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Original Studies |
Institute of Endocrinology, University of Pisa, 56124 Pisa, Italy
Address all correspondence and requests for reprints to: Luca Chiovato, M.D., Institute of Endocrinology, University of Pisa, via Paradisa 2, 56124 Pisa, Italy.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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8 mL,
indicating major postradioiodine gland damage. In conclusion: 1) the
early outcome of thyroid function after 131I for GD is
mainly related to pretreatment thyroid volume and to the degree of its
reduction after therapy; 2) high TSAb levels before 131I
are associated with a relative resistance to therapy; 3) a
postradioiodine increase in TSAb levels is related to the development
of hypothyroidism; and 4) the concomitant appearance of TSHBAb and
disappearance of TSAb are not frequent after 131I and play
a role in the development of early postradioiodine hypothyroidism only
in a minority of patients. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Biological effects of 131I include necrosis and impaired replication of nondestroyed follicular cells (8), atrophy, fibrosis, and a chronic inflammatory response, which may ultimately result in permanent thyroid failure (2). Changes in thyroid histology are associated with a reduction in thyroid volume (9), which reflects thyroid damage. Radioiodine treatment for Graves’ disease (GD) is also followed by changes in thyroid autoimmunity, which may result in a transient increase of TSH-receptor antibodies (TRAb) with thyroid stimulating antibody (TSAb) activity (10, 11) and in the de novo appearance of TRAb with TSH-blocking activity (TSHBAb) (11, 12, 13). In a recent paper, TSHBAb were found in most patients developing early postradioiodine hypothyroidism, suggesting that the de novo appearance of TSHBAb could be responsible for the occurrence of thyroid failure (14). This observation remains to be confirmed. Longitudinal studies, comparing the outcome of thyroid function after 131I with changes in thyroid volume and in the levels of TSAb and TSHBAb, also are lacking.
The aim of the present study was to establish the relative role of humoral thyroid autoimmunity and of radioiodine-induced thyroid damage in the development of early postradioiodine hypothyroidism in patients with GD. To this purpose, we measured thyroid volume, as an index of 131I-induced tissue damage, TSAb, and TSHBAb before and at several time-intervals up to 1 yr after radioiodine therapy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thirty-one patients with hyperthyroid GD (7 males, 24 females; age range = 25–70 yr, mean age ± SD = 43.3 ± 12.2 yr) were included in this study. The diagnosis was based on common clinical and laboratory criteria. Twenty-three patients had Graves’ ophthalmopathy that was mild in 17, moderate in 4, and severe in 2. One patient had pretibial myxedema. Before radioiodine therapy, all patients were treated with methimazole (MMI) for a mean period of 13 ± 9 months (range = 4–36 months). MMI was discontinued 1 week before 131I therapy. Serum samples for free T4, free T3, TSH, and antithyroid antibodies were collected immediately before 131I and at 1, 3, 6, and 12 months thereafter. Aliquots of sera were kept frozen at -20 C until used for specific assays. Sera and IgG, obtained from individual patients before and after 131I, were run in the same assay.
The therapeutic dose of radioiodine was calculated with the formula:
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) of 131I.
Thyroid weight was estimated by assuming that 1 mL (ultrasound volume)
corresponds to 1 g of tissue. The mean (±SD)
therapeutic dose of 131I was 518 ± 111 (range =
111–1258) MBq. Antithyroid drugs were not given shortly after
131I. Treatment with MMI was reinstituted 3–6 months after
radioiodine, in 3 patients with persistence of hyperthyroidism. To
prevent an exacerbation of Graves’ ophthalmopathy after radioiodine,
15 patients received prednisone at antiinflammatory doses after
131I. Prednisone (20–30 mg/day; 0.4–0.5 mg/kg BW·day)
was tapered 1 month later and discontinued within 3 months. Informed
consent was obtained from patients under the guidance of the Ethical
Committee, University of Pisa. Thyroid ultrasonography
Thyroid ultrasonography was performed before 131I and afterwards at 1, 3, 6 and 12 months, by the same examiner, using a linear transducer (7.5 MHz) attached to a real-time instrument (AU 590 Asynchronus Apparatus, Esaote Biomedica, Milan, Italy). Thyroid volume was calculated with the ellipsoid formula (15): width (mm) x length x thickness x 0.52 x each lobe = volume (mL). In a preliminary study, we found that thyroid volume in normal adults residing in an iodine-sufficient area in Italy was 11.3 ± 3.4 mL (mean ± SD) in males and 8.6 ± 2.2 mL in females.
Free thyroid hormones and TSH
Free T4 was measured with FT4 Kit (normal range = 8.4–21.2 pmol/L), and free T3 with FT3 Kit (4.0–8.4 pmol/L), both from Technogenetics, Milan, Italy. Serum TSH was measured with an immunofluorometric assay: Delfia hTSH, Pharmacia, Turku, Finland (normal range = 0.4–3.7 mU/L).
Antithyroglobulin antibody (TgAb) and antithyroperoxidase antibody (TPOAb)
TgAb and TPOAb were measured using commercial kits: TGAb IRMA Biocode, Sclessin, Belgium (normal values <50 U/mL), and DYNOtest anti-TPOn BRAHMS Diagnostica GmbH, Berlin, Germany (normal values <30 U/mL).
TSAb and TSHBAb
IgG was prepared from sera of patients by separation on DEAE-Sephadex A 50, precipitation by ammonium sulphate, dialysis in TRIS buffer, and centrifugation at 3000 rpm (16). IgG concentration was measured by optical density at 280 nm (E = 1.46). By immunoelectrophoresis, the preparation contained 90% IgG and 10% of other proteins, mostly albumin.
Chinese hamster ovary (CHO) cells transfected with the recombinant human TSH receptor (CHO-R) (16) were cultured in RPMI-1640 medium plus 1 mmol/L glutamine, 10% FCS, and 0.4 g/L geneticin. CHO-R cells were seeded (30,000 cells/well) in 96-well plates (Costar, Cambridge, MA). Cells were fed fresh culture medium 24 h after seeding and were used for the assay of TSAb or TSHBAb the following day.
TSAb and TSHBAb were measured using previously described methods (16, 17). IgGs were diluted in hypotonic buffer containing 4 g/L BSA and 0.5
mmol/L isobutylmethylxanthine. In the TSAb assay, cell cultures were
incubated with IgG alone (1 g/L). In the TSHBAb assay, cell cultures
were incubated with IgG alone (1 g/L), TSH alone (10 mU/L), or IgG plus
TSH. Hypotonic buffer-BSA-isobutylmethylxanthine alone was added to
some cultures in each experiment to measure basal cAMP production.
After 2-h incubation at 37 C in 5% CO2/95% air
atmosphere, cAMP was measured in extracellular medium by RIA.
Experiments were performed in triplicate; and results (pmol/well) were
expressed as the average of these. The mean (± SD) cAMP
production, obtained with IgGs from 50 normal subjects, was 98 ±
16% of basal value. IgGs increasing cAMP production >2 SD
from the mean of normals (>130% of basal) were considered positive
for TSAb. To measure TSHBAb, an index of inhibition of TSH-dependent
cAMP production (TSH-inhibition index, TSH-II) was calculated with the
formula:
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IgGs producing a reduction of TSH-stimulated cAMP increase
30% were considered positive for TSHBAb (17).
Statistical analysis
Nonparametric tests were used. Results obtained in different
groups of patients were compared by 
2 test with Yeates
correction, Mann-Whitney, or Kruskal-Wallis tests as appropriate.
Sequential results in each subgroup of patients were analyzed by
Wilcoxon signed-rank test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One year after radioiodine, 3 of 31 patients (9.7%) were hyperthyroid (Hyper-group), requiring MMI treatment; 4 of 31 (12.9%) were euthyroid (Eu-group); and 24 of 31 (77.4%) patients were hypothyroid (Hypo-group). In the Hypo-group, 4 of 24 (16.7%) patients became hypothyroid at 1 month after 131I, 12 of 24 (50%) at 3 months, 6 of 24 (25%) at 6 months, and 2 of 24 (8.3%) at 12 months. Hypothyroidism was subclinical in 11 patients and overt in 13 patients. To exclude transient hypothyroidism, L-thyroxine therapy was started at a suboptimal dose that was not increased until evidence for persistently elevated serum TSH was obtained. In the Eu-group, 2 patients experienced transient hypothyroidism 3–6 months after 131I but spontaneously recovered at 1 yr.
Thyroid volume before and after radioiodine
Before radioiodine, the median thyroid vol was 30 mL (mean ± SD = 37.8 ± 28.4 mL) in the whole study group, 29 mL (mean = 57.2 ± 51.7 mL) in the Hyper-group, 76.5 mL (mean = 75.7 ± 18.0 mL) in the Eu-group, and 27.5 mL (mean = 29.1 ± 19 mL) in the Hypo-group. Differences among subgroups of patients were not statistically sig-nificant. When patients in the Eu-group and Hyper-group were considered together, their pretreatment thyroid vol (median = 65 mL, mean = 67.8 ± 34.1 mL) was significantly greater (P = 0.009) than in the Hypo-group.
After radioiodine, a progressive reduction in thyroid volume occurred
that was already significant 1 month after 131I
(P = 0.001) (Fig. 1A
).
One year after 131I, the percent reduction of thyroid
volume in the whole study group ranged from 24–96% (mean %
reduction = 76.4%). The mean percent reduction in thyroid volume
was greater in hypothyroid (80.7%) than in hyperthyroid (35.7%)
(P = 0.007) patients. Euthyroid patients experienced a
mean percent reduction in thyroid volume (83.5%) that was greater,
compared with hyperthyroid (P = 0.033) but not with
hypothyroid patients.
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. One year after radioiodine,
the median thyroid vol was 4 mL (mean = 4.4 ± 2.5 mL) in the
Hypo-group, 14.5 mL (mean = 12.7 ± 8.4 mL) in the Eu-group,
and 22 mL (mean = 31.3 ± 20.6 mL) in the Hyper-group.
Hypothyroid patients had smaller (P = 0.0058) thyroids
than hyperthyroid patients. Euthyroid patients had an intermediate
thyroid volume between that of hypothyroid and hyperthyroid patients,
but the difference was not statistically significant. All hypothyroid
patients had a thyroid vol 8 mL. With one exception, all
euthyroid and hyperthyroid patients had a thyroid vol >11 mL. TgAb and TPOAb before and after radioiodine
Before radioiodine, TgAb were detected in 10 of 31 (32%) patients
(median value = 402 U/L; mean = 636 ± 804 U/L). TgAb
levels significantly increased at 3 (P = 0.0037) and 6
(P = 0.009) months after 131I and then
declined at 1 yr (Fig. 2A). Before
radioiodine, TPOAb were detected in 27 of 31 (87%) patients
(median = 970 U/L; mean = 3008 ± 5156 U/L). TPOAb
levels significantly increased at 3 (P = 0.005) and 6
(P = 0.001) months after radioiodine and then decreased
at 12 months (Fig. 2B). Serum levels of TgAb and TPOAb significantly
increased after radioiodine in the Hypo-group (P =
0.002 and P = 0.006, respectively) but not in the
Hyper-group.
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Before 131I, TSAb were found in 19 of 31 (61.2%) patients (median value = 216%; mean = 461 ± 433%): all 3 patients in the Hyper-group (median = 1010%; mean = 1061 ± 147%), 13 of 24 (54.1%) in the Hypo-group (median = 185%; mean = 380 ± 406%), and 3 of 4 in the Eu-group (median = 216%; mean = 214 ± 29%). Pretreatment TSAb levels in the Hyper-group were higher than in the Hypo-group (P = 0.01) or in the Eu-group (P = 0.03).
Six months after 131I, the number of patients with
detectable TSAb significantly increased to 26 of 31 (83.8%)
(P = 0.04), and TSAb levels were higher
(P = 0.04), compared with pretreatment values (Table 1). One year after 131I, TSAb
were detectable in 25 of 31 (80.6%) patients, but their levels had
decreased (P = 0.006 vs. 6 months after
131I) and did not differ from pretreatment results.
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). In the Eu-group, 1 more patient had
detectable TSAb after 131I, and a significant increase in
TSAb levels was observed in another one (Fig. 3B). One year after
131I, all euthyroid patients were positive for TSAb
(range = 151–812%). Six months after radioiodine, TSAb levels
significantly increased in hypothyroid patients (P =
0.02). In this group, 9 of 11 (81.8%) patients with undetectable TSAb
before 131I became positive for this antibody 3–6 months
after therapy (P = 0.003) (Fig. 4A). Among patients with detectable TSAb
before 131I, 7 of 13 (53.8%) showed an increase greater
than 30% in TSAb levels after therapy (Fig. 4B). In the remaining 6
patients, TSAb levels did not change in 2 and decreased in 4.
Altogether, an increase in TSAb levels was found in 66.6% of patients
with postradioiodine hypothyroidism. One year after 131I,
TSAb were found in 18 of 24 (75%) hypothyroid patients (median =
239%; mean = 454 ± 479%). At that time, there was no
significant difference in TSAb levels among hyperthyroid, euthyroid, or
hypothyroid patients.
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Before 131I, 4 patients (13%) had TSHBAb associated
with strong TSAb activity (Table 2). The
coexistence of TSAb and TSHBAb was not associated with a specific
outcome of thyroid status (2 patients remained hyperthyroid, and 2
developed hypothyroidism). After 131I, 7 more patients
developed TSHBAb, and 2 became negative. TSHBAb were associated with
TSAb in all patients but one, in whom TSAb disappeared 3 months after
131I being replaced by TSHBAb (Table 2). One year after
131I, TSHBAb were found in 1 of 4 (25%) euthyroid, in 1 of
3 (33%) hyperthyroid, and in 5 of 24 (20.8%) hypothyroid patients, in
all but one associated with TSAb.
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One year after 131I, all patients with a thyroid
vol 8 mL but one were hypothyroid, in spite of persistent TSAb
in 75% of them (Fig. 5). The patient who
developed TSHBAb without TSAb after 131I became hypothyroid
with a thyroid vol of 28 mL (Table 2). However, hypothyroidism occurred
3 months after 131I in another patient, who had a thyroid
vol of 29 mL and circulating TSAb without TSHBAb.
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). Among
patients with a thyroid vol 8 mL, only one was euthyroid, caused by
strong TSAb activity in his serum (812%). The other euthyroid patients
had normal or slightly increased thyroid volumes and low TSAb level
(151–250%). Effect of prednisone therapy
Ten of 24 patients (42%) in the Hypo-group, 2 of 4 patients in the Eu-group, and all 3 patients with persistent hyperthyroidism received prednisone after 131I. Differences among subgroups of patients were not statistically significant, even when patients in the Eu-group and Hyper-group were considered together and compared with the Hypo-group. Pre- and posttreatment thyroid volumes did not significantly differ in patients taking or not taking prednisone. Pretreatment TSAb levels were higher (P = 0.03) in patients given prednisone, but this difference was not any longer evident after 131I. The number of patients with detectable TSHBAb, both before and after radioiodine, did not differ in relation to steroid therapy. Pretreatment TPOAb and TGAb levels were similar in patients treated or not treated with prednisone, but the post-131I increase in the levels of these antibodies was lower in patients receiving steroid therapy.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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8 mL. The relevance of postradioiodine thyroid volume
reduction for the outcome of thyroid function was reported by Murakami
at al. (18), but in that study, no relationship was evident between
pretreatment thyroid volume and postradioiodine thyroid function.
Although no influence of pretreatment thyroid volume on the outcome of
radioiodine treatment was also reported by Tsuruta et al.
(19), most previous studies indicated that large Graves’ goiters are
more resistant to 131I (2, 20). Administration of MMI
shortly after radioiodine, that can reduce the effect of radiometabolic
therapy (3), and the use of a relatively low dose of 131I
might influence the results of Murakami et al. (18). In that
study, 50% of hyperthyroid patients treated with 131I were
not cured (18). Pretreatment TSAb levels were significantly higher in patients with persistent hyperthyroidism than in those becoming hypothyroid (P = 0.01) or euthyroid (P = 0.03) after 131I. This finding confirms data from other studies (18, 21), and is consistent with the fact that hyperthyroid patients after radioiodine had larger pretreatment thyroids and experienced a lower reduction in thyroid volume than those developing hypothyroidism. Indeed, the in vitro growth-promoting effect of most TRAb parallels their thyroid-stimulating activity, measured in adenylate-cyclase stimulation assays (22).
The number of patients with detectable TSAb and TSAb levels increased 3–6 months after 131I in patients developing hypothyroidism but not in those with persistent hyperthyroidism. This difference in postradioiodine TSAb changes agrees with previous observations (11, 12, 23). In our view, the increase in TSAb levels is caused by the release of TSH receptor molecules from disrupted follicular cells and to the subsequent boosting of the autoimmune response (10). A significant increase in TPOAb levels was also observed after 131I in patients developing hypothyroidism but not in those remaining hyperthyroid. Because both the TSH receptor and TPO are membrane proteins, the postradioiodine increase in serum levels of the correspondent autoantibodies may be regarded as marker of thyroid cell damage produced by 131I. Conceivably, this phenomenon is related to the degree of thyroid damage produced by 131I, to the subsequent reduction in thyroid volume, and to the development of hypothyroidism. The observation that serum TSAb were still elevated in 75% of hypothyroid patients 1 yr after 131I, underscores the importance of postradioiodine reduction in thyroid volume for the development of hypothyroidism. An exception to this rule was a patient with high levels of TSAb (812%) who was euthyroid in spite of a thyroid markedly reduced in size (2 mL).
The coexistence of TSAb and TSHBAb was observed in a minority of patients (13%) before 131I and was not associated with a specific outcome of thyroid function. In the year after radioiodine, 7 more patients developed TSHBAb, indicating a postradioiodine spreading of the autoimmune response to the TSH receptor (24) caused by the release of TSH receptor molecules from damaged follicular cells. The appearance of TSHBAb after radioiodine was suspected in early investigations (11, 12) and was demonstrated using specific bioassays in subsequent studies (13, 14). In the more recent one (14), TSHBAb were detected in 7 of 11 (63%) patients developing hypothyroidism 6 months after radioiodine, and in 54% of them, TSHBAb were found in the absence of TSAb. It was concluded that the appearance of TSHBAb and the disappearance of TSAb was a mechanism for the development of possibly transient postradioiodine hypothyroidism in patients given a relatively low dose of 131I (240 ± 27 MBq). In our study, TSHBAb were observed in a minority (29% at 6 months; 20% at 12 months) of patients developing hypothyroidism after a medium-high dose of 131I (518 ± 111 MBq), and with one exception, TSHBAb occurred in association with TSAb. Only one patient showed the appearance of TSHBAb and the disappearance of TSAb 3 months after radioiodine. He became hypothyroid, with a thyroid vol of 28 mL, suggesting that the change in biological activity of TRAb was the mechanism responsible for hypothyroidism. However, hypothyroidism at 3 months after 131I was observed in another patient, who had a thyroid vol of 29 mL and circulating TSAb in the absence of TSHBAb. Postradioiodine inflammatory phenomena might explain the development of early hypothyroidism in patients with persistent TSAb and a still enlarged thyroid (8). Our data indicate that the appearance of TSHBAb in the absence of TSAb is not frequent after 131I and is a potential, but unusual, mechanism of early postradioiodine hypothyroidism, at least when high, destructive doses of 131I are given. Administration of prednisone at antiinflammatory doses, to some of the patients included in the present study, did not seem to significantly modify the results.
In conclusion: 1) the early outcome of thyroid function, after 131I for GD, is mainly related to pretreatment thyroid volume and to the degree of its reduction after therapy; 2) high TSAb levels before 131I are associated with persistent hyperthyroidism; 3) a postradioiodine increase in TSAb levels is related to the development of hypothyroidism; and 4) the concomitant appearance of TSHBAb and disappearance of TSAb are not frequent after 131I and play a role in the development of early postradioiodine hypothyroidism only in a minority of patients.
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Acknowledgments |
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Footnotes |
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Received June 26, 1997.
Revised September 15, 1997.
Accepted October 26, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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