Evaluation of stress
2.10 per patient
1.51 ± 0.97
2.4 ± 1.8
No. of SE per patient
Stress score correlated with TRAb activity and thyroid volume; daily hassles score was higher in relapsed GD patients versus remitted GD patients; hypochondriasis, depression, paranoia and psychasthenia were more common in relapsed GD patients versus remitted GD patients
The RR of GD was higher in women with the highest stress score versus women with the lowest stress score
GD patients reported more negative SE and with more impact verus controls
Psychological stress predominated up to the fifth decade, while physical stress was the principal cause in older patients.
GD patients reported more negative SE and with higher scores versus controls
11/790 (1.4 %) women with C1 relative with AITD developed GD during a 5-year follow-up.
Stress scores were associated with HSS but not with biochemical indices; age was inversely correlated with stress scores
The number and the impact of negative SE were higher in GD patients versus TNG patients and controls. The impact of positive SE was higher in GD patients versus TNG patients
GD patients reported more SE with higher impact versus controls
In all 58 patients, the onset was preceded by at least one SE, and so was in each of the six patients with GD exacerbations(s) and each of the 37 patients with GD relapse(s). Patients who experienced exacerbation(s) or relapse(s) had an average of SE significantly greater than patients who remitted. The number of SE was directly and significantly correlated with the number of relapses. Time lag between SE and onset of GD was directly and significantly correlated with the age at onset of GD
Comment
Precipitating factors were classified into 4 categories as follows: psychological stress (no. of patients = 63/116), physical stress (‘‘intense somatic suffering such as several corporeal trauma or burns, prolonged infectious diseases, or major operations that were followed by complications’’) (n = 21/116), psychophysical stress (‘‘caused by a combination of the first two’’) (n = 6/ 116), undetermined (‘‘in which no precipitating factor could be ascertained’’) (n = 26/116) b Data refer to a stratification in four groups, according to age: B29, 30–39, 40–49, and C50 years
a
AITD autoimmune thyroid disease, DEPC Dutch everyday problem checklist, DQ Dutch questionnaire, GD Graves’ disease, HDSLI Hayashi’s day life stress inventory, HRS Holmes–Rahe Stress, HSS hyperthyroid symptom scale score, LES Life Experiences Survey, NSI Natsume’s stress inventory, PIRLE Paykel’s Interview for Recent Life Events, PANAS positive and negative affect schedule, RR relative risk, SE stressful life events, SLES Sarason’s life-event survey, SSQ Sarason’s social support questionnaire, TNG toxic nodular goiter, TRAb TSH receptor antibody
Nation
Authors
Table 5 Comparison of our study with other similar studies on stress-associated Graves’ disease (GD)
Endocrine
Endocrine
of hyperthyroidism (onset), overlooking further episodes (exacerbations and relapses). Lidz [38] reported a 32-yearold nurse that had three distinct episodes of hyperthyroidism, each triggered by psychological stress. Two American pediatricians reported two boys and two girls in whom the bereavement after death of a close relative triggered hyperthyroidism. [39]. A Canadian psychiatrist [40] reported four illustrative cases in whom the onset and the relapses were preceded by psychological or physical stresses [40]. Hidaka et al. [41] evaluated the relationship between thyrotoxicosis relapses and attacks of allergic rhinitis in 83 GD patients. Other Japanese authors [42] reported that in 28/145 GD patients (19 %), thyroid function deteriorated after a major earthquake. Furthermore, of 76 GD patients who were euthyroid before the earthquake, 7 (9.2 %) worsened becoming hyperthyroid again. The subgroup of patients with relapse/aggravation of hyperthyroidism was younger compared to the non-worsened subgroup [42]. A prospective study examined emotional stress and personality trait in 69 GD patients (F/M ratio = 16.2: 1) and 32 controls [37]. Four personality traits (hypochondriasis, depression, paranoia, and psychasthenia) were significantly more common in relapsed versus remitted GD patients. Importantly, total stress score for major life events was double in relapsed compared to remitted patients or controls (approximately 200, 100, or 100), though the large standard deviations rendered differences statistically insignificant. The 2.0-fold greater total score in the relapsed group [37] matches our 2.2-fold significantly greater (P = 0.003) number of SE in the REL group compared with the REM group (2.7 ± 1.6 vs. 1.2 ± 0.6). Conclusions In the present study, we highlight the value of stress as a triggering factor of autoimmune hyperthyroidism. Indeed, we show that (1) there exist patients with GD who are prone to develop hyperthyroidism after one or more stressful events; (2) in those patients in whom GD exacerbates or relapses, every occurrence of hyperthyroidism is systematically preceded by at least one stressful event; (3) such patients are relatively young, particularly when males; (4) the younger these patients are, the shorter is the time lag between stressful event(s) and the onset; (5) as a corollary, at least in a number of GD patients, recurrences of the disease could be avoided if measures were taken to help them to cope with negative life events. Conflict of interest of interest.
The authors declare that they have no conflict
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ORIGINAL ARTICLE
Stress triggers the onset and the recurrences of hyperthyroidism in patients with Graves’ disease Roberto Vita • Daniela Lapa • Francesco Trimarchi Salvatore Benvenga
•
Received: 13 February 2014 / Accepted: 5 May 2014 Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to evaluate the relationship of stressful events (SE) with the onset and outcome of Graves’ disease (GD). Over a period of 21 years, we enrolled 58 consecutive patients in whom at least one SE had occurred B12 months before the onset of GD. Patients were treated with antithyroid drugs (ATD) for C12 months and followed up for C5 years after ATD withdrawal. We divided patients in three groups: REM (who reached remission; 25.9 %); EXA (who experienced C1 exacerbation during ATD; 10.3 %); and REL (who experienced C1 relapse after ATD withdrawal; 63.8 %). The average age at onset was similar in the three groups. All males aged B25 years at GD onset relapsed at least once; no patient aged C51 years at GD onset relapsed C2 times. All patients who exacerbated or relapsed had at least one SE preceding each exacerbation or relapse. The time lag between SE and onset of GD (19.3 ± 11.9 weeks) correlated with the age at onset (r = 0.292, P = 0.0002), particularly in the REL group (r = 0.346, P = 0.001). Overall, EXA and REL patients experienced more SE than REM patients
R. Vita (&) D. Lapa F. Trimarchi S. Benvenga Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy e-mail: [email protected] S. Benvenga Master Program on Childhood, Adolescence and Women’s Endocrine Health, University of Messina, Via Consolare Valeria, 98125 Messina, Italy S. Benvenga Interdepartmental Program of Molecular and Clinical Endocrinology and Women’s Endocrine Health, A.O.U. Policlinico G. Martino, Via Consolare Valeria, 98125 Messina, Italy
(P = 0.0002 and P = 0.003, respectively). In the REL group, the overall number of SE was correlated with the number of relapses (r = 0.486, P \ 0.0001). There exist GD patients who are prone to develop hyperthyroidism and its recurrences when exposed to SE. They are relatively young; the younger these patients are, the shorter is the time lag between SE and the onset of hyperthyroidism. Keywords Thyroid Autoimmunity Graves’ disease Stress Hyperthyroidism Recurrences Age at onset Outcome
Introduction Similar to other autoimmune diseases, autoimmune thyroid diseases (AITD), whose incidence is expected to increase over time [1], develop once one or more exogenous factors (also know as environmental or non-genetic factors) hit genetically predisposed individuals, rendering a factual potential disorder [2–4]. Among the non-genetic factors involved in Graves’ disease (GD), one is stress. The role of stress as a trigger of hyperthyroidism in GD patients remains controversial [5, 6]. Parry [6, 7] was the first to report in 1825 the occurrence of hyperthyroidism symptoms in a distressed patient because she had fallen out of a wheelchair. Many years later, authors reported an increased incidence of GD during every major war [8, 9] the so-called Kriegbasedow. Seven case–control studies focused on the role of stressful events (SE) preceding hyperthyroidism in patients with GD [10– 16], but they were criticized because of the recall bias and the difficulty to ascertain the cause–effect relationship between SE and GD [17]. In a recent paper, Topcu et al. [18] showed that the number of negative life events in GD
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patients is higher compared to healthy controls, but it is similar to the number of negative SE occurred in patients with toxic nodular goiter. Like age, stress is considered a major determinant of the severity of hyperthyroidism in GD patients [19]. However, stress exposure has not been linked with the presence of thyroid autoantibodies [20], strengthening the role of stress as trigger of GD hyperthyroidism only in genetic predisposed individuals [4, 21]. Stress also influences the outcome of hyperthyroidism, since the achievement of euthyroidism is delayed in GD patients who have experienced SE after the beginning of antithyroid drugs (ATD) treatment [22]. Similarly, in GD patients treated with radioiodine, hypothyroidism occurs earlier in those with the history of stress [23]. Therefore, stress management by rest or drugs (beta-blockers, benzodiazepines) is considered important in the GD treatment [24, 25]. The mechanism whereby stress triggers GD is still unknown. A recent review pointed out the imbalance of T-lymphocytes classes in patients with GD [26]. The imbalance of T cell classes [26–31] is, at least in part, related to activation of the hypothalamic–pituitary–adrenal axis induced by stress [27]. Thyroid hormones and proinflammatory cytokines contribute to this shift [17, 32]. Indeed, about 10 % of hyperthyroid patients are at risk of adrenal insufficiency [33]. In this study, we have evaluated the role of stress in triggering hyperthyroidism in GD patients. We reasoned that if stress was a major inducer of hyperthyroidism in GD patients, then negative life events would have preceded not only the onset, but also all or most of the subsequent episodes of hyperthyroidism (exacerbations and/or relapses). For this reason, we have elected not to perform a case– control study, but rather to follow-up GD patients who were already susceptible to stress, that is, whose GD onset had been preceded by negative life events. Accordingly, over a reasonably long period of follow-up, GD patients who remitted would have had fewer SE than patients who relapsed. In turn, among patients who relapsed, those who relapsed once would have had fewer SE than those who relapsed two or more times.
Materials and methods Patients and stressful events Between January 1986 and December 2007, we selected 58 consecutive Caucasian, non-immigrant patients (36 females, 62.1 %; 22 males, 37.9 %, F\M ratio = 1.6:1) with GD in whom one or more SE occurred within the 12 months before the onset of GD. Like done by other authors, the occurrence of SE was ascertained by an
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interview [23, 34] at our first observation and at each subsequent visit throughout the follow-up. Patients were visited monthly or every 2 months during ATD treatment, and at least once a year after ATD withdrawal. All patients were questioned whether one or more SE occurred before overt clinical symptoms, and then, they were asked to identify the SE(s). Patients were helped to remind specific stressful events that had occurred within the 12 months preceding the onset, or during the follow-up within the 12 months preceding the exacerbation(s)/the relapse(s). SE were divided into four types (categories): psychological, infectious, physical, and of other type [34]. We excluded patients with thyroid-associated ophthalmopathy (who could have been treated with corticosteroids), smokers, and patients who had been treated with radioiodine or thyroidectomy, in order to minimize factors that can alter the natural course of the disease and thus represent potential biases. Furthermore, we excluded patients with family history of hyperthyroidism and Hashimoto’s thyroiditis, in order to minimize the strength of genetic predisposition. During the follow-up, AITD appeared in eight consanguineous of seven patients (2/8 GD, 6/8 Hashimoto’s thyroiditis), while non-thyroid autoimmune diseases appeared in two consanguineous of two different patients (Addison’s disease and multiple sclerosis). Patients were treated with ATD (56/58 methimazole, 2/58 propylthiouracil) for at least 12 months. After ATD withdrawal, the 58 patients were followed up for at least 5 years (mean ± SD, 14.7 ± 9.1 years). Recurrences of hyperthyroidism (exacerbations or relapses) were defined by suppressed levels of TSH, coexisting with the increased levels of FT3 and/or FT4. Statistics Data are presented as mean ± SD. Differences between means of continuous variables were handled by ANOVA; if the distribution of the variable was non-Gaussian, we used the Mann–Whitney test. The Kruskal–Wallis test was applied to compare means of three or more groups. Differences in proportions between categorical variables were handled by the chi-square (v2) test or Fisher’s exact test, as appropriate. Correlations between variables were analyzed by linear regression. The level of statistical significance was set at P \ 0.05. P values between 0.05 and 0.10 were considered borderline significant.
Results Depending on the outcome of GD, we divided patients in three groups: REM (patients who reached remission and experienced neither exacerbations nor relapses; n = 15,
Endocrine Table 1 Duration of follow-up and age at onset of Graves’ disease in all patients and in different groups All patients
REM group
EXA group
REL group
Follow-up (years)
[13.0] 14.7 ± 9.1 (5–27)
[10.0] 10.0 ± 4.2 (5–10)
[6.0] 6.0 ± 7.1 (5–11)
[14.0] 17.2 ± 9.4 (6-27)
Age at onset (years)
[34.5] 35.4 ± 14.6 (12–81)
[30.0] 34.5 ± 12.6 (16–57)
[34.5] 35.2 ± 10.5 (17–46)
[35.0] 35.9 ± 16.2 (12–81)
All P values are not statistically significant (P [ 0.05). Data are presented as m ± SD, median in brackets, and range in parenthesis EXA group = patients who experienced one or more exacerbations, namely one or more recurrences of hyperthyroidism during antithyroid drug treatment; REL group = patients who experienced one ore more relapses, namely one or more recurrences of hyperthyroidism after antithyroid drug withdrawal; REM group = patients who reached remission
25.9 %); EXA (patients who experienced one or more exacerbations, namely recurrences of hyperthyroidism during ATD treatment; n = 6, 10.3 %); and REL (patients who experienced relapses, namely one ore more recurrences of hyperthyroidism after ATD withdrawal; n = 37, 63.8 %). In the last two groups, patients experienced either exacerbations or relapses, except for one woman who had two relapses and one exacerbation, and one man who had one relapse and two exacerbations. For the purposes of this paper, in which patients had to be classified in mutually exclusive categories, these two patients were included in the REL group. Of the 37 patients who relapsed, 23 (62.2 %; 14 F, 9 M) experienced one relapse, 10 (27.0 %; 5 F, 5 M) experienced two relapses, and 4 (10.8 %; 3 F, 1 M) experienced three relapses.
Table 2 Distribution of the 58 Graves’ disease patients among the specified classes of age at onset of hyperthyroidism, and relationship of these classes with the outcome of hyperthyroidism Group
Age at onset (years) B20
21–30
31–40
41–50
51–60
C61
Total
REM
1
8
1
2
3
0
15
EXA REL
1 6
0 6
3 15
2 5
0 2
0 3
6 37
df = 10, v2 = 19.08, P = 0.039 B30
31–50
C51
Total
1
9
9
5
23
C2
3
11
0
14
df = 2, v2 = 6.389, P = 0.041 Three to six different classes of age are considered
Gender and follow-up The two genders were represented with similar rates in the REM and in the REL groups (females = 9/15 [60.0 %] vs. 22/37 [59.5 %], P = 1.0; males = 6/15 [40.0 %] vs. 15/37 [40.5 %], P = 1.0), but not in the EXA group (females = 5/6 [83.3 %] vs. 9/15 [60.0 %] REM, P = 0.61 or vs. 22/37 [59.5 %] REL, P = 0.39; males 1/6 [16.7 %] vs. 6/15 [40.0 %] REM, P = 0.61 or vs. 15/37 [40.5 %] REL, P = 0.39). Not unexpectedly, the REL group patients had a longer (but not significantly) follow-up compared to REM and EXA groups (Table 1). Age at onset of hyperthyroidism This age was in the fourth decade of life (35.4 ± 14.6 years) (Table 1). The average age at onset was similar in the three groups (Table 1). In the REM group, women were 7.1 years younger than men, while in the REL group, women were 5.4 years older. In the REM group, most of the patients were B30-year old at onset (9/15, 60.0 %), while in the EXA and in the REL groups, most of the patients were C31-year old at onset (5/6 [83.3 %] and 25/37 [67.6 %], respectively; REM vs. EXA P = 0.041 and REM vs. REL, P = 0.033) (Table 2). Particularly, in the EXA and REL groups, most patients were 31–50-year old at onset (EXA group 5/6 [83.3 %]; REL group 20/37 [54 %]) as opposed to REM
group (3/15 [20 %]) (Table 2). When hyperthyroidism started at B20, at 31–40 or C61 years of age, patients were more likely to relapse (6/8 = 75.0 %, 15/19 = 78.9 %, or 3/3 = 100 %). Furthermore, none of the 14 patients who relapsed at least twice was C51-year old at the onset of GD. Thus, when the onset occurred C51 years of age, there were no chances (0/5) to have two or more relapses (Table 2). The relationship between gender and the age at onset of hyperthyroidism is presented illustratively in Fig. 1. Until age 25, 100 % of males (6/6) relapsed as opposed to approximately half of females (6/10, P = 0.23). Raising the threshold of the onset age at B30 years, the corresponding rates became 75.0 versus 42.9 % (P = 0.20). From C31 years of onset age, the situation reversed with women outnumbering men (Fig. 1). If relapses had been considered disregarding classes of ages, rates would have resulted similar in females versus males (22/36 or 61.1 vs. 15/22 = 68.2 %) (Fig. 1). Stressful events Interval between stressful events and episodes of hyperthyroidism The time lag between SE and onset of GD was always B12 months. This time lag could be chronologically
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Endocrine Fig. 1 Rate of relapse depending on the class of age at onset of Graves’ disease (GD). Hatched columns indicate all patients (females ? males), open columns indicate females, and filled columns indicate males. In males, note the inverse relationship of the relapse rate with age at onset of GD (from 100 % at ages B20 or B25–50 % at age C51)
narrowed down for 43/58 patients (74.1 %), in whom it was 19.3 ± 11.9 weeks (REM, n = 11, 19.7 ± 9.3 weeks; EXA, n = 4, 21.5 ± 8.5; REL, n = 28, 18.9 ± 13.3). This interval was B12 weeks (B3 months) in 20 of the 43 patients (46.5 %). Fifteen out of these 20 patients (75 %) belonged to the REL group, and they were relatively young (27.6 ± 10.3 years), while 5/20 (25 %) belonged to the REM group. This interval was [12 weeks ([3 months) in 23/43 patients (53.5 %). Thirteen out of the 23 patients belonged to the REL group (56.5 %) (13/23 vs. 15/20 REL patients with an interval B12 weeks, P = 0.34). These 13 patients were older if compared to the 15 patients in whom the interval was B12 weeks (45.3 ± 17.7 years vs. 27.6 ± 10.3, P = 0.006). The interval between SE and onset of GD was directly and significantly correlated with the age at onset (r = 0.292, CI 95 % 0.215–0.631, P = 0.0002), and in females more linearly than in males (r = 0.366, CI 95 % 0.199–0.629, P = 0.0005 vs. r = 0.144, CI 95 % -0.211 to 1.00, P = 0.18, respectively). Particularly, this relationship was weaker in the REM group (r = 0.119, CI 95 % -0.262 to 0.762, P = 0.30), intermediate in the EXA group (r = 0.196, CI 95 % -1.45 to 2.01, P = 0.56), and stronger in the REL group (r = 0.346, CI 95 % 0.211–0.735, P = 0.001). In the REL group, this relationship was somewhat steeper in females than in males (r = 0.456, CI 95 % 0.391–1.568, P = 0.0029 vs. r = 0.184, CI 95 % -0.208 to 0.917, P = 0.19). In the REL group, the average time lag between SE and the first relapse was 15.5 ± 8.4 weeks, and it was not significantly longer in females than in males (18.0 ± 7.4 vs. 12.4 ± 8.3 weeks, P = 0.17). This interval was similar
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to the time lag between stressful life events and the second or the third relapse (15.8 ± 14.7 vs. 15.5 ± 8.4 weeks, P = 0.68). In the EXA group, the average time lag between SE and the first exacerbation was 22.0 ± 8.7 weeks. Number of events All patients who exacerbated or relapsed had at least one SE preceding each exacerbation or each relapse. The number of SE per patient did not correlate with the followup period (r = 0.04, P = 0.15). In total, 138 SE occurred in the 58 patients from the 12 months preceding the onset of GD to the last observation at the follow-up (2.4 ± 1.8 per patient), with not significant intergender difference (2.6 ± 2.0 in females vs. 2.0 ± 1.3 in males, P = 0.17) (Table 3). In the REL group, the total number of SE was linearly and significantly correlated with the number of relapses per patient (r = 0.486, P \ 0.0001). This correlation was maintained also upon pooling REL and EXA groups (r = 0.402, P \ 0.0001). Furthermore, the total number of SE per patient did not correlate with the age at onset (r = 0.029, P = 0.20). The average number of SE was relatively low in the REM group (1.2 ± 0.6 per patient), and in females, it was 1.3-fold greater than in males. However, EXA and REL patients experienced more SE than REM patients (3.5 ± 3.2 and 2.7 ± 1.6 vs. 1.2 ± 0.6, P = 0.0002 and P = 0.003, respectively) (Table 3; Fig. 2). This difference was also evident considering only females (3.8 ± 3.5 and 2.9 ± 1.6 vs. 1.3 ± 0.7, P = 0.005 and P = 0.014, respectively). In the REL group, patients who had two or
Endocrine Table 3 Number of SE from the onset throughout the follow-up Group All (n = 58; 36 F, 22 M) REM (N = 15; 9 F, 6 M)
F?M
Females (F)
Males (M)
138
94
44
[2.0] 2.4 ± 1.8 (1–10)
[2.0] 2.6 ± 2.0 (1–10)
[1.5] 2.0 ± 1.3 (1–5)
18
12
6
[1.0] 1.2 ± 0.6 (1–3) EXA (N = 6; 5 F, 1 M) REL (N = 37; 22 F, 15 M) 1 relapse (N = 23; 14 F, 9 M)
a,c
b,d
[1.0] 1.3 ± 0.7 (1–3)
1.0 (1.0)
21
19
1
[2.0] 3.5 ± 3.2 (2–10)c
[2.0] 3.8 ± 3.5 (2–10)d
1.0 (1.0)
99
63
37
[2.0] 2.7 ± 1.6 (1–6)a
[2.0] 2.9 ± 1.6 (1–6)b
[2.0] 2.4 ± 1.4 (1–5)
44
29
15
[2.0] 1.9 ± 1.2 (1–6)
e,h
f,i
[2.0] 2.1 ± 1.3 (1–6)
[1.0] 1.7 ± 1.0 (1–4)g,j
C 2 relapses (N = 14; 8 F, 6 M)
55 [4.0] 3.9 ± 1.3 (2–6)e
34 [5.0] 4.3 ± 1.4 (2–6)f
21 [3.0] 3.5 ± 1.2 (2–5)g
2 relapses (N = 11; 6 F, 5 M)
39
23
16
[3.0] 3.5 ± 1.2 (2–5)h,k
[4.0] 3.8 ± 1.3 (2–5)i
[3.0] 3.2 ± 1.1 (2–5)j
16
11
5
[5.0] 5.3 ± 0.6 (5–6)k
(5–6)
5
3 relapses (N = 3; 2 F, 1 M)
Data are reported as total number and, in italics, number per patient Number per patient is described as median in brackets, m ± SD and range in parenthesis For abbreviations, see Table 1 (footnotes) a
REL versus REM, P = 0.00021
b
REL (females) versus REM (females), P = 0.0053
c
EXA versus REM, P = 0.0029
d
EXA (females) versus REM (females), P = 0.0141 REL—two or more relapses versus REL—one relapse, P \ 0.0001
e f
REL—two or more relapses (females) versus REL—one relapse (females), P = 0.0029
g
REL—two or more relapses (males) versus REL—one relapse (males), P = 0.011
h
REL—two relapses versus REL—one relapse, P \ 0.0001
i
REL—two relapses (females) versus REL—one relapse (females), P = 0.0105
j
REL—two relapses (males) versus REL—one relapse (males), P = 0.0254
k
REL—three relapses versus REL—two relapses, P = 0.046
more relapses experienced more SE than patients who relapsed once (3.9 ± 1.3 vs. 1.9 ± 1.2, P \ 0.0001). This difference was maintained even if females and males were taken separately (females 4.3 ± 1.4 vs. 2.1 ± 1.3, P = 0.0029; males 3.5 ± 1.2 vs. 1.7 ± 1.0, P = 0.011) (Table 3; Fig. 2). Similarly, patients who had two relapses experienced more SE than patients who relapsed once (3.5 ± 1.2 vs. 1.9 ± 1.2, P \ 0.0001; females 3.8 ± 1.3 vs. 2.1 ± 1.3, P = 0.010; males 3.2 ± 1.1 vs. 1.7 ± 1.0, P = 0.025). In turn, patients who relapsed three times had more SE than patients who relapsed twice (5.3 ± 0.6 vs. 3.5 ± 1.2, P = 0.0460) (Table 3; Fig. 2). In the REL group, 26 patients (70.3 %) had at least one SE within the 12 months before the first relapse (16/22 [72.3 %] in females; 10/15 [66.7 %] in males, P = 0.728). The total number of SE prior to the first relapse was 1.38 ± 0.7 per patient (1.6 ± 0.8 in women and 1.1 ± 0.3
in men, P = 0.133). As said for the SE that preceded the onset, patients who experienced two or more relapses had more events than those who relapsed once (1.5 ± 0.7 per patient vs. 1.3 ± 0.7 per patient, P = 0.05). Of the 14 patients who relapsed C2 times, 11 (78.6 %; seven females and four males) had at least one stressful event before the second relapse. Eight out of 11 patients (72.7 %) did not experience a third relapse. Type of events Figure 3 shows the types of stressful events and their frequencies. Psychological stress was by far the leading type of SE, accounting for 104 of the 138 SE (75.4 %). Psychological SE occurred in 49/58 patients (84.5 %) (Fig. 3), more frequently in women than in males (33/36 [91.7 %] vs. 16/22 [72.7 %], P = 0.07). As said for the total events
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Endocrine
(see section Number of events), REL patients experienced more psychological SE than REM patients (2.1 ± 1.6 vs. 0.9 ± 0.8, P = 0.004). In the REL group, patients who
Fig. 2 Mean number of SE per patient in each of the three groups of Graves’ disease patients (REM, EXA, REL) and, within the REL group, in subgroups defined on the basis of the number of relapses. Data are taken from Table 3. Hatched circles indicate all patients (females ? males), open circles indicate females, and filled circles indicate males
Fig. 3 Type of stressful events (SE) and their frequency in our series of 58 Graves’ disease patients. Of the 58 patients, 36 (62.1 %) experienced more than one stressful event throughout the course of the disease. Other type of stressful events is defined as events other than those covered by psychological, physical, and infectious categories
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relapsed at least twice had more psychological events than patients who relapsed once (3.5 ± 1.3 vs. 1.3 ± 1.0, P \ 0.0001). In turn, patients who relapsed three times experienced more psychological SE than those who relapsed twice (5.3 ± 0.6 vs. 3.0 ± 0.9, P = 0.02). The number of psychological SE correlated with the number of relapses per patient (r = 0.42, P \ 0.0001). Psychological events were the most frequent type of SE occurred within the 12 months before the onset of GD (54/ 67 events [80.6 %]). In the REL group, patients who relapsed at least twice had more psychological SE than patients who relapsed once (14/14 [100 %] vs. 15/22 [68.2 %], P = 0.029). Of the above 26 REL patients who had at least one SE within the 12 months before the first relapse (see section Number of events), 21 (80.8 %) had at least one psychological event. This type of event was more frequent in patients who experienced two or more relapses than those who experienced only one relapse (12/14 [85.7 %] vs. 9/23 [39.1 %], P = 0.007). In REL patients who relapsed at least twice, psychological stress was also the leading type of event preceding the second relapse, as it occurred in 9/11 patients (81.8 %), with an average of 1.4 ± 0.7 psychological events per patient. Two (one female, one male) out of three patients who relapsed three times had one psychological stressful event each before the third relapse. All the six patients in the EXA group experienced at least one stressful event before the first exacerbation (average of 2.0 ± 2.0 per patient). Five of these six patients (83.3 %) had psychological stressful events, while two (33.3 %) had infectious events.
Endocrine Table 4 Comparison of our series of stress-associated Graves’ disease patients with other two illustrative European series of consecutive patients with Graves’ disease
No. of patients (F:M ratio) Age (years)
Present study (Italy)
Vitti (ref. [35]) (Italy)
Allahabadia (ref. [36]) (UK)
58 (36 F, 22 M; F:M = 1.6:1)
306 (246 F, 60 M; F:M = 4.1:1)
536 patients (444 F, 92 M; F:M = 4.8:1)
35.4 ± 14.6 (range 12–81)
32.3 ± 12
36.1 ± 0.1 (SEM)
B20 years: 15.7 % 21–39 years: 52.9 % (\40: 68.6 %)
B20 years: 16.7 % 21–39 years: 56.2 % (\40: 72.9 %)
\ 40 years: 65.1 % 40 years: 34.9 %
40 years: 31.4 %
40 years: 15.4 %
Smokers
Excluded
Not specified
37.3 %
Ophtalmopathic
Excluded
37.2 %
40.3 %
Exclusion criteria
Smoking, ophtalmopathy, radioiodine, thyroidectomy
Patients with ophtalmopathy and voluminous goiter
Data not given
Stressful events
Evaluated
Not evaluated
Not evaluated
Onset (years)
Average age F: 36.1 ± 15.2
Data not given
Average age F: 34.8
M: 34.4 ± 14.0
M: 36.3
Therapy
Antithyroid drugs (12–30 months)
Antithyroid drugs (12–24 months in 81 % patients; \12 months in 4 %)
Antithyroid drugs (18 months) in 314/423 patients (74.2 %)
Definition of remission
Euthyroidism achieved after 12 months or more after antithyroid drug withdrawal 5–27 years (14.7 ± 9.1 years)
Euthyroidism achieved after 6 months or more after antithyroid drug withdrawal 28 ± 16 months
Euthyroidism achieved after 6 months or more after antithyroid drug withdrawal 9 months (mean)
Duration of follow-up after antithyroid drugs withdrawal Relapse rate
37/58 patients (63.8 %)
194/306 patients (63.4 %)
198/314 patients (63.1 %)
Relapse rate depending on gender and age
B20 years: 75 % (F: 50 %
B20 years: 76.4 %
\40 years: 67.4 %
21–39 years: 63.6 % (F: 63.6 %
21–39 years: 67.4 %
40 years: 52.2 % (P = 0.0.1)
\40 years: 65.8 % (F: 61.5 %
\40 years: 72.9 %
No data regarding gender
40 years: 58.8 % (F: 60 %
40 years: 47 % (P = 0.002) No data regarding gender
Discussion Even if the triggering role of stress in the pathogenesis of hyperthyroidism due to GD was proposed long time ago, it is still considered controversial (see section Introduction). The present study stems from the hypothesis that every switch from euthyroidism to hyperthyroidism (onset, exacerbations, and relapses) could be triggered by any given precipitating stressful event. Even though the relation between stress and recurrences of GD was evaluated in a prospective fashion, the relation between stress and onset of GD was evaluated retrospectively. Thus, a major limitation of our study and of other similar studies in the literature [17] is the recall bias, which is present in most of studies on this topic [17]. Another limitation, again shared with the literature, is that we have considered only negative SE, disregarding positive SE, which can also have some impact on the course of GD [16]. The number of SE is function of exposure time, so that one can argue that patients followed up for longer time had
more SE. However, this was not the case because the number of SE per patient did not correlate with the duration of the follow-up period (see section Number of events). In Tables 4 and 5, our data are comparable with those from the literature. For instance, the average ages at onset of GD were in the 30’s, and the relapse rates were *64 %; relapse rates were comparable also in age-stratified groups (Table 4). Interestingly, furthermore, in another Italian series [11], in a Portuguese series [16], and in a Chinese series [12], the average number of SE was one to two per patient (Table 5). In a Dutch study [19], in which patients were stratified into four age groups (B29, 30–39, 40–49, and C50 years), the number of negative events (as evaluated with hyperthyroid symptom scale score) decreased as age advanced (interquartile ranges of 3–10, 3–11, 2–7, and 2–7). Using the same stratification, and with negative SE evaluated differently, we observed a similar gradient (ranges of 1–4.5, 1.5–3, 1–3, and 1–2). Most of the studies on the role of stress as a precipitating event of hyperthyroidism have focused on the first episode
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123
Italy
Italy
Portugal
The Netherlands
The Netherlands
Sweden
Argentina
Hong Kong
Japan
Japan
Present study
Sonino (ref. [11])
Matos-Santos (ref. [16])
Vos (ref. [19])
Effraimidis (ref. [21])
Winsa (ref. [10])
Forteza (ref. [34])
Kung (ref. [12])
Yoshiuchi K (ref. [14])
Fukao (ref. [37])
69 (16.2:1)
228 (4.0:1)
95 (5.3: 1)
105 (&8:1)
208 (4.6:1)
11 GD (11:0)
263 (2.8:1)
31 (2.4:1)
70 (4.8:1)
58 (1.6:1)
Number and F:M ratio
&40
M = 42.3 ± 13.2
F = 37.4 ± 12.8
(m ± SEM)
33.1 ± 1.2
19–79
M = 47.9 ± 14.5
F = 45.6 ± 14.1
Selected from a group of women aged 8–65 years
43 (median)
38.4 ± 10.9
39.2 ± 13
35.4 ± 14.6
Age (years)
–
–
0.94 ± 1.54
a
–
NSI for major events, HDSLI for daily events
HRS scale
LES—self-evaluation
Anamnesis
SLESL, SSQ
DQ
DQ, DEPC, PANAS
7, 5, 4, 4b (median) 4 (median)
LES—self-evaluation
PIRLE (semi-structured interview)
Interview [Stewart [23], Forteza [34]
Evaluation of stress
2.10 per patient
1.51 ± 0.97
2.4 ± 1.8
No. of SE per patient
Stress score correlated with TRAb activity and thyroid volume; daily hassles score was higher in relapsed GD patients versus remitted GD patients; hypochondriasis, depression, paranoia and psychasthenia were more common in relapsed GD patients versus remitted GD patients
The RR of GD was higher in women with the highest stress score versus women with the lowest stress score
GD patients reported more negative SE and with more impact verus controls
Psychological stress predominated up to the fifth decade, while physical stress was the principal cause in older patients.
GD patients reported more negative SE and with higher scores versus controls
11/790 (1.4 %) women with C1 relative with AITD developed GD during a 5-year follow-up.
Stress scores were associated with HSS but not with biochemical indices; age was inversely correlated with stress scores
The number and the impact of negative SE were higher in GD patients versus TNG patients and controls. The impact of positive SE was higher in GD patients versus TNG patients
GD patients reported more SE with higher impact versus controls
In all 58 patients, the onset was preceded by at least one SE, and so was in each of the six patients with GD exacerbations(s) and each of the 37 patients with GD relapse(s). Patients who experienced exacerbation(s) or relapse(s) had an average of SE significantly greater than patients who remitted. The number of SE was directly and significantly correlated with the number of relapses. Time lag between SE and onset of GD was directly and significantly correlated with the age at onset of GD
Comment
Precipitating factors were classified into 4 categories as follows: psychological stress (no. of patients = 63/116), physical stress (‘‘intense somatic suffering such as several corporeal trauma or burns, prolonged infectious diseases, or major operations that were followed by complications’’) (n = 21/116), psychophysical stress (‘‘caused by a combination of the first two’’) (n = 6/ 116), undetermined (‘‘in which no precipitating factor could be ascertained’’) (n = 26/116) b Data refer to a stratification in four groups, according to age: B29, 30–39, 40–49, and C50 years
a
AITD autoimmune thyroid disease, DEPC Dutch everyday problem checklist, DQ Dutch questionnaire, GD Graves’ disease, HDSLI Hayashi’s day life stress inventory, HRS Holmes–Rahe Stress, HSS hyperthyroid symptom scale score, LES Life Experiences Survey, NSI Natsume’s stress inventory, PIRLE Paykel’s Interview for Recent Life Events, PANAS positive and negative affect schedule, RR relative risk, SE stressful life events, SLES Sarason’s life-event survey, SSQ Sarason’s social support questionnaire, TNG toxic nodular goiter, TRAb TSH receptor antibody
Nation
Authors
Table 5 Comparison of our study with other similar studies on stress-associated Graves’ disease (GD)
Endocrine
Endocrine
of hyperthyroidism (onset), overlooking further episodes (exacerbations and relapses). Lidz [38] reported a 32-yearold nurse that had three distinct episodes of hyperthyroidism, each triggered by psychological stress. Two American pediatricians reported two boys and two girls in whom the bereavement after death of a close relative triggered hyperthyroidism. [39]. A Canadian psychiatrist [40] reported four illustrative cases in whom the onset and the relapses were preceded by psychological or physical stresses [40]. Hidaka et al. [41] evaluated the relationship between thyrotoxicosis relapses and attacks of allergic rhinitis in 83 GD patients. Other Japanese authors [42] reported that in 28/145 GD patients (19 %), thyroid function deteriorated after a major earthquake. Furthermore, of 76 GD patients who were euthyroid before the earthquake, 7 (9.2 %) worsened becoming hyperthyroid again. The subgroup of patients with relapse/aggravation of hyperthyroidism was younger compared to the non-worsened subgroup [42]. A prospective study examined emotional stress and personality trait in 69 GD patients (F/M ratio = 16.2: 1) and 32 controls [37]. Four personality traits (hypochondriasis, depression, paranoia, and psychasthenia) were significantly more common in relapsed versus remitted GD patients. Importantly, total stress score for major life events was double in relapsed compared to remitted patients or controls (approximately 200, 100, or 100), though the large standard deviations rendered differences statistically insignificant. The 2.0-fold greater total score in the relapsed group [37] matches our 2.2-fold significantly greater (P = 0.003) number of SE in the REL group compared with the REM group (2.7 ± 1.6 vs. 1.2 ± 0.6). Conclusions In the present study, we highlight the value of stress as a triggering factor of autoimmune hyperthyroidism. Indeed, we show that (1) there exist patients with GD who are prone to develop hyperthyroidism after one or more stressful events; (2) in those patients in whom GD exacerbates or relapses, every occurrence of hyperthyroidism is systematically preceded by at least one stressful event; (3) such patients are relatively young, particularly when males; (4) the younger these patients are, the shorter is the time lag between stressful event(s) and the onset; (5) as a corollary, at least in a number of GD patients, recurrences of the disease could be avoided if measures were taken to help them to cope with negative life events. Conflict of interest of interest.
The authors declare that they have no conflict
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