Thyroglobulin (Tg) present in the serum of normal individuals and patients with thyroid disorders could be partly newly synthesized non-iodinated Tg and partly Tg containing iodine and hormone residues originating from the lumen of thyroid follicles. With the aim of examining the contribution of the latter source of Tg to the elevation of serum Tg concentration in thyroid pathophysiological situations, we devised a procedure to identify thyroxine (T4) and tri-iodothyronine (T3) residues on Tg from unfractionated serum. A two-step method, basedon (i)adsorption of Tg on an immobilized anti-human Tg (hTg) monoclonal antibody (mAb) and (ii)recognition of hormone residues on adsorbed Tg by binding of radioiodinated anti-T4 mAb and anti-T3 mAb, was used to analyze serum Tg from patients with either Graves' disease (GD), subacute thyroiditis (ST) or metastatic differentiated thyroid cancer (DTC). Purified hTg preparations with different iodine and hormone contents were used as reference. Adsorption of purified Tg and serum Tg on immobilized anti-hTg mAb ranged between 85 and 90% over a wide concentration range. Labeled anti-T4 and anti-T3 mAbs bound to adsorbed purified Tg in amounts related to its iodine content. Tg adsorbed from six out of six sera from ST exhibited anti-T4 and anti-T3 mAb binding activities. In contrast, significant mAb binding was only observed in one out of eight sera from untreated GD patients and in 1 out of 13 sera from patients with DTC. The patient with DTC, whose serum Tg contained T4 and T3, represented a case of hyperthyroidism caused by a metastatic follicular carcinoma. In conclusion, we have identified, for the first time, T4 and T3 residues on circulating Tg. The presence of Tg with hormone residues in serum is occasional in GD and DTC but is a common and probably distinctive feature of ST.
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L Druetta, H Bornet, G Sassolas, and B Rousset
J Tani, K Mori, S Hoshikawa, T Nakazawa, J Satoh, Y Nakagawa, S Ito, and K Yoshida
OBJECTIVE: Interferon regulatory factor-1 (IRF-1) is a critical regulator of interferon-gamma(IFNgamma)-mediated immune responses. To determine whether IRF-1 is involved in the pathogenesis of thyroiditis in animal models, we evaluated the incidence of iodide-induced lymphocytic thyroiditis (LT) in non-obese diabetic (NOD) mice lacking IRF-1 as well as IRF-1 +/+ and +/- mice. DESIGN: IRF-1 +/+, +/- and -/- NOD mice at 6 weeks of age were fed water (group 1) or iodide water (group 2) for 8 weeks. METHODS: Thyroids were examined histopathologically and intrathyroidal lymphocytic infiltration was arbitrarily graded. Serum thyroxine (T(4)) and anti-mouse thyroglobulin antibody (anti-mTgAb) levels were measured. Spleen cell population was analyzed by flow cytometry, and IFNgamma and interleukin-10 produced by splenocytes were measured by enzyme-linked immunosorbent assay. RESULTS: In group 1, only 4.3% of NOD mice developed LT. In contrast, 67.6% of mice in group 2 developed the disease. Iodide treatment induced LT in more than 80% of IRF-1 +/+ and +/- mice. However, no IRF-1 -/- mice in group 2 developed LT. There was no difference in both serum anti-mTgAb and T(4) levels among the three IRF-1 genotypes of NOD mice. Numbers of splenic CD8(+) T cells and IFNgamma production by Concanavalin A-stimulated splenocytes were markedly decreased in IRF-1-deficient NOD mice. CONCLUSIONS: IRF-1 is involved in the development of iodide-induced LT in NOD mice.
N. J. B. Christiansen, K. Siersbæk-Nielsen, J. E.M. Hansen, and L. Korsgaard Christensen
Serum thyroxine (T4) and other thyroid function tests were studied in 14 patients with subacute thyroiditis and compared with the same parameters in 32 patients with untreated thyrotoxicosis. The mean values of serum T4 and protein-bound iodine (PBI) were found to be elevated to the same extent in the two groups and the calculated T4 iodine did not differ significantly from the PBI in any of the groups. The resin-T3-test and the basal metabolic rate (BMR) mean values were significantly lower in patients with subacute thyroiditis than in patients with thyrotoxicosis. The serum T4 determination based on competitive protein-binding was not influenced by other organic iodinated products, and our results indicate that the elevated serum PBI in subacute thyroiditis is largely due to T4. The lower BMR in patients with subacute thyroiditis is possibly explained by a difference in the thyroxine binding protein (TBP) binding capacity and free T4 in the serum between patients with subacute thyroiditis and those with thyrotoxicosis.
C.J. Pearce and R. L. Himsworth
Abstract. Serum concentrations of total thyroxine (T4) and total triiodothyronine (T3) were measured in a group of patients (n = 113) presenting with untreated hyperthyroidism due to Graves' disease and in subjects receiving oral T4 replacement (n = 93) in whom the total T4 concentration was supraphysiological (> 150 nmol/l). The mean total T4 concentration in the hyperthyroid group was 226 nmol/l, sd 59, range 151–420, and the mean total T3 concentration was 6.8 nmol/l, sd 2.73, range 3.1–17.5. For the group receiving T4 the mean total T4 concentration was 175 nmol/l, sd 25, range 150–258, and the mean total T3 concentration was 2.66 nmol/l, sd 0.45, range 1.7–4.2. In the hyperthyroid group a highly significant linear correlation was found between total T4 and total T3, T3 = 0.0354 T4 – 1.21, r = 0.761, P ⪡0.001, while in the patients taking T4 this correlation was less close, T3 = 0.0073 T4 + 1.39, r = 0.398, P⪡0.001. The two groups are readily distinguished by expressing total T4 as a molar ratio of total T3. In the hyperthyroid group the mean T4:T3 ratio was 35.6, sd 7.8, range 19.9–56.1, compared to the patients on T4 where the mean T4:T3 ratio was 67.0, sd 11.7, range 44.3–114 (t = 22.5, P⪡0.0001). An arbitrarily chosen value of 50 for the T4:T3 ratio affords a simple and convenient means of distinguishing the two categories: in only 3 patients with Graves' disease (2.6%) was the ratio above this, and it was below in only 5 patients (5.4%) taking T4. Where there is doubt as to the aetiology of hyperthyroxinaemia this simple operation will differentiate between hyperthyroidism caused by Graves' disease and surreptitious ingestion of T4. In other clinical situations where symptoms of hyperthyroidism are associated with a T4:T3 ratio greater than 50 the combination may suggest subacute thyroiditis or iodide-induced thyroid dysfunction.
Daniel Glinoer, Nicole Puttemans, André J. Van Herle, Monique Camus, and André M. Ermans
A sequential study of various parameters of thyroid metabolism has been carried out in 2 patients during the weeks following the clinical onset of subacute thyroiditis, the aim being to define the nature and extent of the anomalies of thyroid function. In the early stage, serum thyroxine, protein bound iodine and T3 resin uptake levels were in the thyrotoxic range. In both cases, the serum thyroxine values further decreased with a half-life of 7 days and reached the hypothyroid range at the 6–7th week. Both 131I uptake and TSH plasma levels were found to be low and concomitantly rose at the 6–7th week. In one patient the serum thyroglobulin level was strikingly elevated at the beginning and then fell fairly rapidly; however in both patients, the serum thyroglobulin values remained abnormal. The present study confirmed the concept of a sudden release of preformed hormone stores. Furthermore, the following points were evident: a) marked and transient release of thyroglobulin; b) interruption of the secretory activity during at least 7 weeks; c) adequate functioning of the pituitary-thyroid control mechanism and d) partial recovery of the thyroidal iodine uptake at a time when the hormone secretion was still undetectable.
HB Shahbazian, F Sarvghadi, and F Azizi
OBJECTIVE: To determine the prevalence of postpartum thyroiditis (PPT), one of the autoimmune disorders of the thyroid which usually occurs in women in the first year after parturition. PPT presents with periods of transient thyrotoxicosis and hypothyroidism, in many cases resulting in permanent hypothyroidism. DESIGN: The study involved 1040 mothers who had contacted five health centers in Tehran for vaccination of their children. METHODS: Signs and symptoms of hypothyroidism and thyrotoxicosis, and the presence of goiter (using the World Health Organization classification), were sought. Serum T3, T4, TSH, anti-TPO and anti-Tg antibodies were measured at 3, 4.5, 6 and 9 months after parturition. In those with hypothyroidism or thyrotoxicosis and a matched group of normal women, thyroid sonography was performed. RESULTS: The prevalence of thyroiditis was 11.4%. Hypothyroidism and thyrotoxicosis occurred in 68 and 42 mothers respectively. Nine had thyrotoxicosis followed by hypothyroidism. There was one case of Graves' disease. Out of 68 hypothyroid patients, 33 women underwent treatment with levothyroxine (because of the severity of symptoms) for 12 months. Six women showed increased TSH at 6 weeks after discontinuation of thyroxine. Stage II goiter (World Health Organization classification) were observed in 21.8% of patients and in 6.7% of pospartum euthyroid women (P<0.001). Positive anti-TPO was found in 61.5% of patients and in 19% of the control group; positive anti-Tg was found in 58% of patients and in 6% of the control group (P<0.001). Sonographic changes were observed in 96% of the patients and in 7% of the control group (P<0.001). There was no significant correlation between the occurrence of thyroiditis and parity, the age of the mother, a previous history of thyroid disease in the patient or family, breast-feeding, or the gender of the child. CONCLUSION: The results of this study show a high prevalence of PPT in Tehranian women. This may be due to the length and frequency of follow-up and/or the transition from low to adequate iodine intake. The major difference with respect to other studies is the low frequency of the biphasic form of PPT.
M Rotondi, G Mazziotti, F Sorvillo, M Piscopo, M Cioffi, G Amato, and C Carella
OBJECTIVE: To compare the effects of pregnancy on the serum free thyroxine (FT4) levels in two cohorts of primary hypothyroid women treated with different levothyroxine (L-T4) doses before gestation. DESIGN AND METHOD: Twenty-five women with compensated hypothyroidism of different aetiology (thyroidectomized and Hashimoto's thyroiditis) were enrolled in this prospective study. The women were receiving substitutive doses of L-T4 and were anticipating pregnancy. They were assigned to two groups: 14 patients (group I) were switched to partially suppressive treatment while 11 patients (group II) continued the same therapeutic regimen. RESULTS: Pre-conceptional thyroid function evaluation demonstrated significantly higher FT4 and lower TSH in group I (P<0.001, for both hormones) and comparable free 3,5,3'-triiodothyronine (FT3) levels. The first post-conception thyroid function evaluation occurred at a median time of 6 (5-8) and 7 (5-9) weeks of gestation, for groups I and II respectively (P<0.05); all women in group I showed adequate serum FT4 levels while three patients in group II showed low-normal FT4 levels and one case was below normal levels. Statistical analysis demonstrated significantly higher frequencies (0% vs 36.4%; P<0.05) of low-normal FT4 levels in patients receiving substitutive doses of L-T4. None of the Hashimoto's-affected patients showed low or low-normal serum FT4 levels regardless of their therapeutic regimen. CONCLUSION: Our results suggest that in hypothyroid women anticipating pregnancy (with serum TSH in the lower quartile of normal range), the pre-conception adjustment of L-T4 doses may result in adequate maternal thyroid function up to the first post-conception evaluation. The procedure seems safe and inexpensive; it may be a worthwhile treatment, at least in thyroidectomized women, in view of the well-known potential effects of even marginal maternal thyroid hypofunction on the subsequent IQ of the progeny.
LH Duntas, E Mantzou, and DA Koutras
OBJECTIVE: Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyse the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and the autoimmune process. Therefore, we performed a randomised, placebo-controlled prospective study to investigate the effects of Se treatment on patients with autoimmune thyroiditis (AIT). DESIGN AND METHODS: Sixty five patients aged 22-61 years (median age 48 years) with AIT were recruited into two groups. Group I (Gr I) (n=34) was treated with selenomethionine (Seme) 200 microg, plus L-thyroxine (LT(4)) to maintain TSH levels between 0.3-2.0 mU/l, whereas group II (Gr II) (n=31) received LT(4) plus placebo over a period of 6 months. Moreover, the pharmacokinetics of Seme were studied in 10 patients and eight volunteers at baseline and 2 h, 4 h, 6 h and 24 h after oral administration of a 200 microg tablet of Seme. Finally, Se levels were measured at the end of the study in some patients of both groups and their results were correlated with thyroid hormone levels. RESULTS: In the pharmacokinetics study, basal serum concentration of Se (75+/-6 microg/l) was within the reference range (70-125 microg/l), it promptly increased at 2 h, peaked at 4 h (147+/-17 microg/l; P<0.0001) and it was abundant in serum at 24 h. In Gr I, antibodies against thyroid peroxidase (anti-TPO) levels showed an overall decrease of 46% at 3 months (from 1875+/-1039 U/l to 1013+/-382 U/l; P<0.0001) and of 55.5% at 6 months. In Gr II the overall decrease of anti-TPO amounted to 21% at 3 months and to 27% at 6 months (from 1758+/-917 U/l to 1284+/-410 U/l; P<0.005). There were no significant changes of antibodies against thyroglobulin levels between the groups. At the end of this study Se levels were found to be statistically significantly increased in Gr I (n = 9/34) compared with Gr II (n=11/31) (97+/-8.4 vs 79+/-8; P<0.01) but no correlation with thyroid hormone was found. CONCLUSIONS: Seme is proven to be rapidly absorbed by the gastrointestinal tract. It appears to be useful as adjunctive therapy with LT(4) in the treatment of AIT. The exact mechanism(s) is not very well determined, it might enhance the activity of detoxifying enzymes and enforce the defense against oxidative stress.
Kimio Nakanishi, Yoshiyasu Taniguchi, and Yasuyuki Ohta
We measured soluble interleukin 2 receptor, a part of the Tac protein (p55), in peripheral blood to study the immunological condition of the T cell in autoimmune thyroid disease. In 26 patients with untreated Graves' disease and 7 hyperthyroid patients with Hashimoto's thyroiditis, the mean levels of soluble IL-2 receptor were both significantly higher than in normal controls (1497±649 (mean ± sd), 641±137 vs 221±63 103 U/l, p<0.001). There was good correlation between soluble IL-2 receptor levels and blood thyroxine levels (r=0.684, p<0.001) in patients with untreated Graves' disease, but no correlation of soluble IL-2 receptor with TSH-inhibitory immunoglobulins, TS-ab, thyroidal autoantibodies to thyroglobulin and thyroidal microsomal antigen was found. We thought that the level of soluble IL-2 receptor is not dependent only on immunological conditions, but also on thyroid hormone status. When T3 was administered to subjects in remission from Graves' disease and in normal controls, the soluble IL-2 receptor levels significantly increased. Moreover, the mean level of soluble IL-2 receptor in patients with toxic multinodular goitre was also significantly higher than in normal controls (411±148 vs 221±63 103U/l, p<0.05). We conclude that the soluble IL-2 receptor levels are higher in sera of subjects with elevated levels of thyroid hormone.
A. Gordin and B.-A. Lamberg
Fourteen patients with subacute thyroiditis were studied. In the acute stage 6 were overtly and 2 equivocally hyperthyroid. Total thyroxine (T4) or protein-bound iodine (PBI) was elevated in 10 patients out of 14 and absolute free thyroxine (AFT4) in 10 out of 13 cases. The serum thyrotrophin (TSH) values ranged from 1.3 to 7.9 μU/ml, all but one being below 4.0 μU/ml (normal range 1.6–6.9 μU/ml). There was no response in serum TSH to thyrotrophin releasing hormone (TRH) in 9 subjects tested in the acute stage, irrespective of whether they were clinically hyperthyroid or euthyroid. This indicates that in the acute stage of subacute thyroiditis the thyroid hormone level is increased sufficiently to inhibit TSH release. In 8 patients the TRH stimulation test was carried out serially at 2 to 3 monthly intervals but in 5 only after 2 to 6 months. In a few patients the serum TSH level rose above the normal upper limit. The response to TRH became normal within 2 to 5 months but in one patient only after a period of exaggerated response indicative of temporary subclinical hypothyroidism. In one patient the response was still exaggerated one year after the acute phase, indicating that normalization of the thyroid-pituitary relationship may be a very slow process.