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Endocrine Care |
Second Department of Internal Medicine (I.K., T.K., N.T.), University of the Ryukyus School of Medicine, Okinawa 903-0215; Department of Medicine (T.Y., T.N.), Kashiwa City Hospital, Chiba 277-0825; and Department of Medicine (A.S.), Dokkyo Koshigaya Hospital, Dokkyo University School of Medicine Koshigaya, Saitama 343-8555, Japan
Address all correspondence and requests for reprints to: Ichiro Komiya, M.D., Associate Professor of Internal Medicine, Second Department of Internal Medicine, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. E-mail: ikomiya{at}med.u-ryukyu ac.jp.
Abstract
We analyzed the relationship between serum IgE concentrations and the remission or recurrence of Graves’ disease. One hundred seven patients with Graves’ disease were treated with methimazole (MMI). Serum IgE concentration greater than 170 IU/ml was found in 41 of 107 untreated patients (38.3%). However, the presence of TSH-binding inhibiting immunoglobulin or thyroid-stimulating antibody did not correlate with the IgE concentrations. Remission was found in 20 of 41 patients with elevated IgE concentrations (48.8%) after 18 months of MMI treatment, as opposed to 53 of 66 patients with normal concentrations (80.3%) (P = 0.0014). MMI treatment was discontinued in 73 patients who were followed for 26–48 months. The recurrence of Graves’ disease was found in 13 patients, whereas the remaining 60 were still in remission. The rate of long-standing remission was lower in patients with elevated than normal IgE concentration (34.1% vs. 69.7%, P = 0.0007). We also analyzed serum levels of interleukin (IL)-13. Although IL-13 was not detected in all patients, the detection rate was higher in patients without remission and in those with recurrence than in those with long-standing remission (47.1%, 38.5%, and 13.3%, respectively; P = 0.0012). More patients with elevated IgE were positive for allergic diseases and for family history of allergic diseases in their first-degree relatives. We conclude that the elevation of IgE and the higher detection rate of IL-13 are associated with both remission and recurrence of Graves’ disease.
PREVIOUS STUDIES HAVE found that 30–40%
of hyperthyroid patients with Graves’ disease have an elevation of
serum IgE concentrations (
170 IU/ml) (1). In contrast,
the prevalence of IgE elevation was significantly less in autoimmune
Hashimoto’s thyroiditis (1). Interestingly, decreases in
TSH-binding inhibiting immunoglobulin (TBII) and thyroid-stimulating
antibody (TSAb) in response to antithyroid drugs were less pronounced
in patients with than without IgE elevation (1). However,
the role on IgE in autoimmune Graves’ disease is not known.
Quite interestingly, interleukin (IL)-4 and IL-13 in the lungs of asthmatic patients stimulate IgE secretion (2, 3, 4, 5). It has also been shown that IL-13 stimulates secretion of IgG, IgM, and IgE (6). Thus, one may expect an elevation of IL-4 and/or IL-13 in patients with Graves’ disease who have an increase in IgE synthesis. Although abnormalities of intrathyroidal lymphocytes are not reflected in circulating lymphocytes (7, 8), circulating IL-4 and/or IL-13 may stimulate the synthesis of IgE as well as IgG (TBII or TSAb). To better define the role of ILs in the pathophysiology of Graves’ disease, we measured circulating ILs (IL-4, IL-6, IL-10, and IL-13) and analyzed the relationship between IL concentrations and the remission or recurrence of Graves’ disease during and after the discontinuation of methimazole (MMI) treatment.
Patients and Methods
One hundred seven patients with Graves’ disease (17 men and 90 women, ages 17–67) were treated with MMI for 18 months. Thirty-four of 107 patients were in a euthyroid state; however, because of continuous elevation of thyroglobulin (Tg), TBII, and/or TSAb concentrations, MMI treatment could not be discontinued as reported previously (group I) (9, 10). In the remaining 73 patients (groups II and III), MMI treatment was discontinued because of normalization in serum concentrations of T4, Tg, TBII, and TSAb (9, 10); those patients were followed for 26–48 months. During follow-up, the recurrence of Graves’ disease was noted in 13 patients within 8–26 months after MMI withdrawal (group III), whereas the remaining 60 patients were still euthyroid at 26–48 months (group II). Patients who had allergy to MMI were excluded from this study, because MMI treatment could not be continued for a long period. We analyzed the presence of allergic diseases (atopy, allergic rhinitis, and asthma) in patients with Graves’ disease and allergic diseases and autoimmune thyroid disorders (AITDs) in their first-degree relatives.
Serum T4, TSH, TBII, TSAb, Tg, and IgE
concentrations were measured monthly (1, 9, 10).
IFN-
and IL-4, IL-6, IL-10, and IL-13 concentrations were
measured at the time of MMI treatment, at the time of recurrence, or at
the latest follow-up. The detection limit for TSH was 0.02 mU/liter.
Concentrations of IgE and cytokines were confirmed by ELISA (Mitsubishi
Kagaku Bio-Chemical Laboratory Inc., Tokyo, Japan). Fresh sera from
hyperthyroid patients were used for cytokine measurement. A normal IgE
concentration was defined as less than 170 IU/ml, because mean serum
IgE level was 61.6 IU/ml (range, 27.54–138.34) obtained from 43 normal
subjects without history of allergic diseases and negative for specific
antibodies against 16 common antigens (1, 11). The intra-
and interassay coefficients of variation for IgE were 7.2% (n =
8) and 6.8% (n = 8), respectively. The minimal detectable levels
were 1.56 pg/ml for IFN-, 15 pg/ml for IL-4, 0.15 pg/ml for IL-6,
0.5 pg/ml for IL-10, and 3.12 pg/ml for IL-13. The intra-assay
coefficients of variation for IFN-, IL-4, IL-6, IL-10, and IL-13
were 4.5% (n = 6), 3.9% (n = 8), 2.9% (n = 20), 4.5%
(n = 16), and 4.1% (n = 6), respectively. The interassay
coefficients of variation for IFN-, IL-4, IL-6, IL-10, and IL-13
were 5.7% (n = 6), 6.7% (n = 8), 10.9% (n = 20),
7.8% (n = 16), and 5.0% (n = 6), respectively. Serum
T4, T3, TBII, TSAb, and Tg
concentrations were measured as reported previously (1).
Under normal conditions, TBII is less than 10% and TSAb is less than
180% (12). Statistical analysis was performed by ANOVAs,
2 test with Yate’s correction, or Fisher’s
exact probability test using StatView software (SAS Institute, Inc., Cary, NC). A P value less than 0.05 was
considered statistically significant.
Results
Remission and recurrence rates during and after MMI treatment in Graves’ disease with or without IgE elevation
The elevation of serum IgE was found in 41 of 107 untreated
hyperthyroid patients with Graves’ disease (38.3%) (Table 1
). After 18 months of treatment,
concentrations of T4, TSH, TBII, TSAb, and Tg
normalized in 73 of 107 patients (68.2%, remission; groups II and
III). Furthermore, the remission occurred in 20 of 41 patients with
elevated concentrations of IgE (48.8%) and in 53 of 66 patients with
normal IgE concentrations (80.3%, P = 0.0014) (Table 1). During follow-up (26–48 months), 60 of 73 patients had a
long-standing remission (group II). The long-standing remission rate
was significantly lower in patients with elevated than normal IgE
(34.1% vs. 69.7%, P = 0.0007). However, no
difference in the recurrence rate was seen between group III patients
with elevated IgE and with normal IgE (30.0% vs. 13.2%,
P = 0.1721), because of the limited number of patients
(Table 1).
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As shown in Table 2, 34 patients
without remission (group I) were euthyroid after 18 months of
treatment. However, TBII and/or TSAb did not normalize regardless of
the IgE level. In 60 patients with long-standing remission for the
follow-up period (group II), TBII and TSAb normalized, but not IgE
concentrations in the majority of those patients (Table 3). Recurrence was found in 13 patients
within 8–24 months after discontinuation of MMI treatment (group III).
As expected, concentrations of T4, TBII, and TSAb
were increased at the time of recurrence (Table 2).
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and ILs in sera of patients with Graves’ disease during
and after MMI treatment
IFN- was detected in only four patients with elevated IgE
concentrations, whereas IL-4 was not detected in any patients at any
time of follow-up. The detection rate of IL-6 varied from 85–100%.
IL-10 was detected in all patients studied at any time of follow-up. We
analyzed the concentration of IL-6 and IL-10 quantitatively, and no
specific relationship was found in IL-6 and IL-10 concentrations
between patients with normal and those with elevated IgE concentrations
(data not shown). Recurrence did not induce any significant
changes in IL-6 concentrations, as was the case with IL-10, except the
highest IL-10 concentration was found at recurrence (data not
shown).
The detection rate of IL-13 varied from 8.7–83.3%, and in all
patients studied the detection rate of IL-13 was higher in those with
elevated IgE than with normal IgE (P < 0.0001) (Fig. 1). The detection rate was higher in
patients with elevated than normal IgE in each group, but statistical
significance was found only for group III patients (P =
0.025). The detection rate of IL-13 in patients with remission (groups
II and III) was higher in those with elevated than normal IgE
(P = 0.0048, Fig. 1). Moreover, the detection rate was
lower in patients with long-standing remission than in those without
remission and with recurrence (13.3%, 38.5%, and 47.7%,
respectively; P = 0.0012).
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More patients with elevated IgE were positive for allergic
diseases, and for family history of allergic diseases and AITDs in
the first-degree relatives (Table 4).
Compared with patients with normal IgE, those with elevated IgE had
high frequency of allergic diseases (P = 0.0017) and
family history of allergic diseases (P < 0.0001).
Allergic rhinitis was the most frequent both in patients with elevated
IgE (29.3%) and in the first-degree relatives of those with elevated
IgE (41.5%). However, we could not find that attack of allergic
rhinitis preceded the recurrence of Graves’ disease.
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The study indicates that 38.3% of patients with Graves’ disease
have elevated serum IgE concentrations (170 IU/ml). If an IgE
concentration of 100 IU/ml or greater was considered abnormal, then
50% of patients with untreated Graves’ disease had abnormal
concentrations of IgE. This high prevalence of elevated concentrations
of IgE was comparable with that found in patients with bronchial asthma
(70%) (13). Our previous study indicated that the
decrease in TBII that occurred in response to antithyroid drug
treatment was less pronounced in patients with elevated than normal IgE
(1). In concordance with this, we found that normalization
of TBII and/or TSAb during 18 months of treatment occurred less
frequently in patients with elevated IgE than with normal IgE. As a
result, the rate of remission (normalization of
T4, TSH, Tg, TBII, and TSAb) was lower in the
patients with elevated than normal IgE. Interestingly, it was reported
that allergic rhinitis could be an aggravating factor of Graves’
disease and increased eosinophils could be a predictive indicator of
recurrence of Graves’ disease (14). Allergic response
should be considered as a cofactor to change the process of Graves’
disease. Thus, in addition to IgG-TBII (TSAb), IgE-TBII (TSAb) should
be included in the evaluation of Graves’ disease.
The most likely hypothesis is that intrathyroidal lymphocytes affect
the synthesis of TBII, TSAb, and IgE. We measured peripheral IFN-, a
marker for Th-1 cells, after 18 months of treatment in patients with
Graves’ disease. Although three of four patients who had detected
IFN- were without remission, no conclusion can be made. We also
measured peripheral IL-4 concentrations at the time of remission and
recurrence because it is a marker for Th-2 cells and stimulates IgE
secretion (15, 16). Unfortunately, IL-4 was not detected
at any time in any patients. Peripheral IL-6 and IL-10 concentrations
were measured after 18 months of treatment, at remission, or at
recurrence. These ILs were detected in the majority of patients, but no
correlation was found among patients without remission, with remission,
or with recurrence. Finally, we measured peripheral IL-13, which also
is a marker for Th-2 cells and has modulating activities on many cell
types, including stimulation of IgE secretion (2, 6). It
is not possible to quantify the role of IL-13 in the autoimmune process
of Graves’ disease, because its measurement using patient’s sera is
impaired by poor sensitivity. It may be more important to measure
intrathyroidal concentration of IL-13. However, the detection rate of
IL-13 did provide qualitative information. For example, the rate of
detectable IL-13 was higher 1) in patients who did not have than did
have remission, 2) at the time of recurrence than at the time of
remission, and 3) in patients with elevated than normal IgE
concentration. Thus, the most plausible explanation is that IL-13 is
secreted from Th-2 cells and has functions to stimulate B cells to
secrete TBII, TSAb, and IgE. Additional studies are required to confirm
this concept.
An elevation in IgE concentration is thought to be linked with
hereditary abnormalities (17, 18). Human IL-4 operates
through the IL-4 receptor (IL4R), thereby modulating IgE production and
Th-2 inflammatory reaction (19). As is the case with IL-4,
IL-13 operates through the IL-13R to stimulate IgE production and Th-2
inflammatory reactions. Moreover, IL-13R and IL4R share a common
component in IL4R
(2, 6) that is crucial for IL-4 (or
IL-13) binding and signal transduction. Gain-in-function mutations in
IL4R have been reported to be associated with atopy or asthma
patients with elevated IgE concentrations (20, 21). These
might be present in Graves’ patients with elevated IgE, even if
peripheral IL-13 or IL-4 were within normal range or not detected.
Additional experiments are required to analyze gain-in-function
mutations in IL4R in the patients with Graves’ disease.
Footnotes
Abbreviations: AITD, Autoimmune thyroid disorder; IL,
interleukin; IL4R, IL-4 receptor; IFN-, interferon ; MMI,
methimazole; TBII, TSH-binding inhibiting immunoglobulin; Tg,
thyroglobulin; TSAb, thyroid-stimulating antibody;
Received October 26, 2000.
Accepted April 9, 2001.
References
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J Med 337:1720–1725This article has been cited by other articles:
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, patients with elevated IgE;
, patients with normal IgE). Statistical analysis was performed by